Facilitation Among Saproxylic Insects Inhabiting Tree Hollows In A Mediterranean Forest The Case Of

Abstract

Tree hollows offer an ideal niche for saproxylic insects in mature Mediterranean forests, where Diptera and Coleoptera are the richest groups. Co-occurrence is frequently observed among many species of both groups in these microhabitats, and some of these species have been considered to facilitate the presence of other species by acting as ecosystem engineers. One of the systems that is found in Mediterranean tree hollows is formed by cetonid (Coleoptera: Cetoniidae) and syrphid (Diptera: Syrphidae) larvae. Here, cetonid larvae feed on wood and litter and produce a substrate that is easier to decompose. To assess the possible role of these larvae as facilitating agents for the saproxylic guild, we studied whether the presence of saprophagous Syrphidae inside tree hollows is associated with the activity of cetonid larvae. Furthermore, in laboratory conditions, we tested whether cetonid larvae activity can improve the development and fitness of the saprophagous syrphid species. Our results show that “cetonid activity” was the variable that best explained the presence of saprophagous syrphid species in natural conditions. Myathropa florea (L. 1758) was one of the species most influenced by this activity. The laboratory experiment gave similar results, demonstrating that an enriched substrate with Cetonia aurataeformis Curti, 1913 larval feces improves syrphid larval growth rate and fitness of adults (measured as longer wing length) of M. florea.

Mediterranean forest

Cetonia aurataeformis

Myathropa florea

co-occurrence

ecosystem engineer

Saproxylic insects depend on decaying processes that occur in woody substrates, associated with living and dead trees (standing or fallen wood) in extensive types of microhabitats (Speight 1989. Alexander 2008 ). These natural microhabitats have proved to be particularly attractive for studies of community organization and as a model to study factors that determine the structure of a community (Barrera 1996 ). Tree hollows house a rich biota of microorganisms and arthropods (Bell et al. 2005 ), and in Europe, the arthropod fauna comprises mainly the immature stages of more or less specialized Diptera and Coleoptera. Tree hollows are one of the most important habitats for saproxylic insects in Iberian Mediterranean forests (Marcos-Garcia et al. 2010. Mico et al. 2010 ; Fig. 1 A). The insect community linked to tree hollows is organized into interacting groups of a complex network that involves different trophic guilds: xylophagous, saproxylophagous, xylomycetophagous, predators, and commensals. Competition and facilitation relationships among different species are important factors that condition the community composition of each particular tree hollow (Jonson et al. 2004. Quinto et al. 2012 ). Bradshaw and Holzapfel (1992) and Schmidl et al. (2008) examined intra - and interspecific interactions among insects living in these microhabitats. Other commensalistic interactions within tree hollow communities have been studied by Heard (1994). Paradise and Dunson (1997). Paradise (1999). and Paradise and Kuhn (1999). but no work has been dedicated to the study of the facilitation process among different animal species inside the tree hollow itself.

(A) The interior of a tree hollow with accumulated rain water and organic matter. (B) Cetonid larvae feces in a tree hollow showing the amount and shape of feces. (C) A saprophagous syrphid larva with its typical long tail, feeding on the organic matter containing cetonid feces inside a tree hollow.

Facilitation relationships occur when one species is favored by the previous presence and activity of another species (Munguia et al. 2009 ). This positive interaction has been studied extensively in plant–plant interactions as a “nurse effect” (Callaway and Pugnaire 1999. Valiente-Banuet and Verdu 2008. Verdu and Valiente-Banuet 2008 ), as well as in insect–plant interactions, that is, the nest-building activity of Macrotermes spp. (Isoptera: Macrotermitinae), which provides nutrient-enriched microhabitats in savanna soils, supporting a high density of woody plant species (Moe et al. 2009 ). Facilitation relationships are also known in insect–insect interactions, for example, building of shelters has been reported in leaf rollers ( Anacampsis niveopulvella (Chambers, 1875) and Pseudotelphusa sp.; Martinsen et al. 2000. Lill and Marquis 2003. Diniz et al. 2012 ), gall makers ( Pemphigus betae Doane, 1900; Waltz and Whitham 1997 ), leaf miners ( Phyllonorycter pastorella Zellar, 1846; Johnson et al. 2002. Kagata and Ohgushi 2004 ), and stem borers ( Oncideres albomarginata chamela Chemsak & Giesbert, 1986; Calderon-Cortes et al. 2011 ). A common denominator of these examples is the existence of ecosystem engineer species that act as chemical or physical transformers that determine a more suitable environment (Jones et al. 1994. Jonson et al. 2004 ) for the subsequent colonization and development of secondary species (Connell and Slatyer 1997. Bronstein 2009 ).

One classic example of ecosystem engineer insects linked to deadwood is Cerambyx cerdo (L. 1758) (Coleoptera: Cerambycidae), whose larvae create galleries within trunks of living trees, facilitating colonization by other saproxylic species (Buse et al. 2008 ). The presence of Osmoderma eremita (Scopoli, 1763) (Coleoptera: Cetoniidae) larvae in tree hollows also seems to favor the saproxylic beetle diversity of the assemblage (Jonson et al. 2004. Ranius et al. 2005 ).

Leaf litter is the main energy source in tree hollow systems; however, an additional supply of nutrients for the saprophagous fauna within tree hollows is provided by arthropod cadavers and residues (e. g. molts and feces; Yee and Juliano 2006 ). Saproxylic Cetoniidae larvae develop inside tree hollows in Mediterranean forests, where they become abundant (Mico and Galante 2002. Ricarte et al. 2009. Mico et al. 2011 ). These cetonid larvae transform large fragments of rotten wood and litter into feces that are richer than the original substrate (Murayama 1931 ; Mico et al. 2008. 2011 ; Fig. 1 B). This enriched and thinner substrate could facilitate the occurrence of other saproxylic organisms, such as the species with filtering mouthparts (Rotheray and Gilbert 2011 ; Fig. 1 C). Therefore, cetonid larvae could also be considered as ecosystem engineers in tree hollows in Mediterranean forests. Quinto et al. (2012) provided a first approach to characterizing and analyzing specialized interacting patterns that occur in quantitative tree hollow or saproxylic insect (Coleoptera, Diptera: Syrphidae) food webs in the Cabaneros National Park, Spain. In that study, we had reported that cetonid beetles and saprophagous Syrphidae (Diptera) co-occur in tree hollows in Mediterranean forests (Fig. 1 ). However, to the best of our knowledge, there are no studies that analyze either these spatiotemporal co-occurrences or whether this co-occurrence is mediated by facilitation events. Here, we extend the studies of Quinto et al. (2012) to assess whether the presence of saprophagous Syrphidae inside tree hollows is related to the activity of cetonid larvae (feces' presence) and whether cetonid larvae feces improve the development and fitness of the saprophagous syrphid species in laboratory conditions.

Materials and Methods

Study Area.

The study was conducted from February 2009 to February 2010 in the Cabaneros National Park (39° 23?47? N, 4° 29?14? W), Spain. This protected area has a wide diversity of habitats formed by well-preserved Mediterranean woodlands (Vaquero 1997 ). The area of the park is 40,856 ha and altitude ranges from 560 to 1,448 m. This zone belongs to the Mediterranean region, where the climate is characterized by a dry summer period, with annual rainfall ranging from 500 to 750 mm. The average annual temperature varies from 12.9 to 15.6°C, with maximum temperatures of 40°C in summer and minimum temperatures of ?12°C in winter (Vaquero 1997 ).

Field Experiment.

To evaluate whether the presence of saprophagous Syrphidae in the study area was related to cetonid larval activity, our field work was carried out in the most representative Mediterranean forests of the National Park: sclerophyllous forest of Quercus rotundifolia Lamarck, mixed deciduous forest dominated by Quercus pyrenaica Willdenow and Quercus faginea Lam. and riparian forest of Fraxinus angustifolia Vahl (Quinto et al. 2012. Mico et al. 2013 ). We selected 30, 30, and 27 tree hollows from each forest type, respectively; these were then monitored using emergence traps (Colas 1974. Gouix and Brustel 2012. Quinto et al. 2012 ). Each tree hollow was covered with acrylic mesh and sealed up with staples. Adults emerged and came into a collecting pot that contained ethylene glycol as a preservative. This kind of trap has been proved to be the most effective for sampling saproxylic insects in tree hollows in Mediterranean areas (Quinto et al. 2013 ).

Pots were replaced every month for a year (February 2009–March 2010).

Before installing the traps, we registered the presence of cetonid feces in the substrate contained in the tree hollow; cetonid larvae eat large quantities of wood, and their feces, which remain in the substrate for a long time, are often a dominant content in the tree hollow (Jonson et al. 2004. Mico et al. 2011 ). The feces are easily distinguishable from the rest of the substrate owing to their shape, size, and abundance (Fig. 1 B).

To assess the effect of cetonid activity on syrphid species distribution, we recorded the presence and absence of cetonid larvae or larval feces in each of the 87 tree hollows selected. We measured 10 variables in each hollow to model Syrphidae saproxylic assemblages at microhabitat scale (further details in J. Q. unpublished data): 1) trunk diameter (Diam). We measured the tree perimeter at 0.30 and 1.30 cm and applied the equation diam = $$mathtex$$frac $$mathtex$$ (cm), where P is the mean perimeter of the two heights considered; 2) tree hollow volume (Volth). We homogenized the volume of each hollow as a cylinder with a circular base and then Volth =? r 2 h (cm 3 ), where r is the radius of the hollow opening level (the unique measurable radius in many cases) and h the total height of the tree hollow; 3) organic matter volume contained in each hollow (Volmo). This was estimated by considering the volume as a hypothetical semisphere and then Volwm = $$mathtex$$frac $$mathtex$$ ? r 3 (cm 3 ), where r is the radius of the upper level of the organic matter; 4) height of hollow from the ground (Height); 5) distance (cm) from the lower hollow opening point to the ground; 6) hollow opening area (Area): considering the opening area as an ellipse; 7) hollow orientation (Orient): this value considered eight cardinal and intermediate directions from North to Northwest, and horizontal hollows were considered as “without orientation”; 8) accumulated water presence (Water) in the hollow. Before trap installation, we registered the presence or absence of accumulated water in each selected tree hollow; 9) presence of Scolytinae galleries (Scolyt); 10) activity of vertebrates (Verteb). We also recorded tree hollows that presented vertebrate activity (hairs, feathers, nests, etc.).

Laboratory Experiment.

The experiment was performed using Myathropa florea (L. 1758), the most abundant syrphid species living in tree hollows in the study area (Quinto et al. 2012 ). The larvae of this species live in liquefied decaying vegetal matter (Hartley 1961 ). However, one of the most abundant cetonid species living inside tree hollows is Cetonia aurataeformis Curti, 1913 (Mico et al. 2011 ).

The laboratory experiment was conducted to assess the effect of the presence of feces of C. aurataeformis larvae on the life cycle and fitness of M. florea . In January 2011, we collected 60 third-instar larvae of M. florea (L3) by hand from several tree hollows of Q. pyrenaica Willdenow in the Cabaneros National Park. Species identification and L3-instar of the larvae were confirmed in the laboratory using the method by Rotheray (1993). Each larva was placed in a 100-ml plastic box with three different breeding media (see below). This box was open at the top and was placed inside a larger box with sawdust to provide a dry substrate for larva pupation. A Q. pyrenaica stump was also placed inside the breeding box, to allow larvae to go out and pupate in the dry substrate (Fig. 2 ). The top of the large box containing sawdust was closed with fine mesh. The larvae were reared until adult emergence in a climatic room under dark conditions (20 ± 1°C; 75 ± 10% relative humidity [RH]). The three different breeding media were tested using 20 larvae per treatment.

Rearing box with breeding media where larvae of M. florea were placed until pupation. A plastic box containing the breeding media was placed inside a larger plastic box. We placed a wooden stump in the breeding media to enable the syrphid larvae to access the dry area to pupate.

Treatment 1. Optimal conditions for saprophagous syrphid larvae growth, simulating natural conditions for larvae inside tree hollows (sensu Rotheray 2012 ). This treatment consisted of 40 ml of detritus ( Q. pyrenaica wood sawdust) and 60 ml of purified water.

Treatment 2. Substrate enriched with feces of C. aurataeformis larvae. This treatment consisted of 20 ml of detritus ( Q. pyrenaica wood sawdust), 20 ml of feces of C. aurataeformis larvae, and 60 ml of purified water.

Treatment 3. Suboptimal treatment (sensu Rotheray 2012 ). This treatment consisted of 20 ml of detritus ( Q. pyrenaica wood sawdust) and 80 ml of purified water.

At the beginning of each treatment, a drop of the original liquid collected from tree hollows in the field was added to the substrate to accelerate bacterial growth (Rotheray 2012 ). Each L3 larva and newly formed pupa was weighed using a precision scale (Acculab ALC-110.4 Analytical Balance, CE, Germany). Larval growth rate (measured as the increase in weight per week) and pupal weight were considered as indicators for the breeding success of each treatment (greater weight is better; Kingsolver and Huey 2008 ).

We compared larval growth rate during development until pupation per treatment. The duration of the larval period was regarded as a surrogate for the quality of larva food (a shorter developmental period is better; Dziock 2005. Amoros-Jimenez et al. 2012 ).

Each pupa was placed separately in a petri dish until adult emergence. The weight of the pupae in all treatments was recorded the day after pupation as in the study by Amoros-Jimenez et al. (2012). We registered the number of pupae that developed into adults to obtain adult emergence rate for each treatment. Wing length of the emerged adults was also measured as a surrogate for total body size in syrphids and as a good indicator for adult fitness (Kingsolver and Pfennig 2004. Dziock 2005. Kingsolver and Huey 2008 ). Specifically, the shortest length between the junction of the costal vein (C) with the humeral cross vein (h) and the junction of R4+5 with the medial vein (M) was measured (Dziock 2005 ; Fig. 3 ). Measurements were analyzed separately for each sex owing to differences between males and females, and the right wing was always used to avoid any effect caused by asymmetry. We used an Image Analyzer LEIKA (M205C/DFC425, Cambridge, United Kingdom) for wing length measurements.

Wing of M. florea . The distance between the two marked points is the shortest length between the junction of the costal vein (C) with the humeral cross vein (h) and the junction of R4+5 with the medial vein (M) (Dziock 2005 ).

Statistical Analysis.

We used CANOCO 4.5 (ter Braak and Smilauer 2002 ) to assess the influence of cetonid activity on syrphid species distribution in tree hollows (Table 1 ), as well as to discover which syrphid species is most affected by this biotic variable. This is a canonical correspondence analysis for the total abundance of each syrphid species (CCA, Hill's scaling, down-weighting rare species). The species most related to a variable is represented by those points that are distributed closest, representing the weights with a higher linear correlation index (Morrison 1967 ).

Saproxylic Syrphidae species composition in tree hollows in the Cabaneros National Park, Spain, collected from emergence traps (modified from Quinto et al. 2012 )

The data with normal distribution, such as larval growth rate, pupal weight, and wing length of the adults of M. florea, were tested with one-way analysis of variance tests to evaluate intrinsic differences among treatments. Moreover, a nonparametric Kaplan–Meier test was performed to determine whether there were any differences between mean larval growth period and adult emergence rate among treatments (Zar 1999 ).

Results

Influence of Cetonid Activity on Saprophagous Syrphidae Presence.

Just over 63.22% of the studied tree hollows exhibited evidence, presence, or both, of feces of C. aurataeformis larvae. The CCA showed that six microenvironmental variables influence Syrphidae species distribution (Fig. 4 ; Tables 2 and 3 ), with “cetonid activity” being the variable that explains the highest percentage of the variation (Monte Carlo test=1.67; F =2.55; P < 0.01), followed by hollow height from the ground ( F =2.19; P < 0.01), presence of Scolytidae galleries ( F =1.88; P < 0.05), presence of accumulated water ( F =1.65; P < 0.05), internal volume of hollow ( F =1.67; P < 0.05), and hollow orientation ( F =1.58; P < 0.05).

CCA representation of the significant microenvironmental variables that affect the Syrphidae species distribution. The syrphid species other than M. florea labels (S17) can be found in Tables 2 and 3. Cet Act, Cetonid activity; Volth, tree hollow volume; Scolyt, presence of Scolytinae galleries; Height, height of hollow from the ground; Water, water presence; Orient, hollow orientation.

Asterisk indicates the highest eigenvalue corresponding to “Cetonid activity”.

The syrphid species most related to cetonid activity was M. florea (present in 35% of the tree hollows examined), followed by Brachyopa grunewaldensis (Kassebeer 2000) (13%), Myolepta difformis (Strobl, 1909) (10%), and Spilomyia digitata (Rondani, 1865) (7%).

Scolytidae galleries were found to be particularly related to the presence of the syrphid Criorhina pachymera Egger, 1858, whereas hollow orientation and water content were mainly related to the presence of Myolepta obscura Becher, 1882, and Mallota dusmeti (Andreu 1926). Furthermore, both water presence and height of hollow from the ground positively promoted the presence and abundance of Cr. pachymera, Mallota fuciformis (F. 1794), S. digitata, and Brachypalpus valgus (Panzer, 1798). Finally, the species most influenced by the hollow volume was B. grunewaldensis (Fig. 4 ).

Influence of Cetonid Feces on M. florea Larval Development and Adult Fitness.

The larval growth rate of M. florea for treatment 2 (enriched with cetonid feces) was significantly higher than that for the other two treatments ( F =7.50; df=2; P < 0.01). In addition, wing length average was also significantly greater in adults from treatment 2 ( F =3.54; df=2; P < 0.05), which indicated an improvement of adult fitness. Differences in larval mortality rate, pupal weight, and period of larval development among treatments were not statistically significant. However, in all cases, better performance was obtained in treatment 2 (? 2 =4.43; df=2; P > 0.05; Table 4 ).

Discussion

It has been suggested that several beetle species considered as ecosystem engineers (e. g. C. cerdo and O. eremita ) could be important facilitation factors that determine higher species richness of saproxylic insects in tree hollows (Jonson et al. 2004. Ranius et al. 2005. Buse et al. 2008 ). The study of the ecological role of these species in these microhabitats, where species of different trophic guilds live together and interact, is of the utmost importance to understand the biodiversity hosted by tree hollows.

Our results show that cetonid activity (as feces and larval presence in tree hollows) was the most important microenvironmental factor determining the presence of saprophagous syrphid species. In particular, this was the case of M. florea, whose larvae were present in 35% of the tree hollows studied with observed cetonid activity.

M. florea is a cosmopolitan saprophagous hoverfly (Speight and Castella 2011 ), whose distribution in the Iberian Peninsula is wide (Marcos-Garcia 1985 ). The aquatic larvae of M. florea filter microorganisms and are common in the metazoan communities that occur in water-filled tree hollows in European temperate deciduous forests with low litter content (Schmidl et al. 2008 ). Nevertheless, this species is not an obligatory dendrolimnetobiont, species that only occur in tree hollows or similar phytotelmata (Yanoviak 2001 ), and whose larvae require a high supply of organic substrates on which to feed (Rotheray and Gilbert 2011 ). They have also frequently been observed developing in decaying vegetal matter such as ripe fruit of Opuntia (M. A.M. G. unpublished data). The nutrients provided by the cetonid feces represent a facilitating factor for the successful development of M. florea, which can extend to over a year in natural conditions (Rotheray and Gilbert 2011 ). This food enrichment provided by cetonid feces can lead to a lack of synchrony in the life cycle of M. florea at local scale (i. e. shortening the life cycle of M. florea in hollows with feces). This asynchrony can be considered as an advantage, as it enables the mixing of individuals from different generations and contributes to genetic variability. This can also partially explain why saproxylic larvae population in tree hollows frequently consist of different sizes and instars (Rotheray and Gilbert 2011 ).

The laboratory experiment corroborates our field facilitation results, demonstrating that M. florea larvae had a higher growth rate when reared in an enriched substrate with C. aurataeformis feces. In addition, the wing length average was significantly greater in adults reared with the enriched substrate. Longer average wing length indicates an increase in adult fitness of this syrphid species and better flight capacity (Dziock 2005 ). However, other studies on larval interspecific relations undertaken with M. florea and three other common insects (two Nematocera and one Coleoptera species) that live in tree hollows have not shown any evidence of facilitation interaction (Schmidl et al. 2008 ).

The higher occurrence of some syrphids in tree hollows with cetonid activity is probably owing to the attractiveness for elective oviposition exerted on gravid syrphid females by tree hollows enriched with organic matter (Speight and Castella 2011 ). This attraction seems to be mediated by a combination of physical and chemical volatile compounds emitted by biological processes of decomposition, as has been reported for other species of Diptera (Kellner 2002 ). However, without further and more extensive and rigorous comparisons with other similar field situations, no particular mechanism can be indicated. We conclude that cetonids in general, particularly C. aurataeformis, act as ecosystem engineers within tree hollows, favoring the establishment, survival, and fitness of M. florea and probably other saprophagous syrphid species.

Nevertheless, our results show that not all syrphid species are equally affected by cetonid activity. For instance, Ferdinandea spp. whose facultative saproxylic larvae live in tree hollows and sap-runs located on different parts of the tree trunk surface (Rotheray 1993. Speight and Castella 2011 ) are not dependent on cetonid larvae activity.

Moreover, richness and abundance of syrphid species are favored in tree hollows containing accumulated water, with horizontal openings that are highest from the ground. The majority of saprophagous syrphid species have aquatic larvae (Rotheray and Gilbert 2011 ) that require deep hollows to survive the long drought periods that are characteristic of the Mediterranean climate. These horizontal hollows constitute a suitable habitat for the development of large M. florea larvae (Schmidl et al. 2008 ). The preference of this species for tree hollows with a greater volume of water, as observed in My. obscura and Ma. dusmeti, is related to their long respiratory processes that allow them to obtain oxygen from the air outside (Rotheray 1993 ). In addition, other species such as Cr. pachymera, Ma. fuciformis, and Br. valgus tend to occupy higher tree hollows, which is consistent with their adult habits. These are primarily arboreal, flying high, and descending to flowering understorey trees to feed (Speight and Castella 2011 ).

Taking into account that saproxylic insects are one of the most threatened groups in Europe (Nieto and Alexander 2010. Radenkovic et al. 2013 ), the identification of ecosystem engineer species is of the utmost importance to understand the key processes that structure communities. As a consequence, when conservation programs for saproxylic communities are being established, interspecific relationships should be taken into consideration and special attention should be paid to the facilitation processes that model these communities.

Acknowledgments

We are very grateful to the staff of the Cabaneros National Park for their help during the study. We especially thank V. Rico for his suggestions. Thanks to K. Burke for help with language corrections. Financial support was provided by the Spanish Minister of Science and Innovation (CGL2008-04472, CGL2009-09656, CG L2011-23658, CGL2012-31669) and the Generalitat Valenciana (PROMETEO/2013/034 Project). I. R.S. G. was supported by Grisolia fellowships of the Generalitat Valenciana. We thank the reviewers for their comments, which have greatly helped to improve our article.

© 2014 Entomological Society of America

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Facilitation Among Saproxylic Insects Inhabiting Tree Hollows in a Mediterranean Forest: The Case of Cetonids (Coleoptera: Cetoniidae) and Syrphids (Diptera: Syrphidae)

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Citations Citations 7

References References 60

"This is consistentwith previous studies that were carried out in other communities dominated by different fauna (e. g. SGalv an et al. 2014). In our study, we found that the abundances of small Annelida, other Coleoptera, Diplopoda and Isopoda (Fig. 4aed) were positively related to the number of bark holes made by bark beetles. "

[Show abstract] [Hide abstract] ABSTRACT: Facilitation between species is thought to be a key mechanism in community assembly and diversity, as certain species create microhabitats for others. A profound characteristic of forest ecosystems is a large amount of dead wood which is colonised by a vast array of invertebrate species. Bark beetles (Scolytinae) feed and breed on dying or dead trees, puncturing holes into the bark and engraving inner bark and outer wood with their galleries. These holes and galleries might facilitate other invertebrates by providing access to the inner bark for shelter, feeding and reproduction. We tested this hypothesised facilitative interaction during the early decomposition phase of coarse woody debris of spruce (Picea abies L. Karst.) incubated in two environmentally contrasting forest sites in the 'common garden' experiment LOGLIFE. We sampled invertebrates in 25 cm diameter logs at different degrees of colonisation by bark beetles. Our results indicated that (1) bark beetles facilitated the entrance into spruce logs of other invertebrates with body width that matched the size of bark-beetle holes, and (2) the abundance of invertebrates was often positively related to the proportional surface area of inner bark consumed by bark beetles, but more so in the nutrient-rich site than in the nutrient poor site. This study provides the first quantitative test of facilitation between invertebrate clades in dead wood communities. Including facilitative interaction in community assembly studies may change some predictions about relationships between tree functional traits and invertebrate diversity and will lead to a more accurate and comprehensive understanding of dead wood communities.

Full-text · Article · Apr 2016

"In addition, and as inferred above, forest management should aim towards ensuring a more natural 'age-composition' of tree populations or rational agro-silvo-pastoral management which could allow the development of a variety of natural microhabitats in the forests (Duuren et al. 2003; Ramirez-Hernandez et al. 2014). Syrphidae are an important key indicator species in saproxylic communities (Radenkovic et al. 2013; Sanchez-Galvan et al. 2014,), but they depend on specific stages of wood decay, forming small and isolated populations (Speight 1989; Rotheray et al. 2009 Rotheray et al. 2012). In the case of the species studied here, these factors and their limited dispersal abilities increase their susceptibility to habitat fragmentation, thus depending on management of tree plantations as well as natural habitats. "

[Show abstract] [Hide abstract] ABSTRACT: An on-going study of the hoverfly fauna of the Northern Aegean Islands (Greece) has revealed the presence of four species of the genus Brachyopa Meigen. During the survey the following species were found: B. bicolor (Fallen), B. quadrimaculosa Thompson in Kaplan & Thompson, B. minima Vuji. & Perez-Banon sp. nov. and an unidentified species very close to B. pilosa (Collin). Morphological characters and mitochondrial COI barcodes were used to link different life stages of B. minima, and to identify a larval specimen of B. bicolor. In this study adult and larval morphology and habitat preferences for B. minima are described. The description of larval morphology of B. bicolor and Brachyopa sp. aff. pilosa is amended too. An identification key to the adults of the B. quadrimaculosa group sensu Kassebeer (2002) in the Eastern Mediterranean (Greece, Israel and Turkey) is provided. The importance of specific microhabitats for the continued existence of these taxa is discussed.

Full-text · Article · Jan 2016

CELESTE PEREZ-BANON SNEZANA RADENKOVIC ANTE VUJIC THEODORA PETANIDOU

"Es en esta amplia gama de microhabitats donde se producen una serie de interacciones que estan condicionadas por la relacion entre las caracteristicas concretas del arbol y la calidad del microhabitat, y la presencia de especies concretas que determinan la presencia de otras. No obstante, se sabe muy poco sobre la importancia de las interacciones entre los distintos gremios troficos que conviven en los microhabitats que ofrece la madera muerta (Quinto et al. 2012), a pesar de que algunas especies son capaces de favorecer la disponibilidad de recursos para otras especies, al causar cambios fisicos o quimicos en las caracteristicas del medio (Jones et al. 1994; Mico et al. 2011b; Sanchez-Galvan et al. 2014, Mico et al. 2015). Por su dependencia con la madera de los arboles. los insectos saproxilicos se han visto altamente afectados por malas practicas de explotacion forestal desarrolladas en las ultimas decadas, que han alterado considerablemente estos habitats (Grove, 2002). "

[Show abstract] [Hide abstract] ABSTRACT: The “dehesa” (grassland with scattered oak trees) is a typical Mediterranean ecosystem from west Iberian Peninsula that has resulted from the transformation of the forest by clearing and brushwood removing and the landscape is maintained mainly bulls and/or Iberian pigs. This ecosystem is characterized by the presence of old scattered trees that are considered as “keystone-structures”, which favor the presence of a wide range of biodiversity, especially those species that are wood-dependent (saproxylic insects). Saproxylics are a diversified group involved in the recycling process of nutrients in forest, and thus they are considered as a bioindicator group of the quality and conservation status of habitats, including a wide number of species under some categories of threat according the IUCN criteria. It is widely recognized the importance of studying the main factors that determine the structure and distribution of species assemblages at both spatial and temporal scales, nevertheless, the saproxylic assemblages has been poorly studied from the temporal dimension. With this study we provide knowledge about the effect of the “dehesa” heterogeneity, species seasonality and distribution on this habitat and we highlight the importance of the maintaining of traditional practices as a tool for saproxylic insect diversity and conservation.

Full-text · Article · May 2015

Alfredo Ramirez-Hernandez Estefania Mico Eduardo Galante

Glucosamine Hydrochloride Uses, Side Effects, Interactions And Warnings, Glusamin

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Scroggie DA, Albright A, Harris MD. The effect of glucosamine-chondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized clinical trial. Arch Intern Med 2003;163:1587-90. View abstract.

Shankar RR, Zhu JS, Baron AD. Glucosamine infusion in rats mimics the beta-cell dysfunction of non-insulin-dependent diabetes mellitus. Metabolism 1998;47:573-7. View abstract.

Shankland WE. The effects of glucosamine and chondroitin sulfate on osteoarthritis of the TMJ: a preliminary report of 50 patients. Cranio 1998;16(4):230-5. View abstract.

Shikhman AR, Brinson DC, Valbracht J, Lotz MK. Differential metabolic effects of glucosamine and N-acetylglucosamine in human articular chondrocytes. Osteoarthritis Cartilage 2009;17(8):1022-8. View abstract.

Stumpf JL, Lin SW. Effect of glucosamine on glucose control. Ann Pharmacother 2006;40:694-8. View abstract.

Tallia AF, Cardone DA. Asthma exacerbation associated with glucosamine-chondroitin supplement. J Am Board Fam Pract 2002;15:481-4. View abstract.

Tannis AJ, Barban J, Conquer JA. Effect of glucosamine supplementation on fasting and non-fasting plasma glucose and serum insulin concentrations in healthy individuals. Osteoarthritis Cartilage 2004;12:506-11. View abstract.

Tannock LR, Kirk EA, King VL, et al. Glucosamine supplementation accelerates early but not late atherosclerosis in LDL receptor-deficient mice. J Nutr 2006;136:2856-61. View abstract.

Toegel S, Wu SQ, Piana C, Unger FM, Wirth M, Goldring MB, Gabor F, Viernstein H. Comparison between chondroprotective effects of glucosamine, curcumin, and diacerein in IL-1beta-stimulated C-28/I2 chondrocytes. Osteoarthritis Cartilage 2008;16(10):1205-12. View abstract.

Tsai CY, Lee TS, Kou YR, Wu YL. Glucosamine inhibits IL-1beta-mediated IL-8 production in prostate cancer cells by MAPK attenuation. J Cell Biochem 2009;108(2):489-98. View abstract.

Uitterlinden EJ, Koevoet JL, Verkoelen CF, Bierma-Zeinstra SM, Jahr H, Weinans H, Verhaar JA, van Osch GJ. Glucosamine increases hyaluronic acid production in human osteoarthritic synovium explants. BMC Musculoskelet Disord 2008;9:120. View abstract.

Weiden S and Wood IJ. The fate of glucosamine hydrochloride injected intravenously in man. J Clin Pathol 1958;11:343-349.

Weimann G, Lubenow N, Selleng K, et al. Glucosamine sulfate does not crossreact with the antibodies of patients with heparin-induced thrombocytopenia. Eur J Haematol 2001;66:195-9. View abstract.

Wu D, Huang Y, Gu Y, Fan W. Efficacies of different preparations of glucosamine for the treatment of osteoarthritis: a meta-analysis of randomised, double-blind, placebo-controlled trials. Int J Clin Pract 2013;67(6):585-94. View abstract.

Wu H, Liu M, Wang S, Zhao H, Yao W, Feng W, Yan M, Tang Y, Wei M. Comparative fasting bioavailability and pharmacokinetic properties of 2 formulations of glucosamine hydrochloride in healthy Chinese adult male volunteers. Arzneimittelforschung. 2012 Aug;62(8):367-71. View abstract.

Wu YL, Kou YR, Ou HL, Chien HY, Chuang KH, Liu HH, Lee TS, Tsai CY, Lu ML. Glucosamine regulation of LPS-mediated inflammation in human bronchial epithelial cells. Eur J Pharmacol 2010;635(1-3):219-26. View abstract.

Yomogida S, Hua J, Sakamoto K, Nagaoka I. Glucosamine suppresses interleukin-8 production and ICAM-1 expression by TNF-alpha-stimulated human colonic epithelial HT-29 cells. Int J Mol Med 2008;22(2):205-11. View abstract.

Yomogida S, Kojima Y, Tsutsumi-Ishii Y, Hua J, Sakamoto K, Nagaoka I. Glucosamine, a naturally occurring amino monosaccharide, suppresses dextran sulfate sodium-induced colitis in rats. Int J Mol Med 2008;22(3):317-23. View abstract.

Yu JG, Boies SM, Olefsky JM. The effect of oral glucosamine sulfate on insulin sensitivity in human subjects. Diabetes Care 2003;26:1941-2. View abstract.

Yue QY, Strandell J, Myrberg O. Concomitant use of glucosamine may potential the effect of warfarin. The Uppsala Monitoring Centre. Available at: www. who-umc. org/graphics/9722.pdf (Accessed 28 April 2008).

Yun J, Tomida A, Nagata K, Tsuruo T. Glucose-regulated stresses confer resistance to VP-16 in human cancer cells through a decreased expression of DNA topoisomerase II. Oncol Res 1995;7:583-90. View abstract.

Glucosamine Hydrochloride Uses, Side Effects, Interactions And Warnings, Glusamine

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GLUCOSAMINE HYDROCHLORIDE

Dudics, V. Kunstar, A. Kovacs, J. Lakatos, T. Geher, P. Gomor, B. Monostori, E. and Uher, F. Chondrogenic potential of mesenchymal stem cells from patients with rheumatoid arthritis and osteoarthritis: measurements in a microculture system. Cells Tissues. Organs 2009;189(5):307-316. View abstract.

Kanzaki, N. Saito, K. Maeda, A. Kitagawa, Y. Kiso, Y. Watanabe, K. Tomonaga, A. Nagaoka, I. and Yamaguchi, H. Effect of a dietary supplement containing glucosamine hydrochloride, chondroitin sulfate and quercetin glycosides on symptomatic knee osteoarthritis: a randomized, double-blind, placebo-controlled study. J. Sci. Food Agric. 3-15-2012;92(4):862-869. View abstract.

Sawitzke, A. D. Shi, H. Finco, M. F. Dunlop, D. D. Harris, C. L. Singer, N. G. Bradley, J. D. Silver, D. Jackson, C. G. Lane, N. E. Oddis, C. V. Wolfe, F. Lisse, J. Furst, D. E. Bingham, C. O. Reda, D. J. Moskowitz, R. W. Williams, H. J. and Clegg, D. O. Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT. Ann. Rheum. Dis. 2010;69(8):1459-1464. View abstract.

Yue, J. Yang, M. Yi, S. Dong, B. Li, W. Yang, Z. Lu, J. Zhang, R. and Yong, J. Chondroitin sulfate and/or glucosamine hydrochloride for Kashin-Beck disease: a cluster-randomized, placebo-controlled study. Osteoarthritis. Cartilage. 2012;20(7):622-629. View abstract.

Adams ME. Hype about glucosamine. Lancet 1999;354:353-4. View abstract.

Adebowale AO, Cox DS, Liang Z, et al. Analysis of glucosamine and chondroitin sulfate content in marketed products and the Caco-2 permeability of chondroitin sulfate raw materials. JANA 2000;3:37-44.

Almada A, Harvey P, Platt K. Effects of chronic oral glucosamine sulfate on fasting insulin resistance index (FIRI) in non-diabetic individuals. FASEB J 2000;14:A750.

Audimoolam VK, Bhandari S. Acute interstitial nephritis induced by glucosamine. Nephrol Dial Transplant 2006;21(7):2031. View abstract.

Balkan B, Dunning BE. Glucosamine inhibits glucokinase in vitro and produces a glucose-specific impairment of in vivo insulin secretion in rats. Diabetes 1994;43:1173-9. View abstract.

Baron AD, Zhu JS, Zhu JH, et al. Glucosamine induces insulin resistance in vivo by affecting GLUT 4 translocation in skeletal muscle. Implications for glucose toxicity. J Clin Invest 1995;96(6):2792-801. View abstract.

Braham R, Dawson B, Goodman C. The effect of glucosamine supplementation on people experiencing regular knee pain. Br J Sports Med 2003;37:45-9. View abstract.

Bush TM, Rayburn KS, Holloway SW, et al. Adverse interactions between herbal and dietary substances and prescription medications: a clinical survey. Altern Ther Health Med 2007;13:30-5. View abstract.

Cerda C, Bruguera M, Pares A. Hepatotoxicity associated with glucosamine and chondroitin sulfate in patients with chronic liver disease. World J Gastroenterol 2013;19(32):5381-4. View abstract.

Chesnokov V, Sun C, Itakura K. Glucosamine suppresses proliferation of human prostate carcinoma DU145 cells through inhibition of STAT3 signaling. Cancer Cell Int 2009;9:25. View abstract.

Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 2006;354:795-808. View abstract.

Danao-Camara T. Potential side effects of treatment with glucosamine and chondroitin. Arthritis Rheum 2000;43:2853. View abstract.

Das A Jr, Hammad TA. Efficacy of a combination of FCHG49 glucosamine hydrochloride, TRH122 low molecular weight sodium chondroitin sulfate and manganese ascorbate in the management of knee osteoarthritis. Osteoarthritis Cartilage 2000;8:343-50. View abstract.

Does glucosamine increase serum lipid levels and blood pressure? Pharmacist's Letter/Prescriber's Letter 2001;17(11):171115.

Du XL, Edelstein D, Dimmeler S, et al. Hyperglycemia inhibits endothelial nitric oxide synthase activity by post-translational modification at the Akt site. J Clin Invest 2001;108:1341-8. View abstract.

Eggertsen R, Andreasson A, Andren L. No changes of cholesterol levels with a commercially available glucosamine product in patients treated with lipid lowering drugs: a controlled, randomised, open cross-over trial. BMCPharmacol Toxicol 2012;13(1):10. View abstract.

Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press, 2002. Available at: www. nap. edu/books/0309072794/html/.

Fox BA, Stephens MM. Glucosamine hydrochloride for the treatment of osteoarthritis symptoms. Clin Interv Aging 2007;2(4):599-604. View abstract.

Giaccari A, Morviducci L, Zorretta D, et al. In vivo effects of glucosamine on insulin secretion and insulin sensitivity in the rat: possible relevance to the maladaptive responses to chronic hyperglycaemia. Diabetologia 1995;38:518-24. View abstract.

Glucosamine for knee osteoarthritis--what's new? Drug Ther Bull. 2008: 46(11):81-4. View abstract.

Gray HC, Hutcheson PS, Slavin RG. Is glucosamine safe in patients with seafood allergy (letter)? J Allergy Clin Immunol 2004;114:459-60. View abstract.

Guillaume MP, Peretz A. Possible association between glucosamine treatment and renal toxicity: comment on the letter by Danao-Camara. Arthritis Rheum 2001;44:2943-4. View abstract.

Hochberg MC, Martel-Pelletier J, Monfort J, Moller I, Castillo JR, Arden N, Berenbaum F, Blanco FJ, Conaghan PG, Domenech G, Henrotin Y, Pap T, Richette P, Sawitzke A, du Souich P, Pelletier JP; on behalf of the MOVES Investigation Group. Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a multicentre, randomised, double-blind, non-inferiority trial versus celecoxib. Ann Rheum Dis 2016;75(1):37-44. View abstract.

Hoffer LJ, Kaplan LN, Hamadeh MJ, et al. Sulfate could mediate the therapeutic effect of glucosamine sulfate. Metabolism 2001;50:767-70. View abstract.

Holmang A, Nilsson C, Niklasson M, et al. Induction of insulin resistance by glucosamine reduces blood flow but not interstitial levels of either glucose or insulin. Diabetes 1999;48:106-11. View abstract.

Hong H, Park YK, Choi MS, Ryu NH, Song DK, Suh SI, Nam KY, Park GY, Jang BC. Differential down-regulation of COX-2 and MMP-13 in human skin fibroblasts by glucosamine-hydrochloride. J Dermatol Sci 2009;56(1):43-50. View abstract.

Houpt JB, McMillan R, Wein C, Paget-Dellio SD. Effect of glucosamine hydrochloride in the treatment of pain of osteoarthritis of the knee. J Rheumatol 1999;26:2423-30. View abstract.

Hwang MS, Baek WK. Glucosamine induces autophagic cell death through the stimulation of ER stress in human glioma cancer cells. Biochem Biophys Res Commun 2010;399(1):111-6. View abstract.

Ilic MZ, Martinac B, Samiric T, Handley CJ. Effects of glucosamine on proteoglycan loss by tendon, ligament and joint capsule explant cultures. Osteoarthritis Cartilage 2008;16(12):1501-8. View abstract.

Imagawa K, de Andres MC, Hashimoto K, Pitt D, Itoi E, Goldring MB, Roach HI, Oreffo RO. The epigenetic effect of glucosamine and a nuclear factor-kappa B (NF-kB) inhibitor on primary human chondrocytes--implications for osteoarthritis. Biochem Biophys Res Commun 2011;405(3):362-7. View abstract.

Jackson, C. G. Plaas, A. H. Sandy, J. D. Hua, C. Kim-Rolands, S. Barnhill, J. G. Harris, C. L. and Clegg, D. O. The human pharmacokinetics of oral ingestion of glucosamine and chondroitin sulfate taken separately or in combination. Osteoarthritis Cartilage 2010;18(3):297-302. View abstract.

Ju Y, Hua J, Sakamoto K, Ogawa H, Nagaoka I. Glucosamine, a naturally occurring amino monosaccharide modulates LL-37-induced endothelial cell activation. Int J Mol Med 2008;22(5):657-62. View abstract.

Ju Y, Hua J, Sakamoto K, Ogawa H, Nagaoka I. Modulation of TNF-alpha-induced endothelial cell activation by glucosamine, a naturally occurring amino monosaccharide. Int J Mol Med 2008;22(6):809-15. View abstract.

Kang ES, Han D, Park J, Kwak TK, Oh MA, Lee SA, Choi S, Park ZY, Kim Y, Lee JW. O-GlcNAc modulation at Akt1 Ser473 correlates with apoptosis of murine pancreatic beta cells. Exp Cell Res 2008;314(11-12):2238-48. View abstract.

Kawasaki T, Kurosawa H, Ikeda H, et al. Additive effects of glucosamine or risedronate for the treatment of osteoarthritis of the knee combined with home exercise: a prospective randomized 18-month trial. J Bone Miner Metab 2008;26(3):279-87. View abstract.

Kim DS, Park KS, Jeong KC, Lee BI, Lee CH, Kim SY. Glucosamine is an effective chemo-sensitizer via transglutaminase 2 inhibition. Cancer Lett 2009;273(2):243-9. View abstract.

Kim YB, Zhu JS, Zierath JR, et al. Glucosamine infusion in rats rapidly impairs insulin stimulation of phosphoinositide 3-kinase but does not alter activation of Akt/protein kinase B in skeletal muscle. Diabetes 1999;48:310-20. View abstract.

Knudsen J, Sokol GH. Potential glucosamine-warfarin interaction resulting in increased international normalized ratio: Case report and review of the literature and MedWatch database. Pharmacotherapy 2008;28:540-8. View abstract.

Kuo M, Zilberfarb V, Gangneux N, Christeff N, Issad T. O-GlcNAc modification of FoxO1 increases its transcriptional activity: a role in the glucotoxicity phenomenon? Biochimie 2008;90(5):679-85. View abstract.

Kuo M, Zilberfarb V, Gangneux N, Christeff N, Issad T. O-glycosylation of FoxO1 increases its transcriptional activity towards the glucose 6-phosphatase gene. FEBS Lett 2008;582(5):829-34. View abstract.

Kwoh CK, Roemer FW, Hannon MJ, Moore CE, Jakicic JM, Guermazi A, Green SM, Evans RW, Boudreau R. Effect of oral glucosamine on joint structure in individuals with chronic knee pain: a randomized, placebo-controlled clinical trial. Arthritis Rheumatol. 2014 Apr;66(4):930-9. View abstract.

Leffler CT, Philippi AF, Leffler SG, et al. Glucosamine, chondroitin, and manganese ascorbate for degenerative joint disease of the knee or low back: a randomized, double-blind, placebo-controlled pilot study. Mil Med 1999;164:85-91. View abstract.

Levin RM, Krieger NN, and Winzler RJ. Glucosamine and acetylglucosamine tolerance in man. J Lab Clin Med 1961;58(6):927-932.

Liang CM, Tai MC, Chang YH, Chen YH, Chen CL, Chien MW, Chen JT. Glucosamine inhibits epidermal growth factor-induced proliferation and cell-cycle progression in retinal pigment epithelial cells. Mol Vis 2010;16:2559-71. View abstract.

Lin YC, Liang YC, Sheu MT, Lin YC, Hsieh MS, Chen TF, Chen CH. Chondroprotective effects of glucosamine involving the p38 MAPK and Akt signaling pathways. Rheumatol Int 2008;28(10):1009-16. View abstract.

Liu W, Liu G, Pei F, et al. Kashin-Beck disease in Sichuan, China: report of a pilot open therapeutic trial. J Clin Rheumatol 2012;18(1):8-14. View abstract.

McAlindon T. Why are clinical trials of glucosamine no longer uniformly positive? Rheum Dis Clin North Am 2003;29:789-801. View abstract.

Messier SP, Mihalko S, Loeser RF, et al. Glucosamine/chondroitin combined with exercise for the treatment of knee osteoarthritis: a preliminary study. Osteoarthritis Cartilage 2007;15:1256-66. View abstract.

Meulyzer M, Vachon P, Beaudry F, Vinardell T, Richard H, Beauchamp G, Laverty S. Comparison of pharmacokinetics of glucosamine and synovial fluid levels following administration of glucosamine sulphate or glucosamine hydrochloride. Osteoarthritis Cartilage 2008;16(9):973-9. View abstract.

Monauni T, Zenti MG, Cretti A, et al. Effects of glucosamine infusion on insulin secretion and insulin action in humans. Diabetes 2000;49:926-35. View abstract.

Muniyappa R, Karne RJ, Hall G, et al. Oral glucosamine for 6 weeks at standard doses does not cause or worsen insulin resistance or endothelial dysfunction in lean or obese subjects. Diabetes 2006;55:3142-50. View abstract.

Naito K, Watari T, Furuhata A, Yomogida S, Sakamoto K, Kurosawa H, Kaneko K, Nagaoka I. Evaluation of the effect of glucosamine on an experimental rat osteoarthritis model. Life Sci 2010;86(13-14):538-43. View abstract.

Nakamura H, Masuko K, Yudoh K, et al. Effects of glucosamine administration on patients with rheumatoid arthritis. Rheumatol Int 2007;27:213-8. View abstract.

Nandhakumar J. Efficacy, tolerability, and safety of a multicomponent antiinflammatory with glucosamine hydrochloride vs glucosamine sulfate vs an NSAID in the treatment of knee osteoarthritis--a randomized, prospective, double-blind, comparative study. Integr Med Clin J 2009;8(3):32-38.

Nelson BA, Robinson KA, Buse MG. High glucose and glucosamine induce insulin resistance via different mechanisms in 3T3-L1 adipocytes. Diabetes 2000;49(6):981-91. View abstract.

Nowak A, Szczesniak L, Rychlewski T, et al. Glucosamine levels in people with ischaemic heart disease with and without type II diabetes. Pol Arch Med Wewn 1998;100:419-25. View abstract.

Olszewski AJ, Szostak WB, McCully KS. Plasma glucosamine and galactosamine in ischemic heart disease. Atherosclerosis 1990;82:75-83. View abstract.

Ossendza RA, Grandval P, Chinoune F, Rocher F, Chapel F, Bernardini D. [Acute cholestatic hepatitis due to glucosamine forte]. Gastroenterol Clin Biol. 2007 Apr;31(4):449-50. View abstract.

Park JY, Park JW, Suh SI, Baek WK. D-glucosamine down-regulates HIF-1alpha through inhibition of protein translation in DU145 prostate cancer cells. Biochem Biophys Res Commun 2009;382(1):96-101. View abstract.

Pavelka K, Gatterova J, Olejarova M, et al. Glucosamine sulfate use and delay of progression of knee osteoarthritis: A 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med 2002;162:2113-23. View abstract.

Pham T, Cornea A, Blick KE, et al. Oral glucosamine in doses used to treat osteoarthritis worsens insulin resistance. Am J Med Sci 2007;333:333-9. View abstract.

Pouwels MJ, Jacobs JR, Span PN, et al. Short-term glucosamine infusion does not affect insulin sensitivity in humans. J Clin Endocrinol Metab 2001;86:2099-103. View abstract.

Provenza JR, Shinjo SK, Silva JM, Peron CR, Rocha FA. Combined glucosamine and chondroitin sulfate, once or three times daily, provides clinically relevant analgesia in knee osteoarthritis. Clin Rheumatol 2015;34:1455-62.View abstract.

Qiu GX, Weng XS, Zhang K, et al. [A multi-central, randomized, controlled clinical trial of glucosamine hydrochloride/sulfate in the treatment of knee osteoarthritis]. Zhonghua Yi Xue Za Zhi 2005;85:3067-70. View abstract.

Qiu W, Su Q, Rutledge AC, Zhang J, Adeli K. Glucosamine-induced endoplasmic reticulum stress attenuates apolipoprotein B100 synthesis via PERK signaling. J Lipid Res 2009;50(9):1814-23. View abstract.

Raciti GA, Iadicicco C, Ulianich L, Vind BF, Gaster M, Andreozzi F, Longo M, Teperino R, Ungaro P, Di Jeso B, Formisano P, Beguinot F, Miele C. Glucosamine-induced endoplasmic reticulum stress affects GLUT4 expression via activating transcription factor 6 in rat and human skeletal muscle cells. Diabetologia 2010;53(5):955-65. View abstract.

Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine sulfate on osteoarthritis progression: a randomised, placebo-controlled trial. Lancet 2001;357:251-6. View abstract.

Rossetti L, Hawkins M, Chen W, et al. In vivo glucosamine infusion induces insulin resistance in normoglycemic but not in hyperglycemic conscious rats. J Clin Invest 1995;96:132-40. View abstract.

Rozenfeld V, Crain JL, Callahan AK. Possible augmentation of warfarin effect by glucosamine-chondroitin. Am J Health Syst Pharm 2004;61:306-307. View abstract.

Sakai S, Sugawara T, Kishi T, Yanagimoto K, Hirata T. Effect of glucosamine and related compounds on the degranulation of mast cells and ear swelling induced by dinitrofluorobenzene in mice. Life Sci 2010;86(9-10):337-43. View abstract.

Satia JA, Littman A, Slatore CG, Galanko JA, White E. Associations of herbal and specialty supplements with lung and colorectal cancer risk in the VITamins and Lifestyle study. Cancer Epidemiol Biomarkers Prev 2009;18(5):1419-28. View abstract.

Scotto d'Abusco A, Politi L, Giordano C, Scandurra R. A peptidyl-glucosamine derivative affects IKKalpha kinase activity in human chondrocytes. Arthritis Res Ther 2010;12(1):R18. View abstract.

Scroggie DA, Albright A, Harris MD. The effect of glucosamine-chondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized clinical trial. Arch Intern Med 2003;163:1587-90. View abstract.

Shankar RR, Zhu JS, Baron AD. Glucosamine infusion in rats mimics the beta-cell dysfunction of non-insulin-dependent diabetes mellitus. Metabolism 1998;47:573-7. View abstract.

Shankland WE. The effects of glucosamine and chondroitin sulfate on osteoarthritis of the TMJ: a preliminary report of 50 patients. Cranio 1998;16(4):230-5. View abstract.

Shikhman AR, Brinson DC, Valbracht J, Lotz MK. Differential metabolic effects of glucosamine and N-acetylglucosamine in human articular chondrocytes. Osteoarthritis Cartilage 2009;17(8):1022-8. View abstract.

Stumpf JL, Lin SW. Effect of glucosamine on glucose control. Ann Pharmacother 2006;40:694-8. View abstract.

Tallia AF, Cardone DA. Asthma exacerbation associated with glucosamine-chondroitin supplement. J Am Board Fam Pract 2002;15:481-4. View abstract.

Tannis AJ, Barban J, Conquer JA. Effect of glucosamine supplementation on fasting and non-fasting plasma glucose and serum insulin concentrations in healthy individuals. Osteoarthritis Cartilage 2004;12:506-11. View abstract.

Tannock LR, Kirk EA, King VL, et al. Glucosamine supplementation accelerates early but not late atherosclerosis in LDL receptor-deficient mice. J Nutr 2006;136:2856-61. View abstract.

Toegel S, Wu SQ, Piana C, Unger FM, Wirth M, Goldring MB, Gabor F, Viernstein H. Comparison between chondroprotective effects of glucosamine, curcumin, and diacerein in IL-1beta-stimulated C-28/I2 chondrocytes. Osteoarthritis Cartilage 2008;16(10):1205-12. View abstract.

Tsai CY, Lee TS, Kou YR, Wu YL. Glucosamine inhibits IL-1beta-mediated IL-8 production in prostate cancer cells by MAPK attenuation. J Cell Biochem 2009;108(2):489-98. View abstract.

Uitterlinden EJ, Koevoet JL, Verkoelen CF, Bierma-Zeinstra SM, Jahr H, Weinans H, Verhaar JA, van Osch GJ. Glucosamine increases hyaluronic acid production in human osteoarthritic synovium explants. BMC Musculoskelet Disord 2008;9:120. View abstract.

Weiden S and Wood IJ. The fate of glucosamine hydrochloride injected intravenously in man. J Clin Pathol 1958;11:343-349.

Weimann G, Lubenow N, Selleng K, et al. Glucosamine sulfate does not crossreact with the antibodies of patients with heparin-induced thrombocytopenia. Eur J Haematol 2001;66:195-9. View abstract.

Wu D, Huang Y, Gu Y, Fan W. Efficacies of different preparations of glucosamine for the treatment of osteoarthritis: a meta-analysis of randomised, double-blind, placebo-controlled trials. Int J Clin Pract 2013;67(6):585-94. View abstract.

Wu H, Liu M, Wang S, Zhao H, Yao W, Feng W, Yan M, Tang Y, Wei M. Comparative fasting bioavailability and pharmacokinetic properties of 2 formulations of glucosamine hydrochloride in healthy Chinese adult male volunteers. Arzneimittelforschung. 2012 Aug;62(8):367-71. View abstract.

Wu YL, Kou YR, Ou HL, Chien HY, Chuang KH, Liu HH, Lee TS, Tsai CY, Lu ML. Glucosamine regulation of LPS-mediated inflammation in human bronchial epithelial cells. Eur J Pharmacol 2010;635(1-3):219-26. View abstract.

Yomogida S, Hua J, Sakamoto K, Nagaoka I. Glucosamine suppresses interleukin-8 production and ICAM-1 expression by TNF-alpha-stimulated human colonic epithelial HT-29 cells. Int J Mol Med 2008;22(2):205-11. View abstract.

Yomogida S, Kojima Y, Tsutsumi-Ishii Y, Hua J, Sakamoto K, Nagaoka I. Glucosamine, a naturally occurring amino monosaccharide, suppresses dextran sulfate sodium-induced colitis in rats. Int J Mol Med 2008;22(3):317-23. View abstract.

Yu JG, Boies SM, Olefsky JM. The effect of oral glucosamine sulfate on insulin sensitivity in human subjects. Diabetes Care 2003;26:1941-2. View abstract.

Yue QY, Strandell J, Myrberg O. Concomitant use of glucosamine may potential the effect of warfarin. The Uppsala Monitoring Centre. Available at: www. who-umc. org/graphics/9722.pdf (Accessed 28 April 2008).

Yun J, Tomida A, Nagata K, Tsuruo T. Glucose-regulated stresses confer resistance to VP-16 in human cancer cells through a decreased expression of DNA topoisomerase II. Oncol Res 1995;7:583-90. View abstract.

Glucosamine Hydrochloride Uses, Side Effects, Interactions And Warnings, Glusamon

Find a Vitamin or Supplement

GLUCOSAMINE HYDROCHLORIDE

Dudics, V. Kunstar, A. Kovacs, J. Lakatos, T. Geher, P. Gomor, B. Monostori, E. and Uher, F. Chondrogenic potential of mesenchymal stem cells from patients with rheumatoid arthritis and osteoarthritis: measurements in a microculture system. Cells Tissues. Organs 2009;189(5):307-316. View abstract.

Kanzaki, N. Saito, K. Maeda, A. Kitagawa, Y. Kiso, Y. Watanabe, K. Tomonaga, A. Nagaoka, I. and Yamaguchi, H. Effect of a dietary supplement containing glucosamine hydrochloride, chondroitin sulfate and quercetin glycosides on symptomatic knee osteoarthritis: a randomized, double-blind, placebo-controlled study. J. Sci. Food Agric. 3-15-2012;92(4):862-869. View abstract.

Sawitzke, A. D. Shi, H. Finco, M. F. Dunlop, D. D. Harris, C. L. Singer, N. G. Bradley, J. D. Silver, D. Jackson, C. G. Lane, N. E. Oddis, C. V. Wolfe, F. Lisse, J. Furst, D. E. Bingham, C. O. Reda, D. J. Moskowitz, R. W. Williams, H. J. and Clegg, D. O. Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT. Ann. Rheum. Dis. 2010;69(8):1459-1464. View abstract.

Yue, J. Yang, M. Yi, S. Dong, B. Li, W. Yang, Z. Lu, J. Zhang, R. and Yong, J. Chondroitin sulfate and/or glucosamine hydrochloride for Kashin-Beck disease: a cluster-randomized, placebo-controlled study. Osteoarthritis. Cartilage. 2012;20(7):622-629. View abstract.

Adams ME. Hype about glucosamine. Lancet 1999;354:353-4. View abstract.

Adebowale AO, Cox DS, Liang Z, et al. Analysis of glucosamine and chondroitin sulfate content in marketed products and the Caco-2 permeability of chondroitin sulfate raw materials. JANA 2000;3:37-44.

Almada A, Harvey P, Platt K. Effects of chronic oral glucosamine sulfate on fasting insulin resistance index (FIRI) in non-diabetic individuals. FASEB J 2000;14:A750.

Audimoolam VK, Bhandari S. Acute interstitial nephritis induced by glucosamine. Nephrol Dial Transplant 2006;21(7):2031. View abstract.

Balkan B, Dunning BE. Glucosamine inhibits glucokinase in vitro and produces a glucose-specific impairment of in vivo insulin secretion in rats. Diabetes 1994;43:1173-9. View abstract.

Baron AD, Zhu JS, Zhu JH, et al. Glucosamine induces insulin resistance in vivo by affecting GLUT 4 translocation in skeletal muscle. Implications for glucose toxicity. J Clin Invest 1995;96(6):2792-801. View abstract.

Braham R, Dawson B, Goodman C. The effect of glucosamine supplementation on people experiencing regular knee pain. Br J Sports Med 2003;37:45-9. View abstract.

Bush TM, Rayburn KS, Holloway SW, et al. Adverse interactions between herbal and dietary substances and prescription medications: a clinical survey. Altern Ther Health Med 2007;13:30-5. View abstract.

Cerda C, Bruguera M, Pares A. Hepatotoxicity associated with glucosamine and chondroitin sulfate in patients with chronic liver disease. World J Gastroenterol 2013;19(32):5381-4. View abstract.

Chesnokov V, Sun C, Itakura K. Glucosamine suppresses proliferation of human prostate carcinoma DU145 cells through inhibition of STAT3 signaling. Cancer Cell Int 2009;9:25. View abstract.

Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 2006;354:795-808. View abstract.

Danao-Camara T. Potential side effects of treatment with glucosamine and chondroitin. Arthritis Rheum 2000;43:2853. View abstract.

Das A Jr, Hammad TA. Efficacy of a combination of FCHG49 glucosamine hydrochloride, TRH122 low molecular weight sodium chondroitin sulfate and manganese ascorbate in the management of knee osteoarthritis. Osteoarthritis Cartilage 2000;8:343-50. View abstract.

Does glucosamine increase serum lipid levels and blood pressure? Pharmacist's Letter/Prescriber's Letter 2001;17(11):171115.

Du XL, Edelstein D, Dimmeler S, et al. Hyperglycemia inhibits endothelial nitric oxide synthase activity by post-translational modification at the Akt site. J Clin Invest 2001;108:1341-8. View abstract.

Eggertsen R, Andreasson A, Andren L. No changes of cholesterol levels with a commercially available glucosamine product in patients treated with lipid lowering drugs: a controlled, randomised, open cross-over trial. BMCPharmacol Toxicol 2012;13(1):10. View abstract.

Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press, 2002. Available at: www. nap. edu/books/0309072794/html/.

Fox BA, Stephens MM. Glucosamine hydrochloride for the treatment of osteoarthritis symptoms. Clin Interv Aging 2007;2(4):599-604. View abstract.

Giaccari A, Morviducci L, Zorretta D, et al. In vivo effects of glucosamine on insulin secretion and insulin sensitivity in the rat: possible relevance to the maladaptive responses to chronic hyperglycaemia. Diabetologia 1995;38:518-24. View abstract.

Glucosamine for knee osteoarthritis--what's new? Drug Ther Bull. 2008: 46(11):81-4. View abstract.

Gray HC, Hutcheson PS, Slavin RG. Is glucosamine safe in patients with seafood allergy (letter)? J Allergy Clin Immunol 2004;114:459-60. View abstract.

Guillaume MP, Peretz A. Possible association between glucosamine treatment and renal toxicity: comment on the letter by Danao-Camara. Arthritis Rheum 2001;44:2943-4. View abstract.

Hochberg MC, Martel-Pelletier J, Monfort J, Moller I, Castillo JR, Arden N, Berenbaum F, Blanco FJ, Conaghan PG, Domenech G, Henrotin Y, Pap T, Richette P, Sawitzke A, du Souich P, Pelletier JP; on behalf of the MOVES Investigation Group. Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a multicentre, randomised, double-blind, non-inferiority trial versus celecoxib. Ann Rheum Dis 2016;75(1):37-44. View abstract.

Hoffer LJ, Kaplan LN, Hamadeh MJ, et al. Sulfate could mediate the therapeutic effect of glucosamine sulfate. Metabolism 2001;50:767-70. View abstract.

Holmang A, Nilsson C, Niklasson M, et al. Induction of insulin resistance by glucosamine reduces blood flow but not interstitial levels of either glucose or insulin. Diabetes 1999;48:106-11. View abstract.

Hong H, Park YK, Choi MS, Ryu NH, Song DK, Suh SI, Nam KY, Park GY, Jang BC. Differential down-regulation of COX-2 and MMP-13 in human skin fibroblasts by glucosamine-hydrochloride. J Dermatol Sci 2009;56(1):43-50. View abstract.

Houpt JB, McMillan R, Wein C, Paget-Dellio SD. Effect of glucosamine hydrochloride in the treatment of pain of osteoarthritis of the knee. J Rheumatol 1999;26:2423-30. View abstract.

Hwang MS, Baek WK. Glucosamine induces autophagic cell death through the stimulation of ER stress in human glioma cancer cells. Biochem Biophys Res Commun 2010;399(1):111-6. View abstract.

Ilic MZ, Martinac B, Samiric T, Handley CJ. Effects of glucosamine on proteoglycan loss by tendon, ligament and joint capsule explant cultures. Osteoarthritis Cartilage 2008;16(12):1501-8. View abstract.

Imagawa K, de Andres MC, Hashimoto K, Pitt D, Itoi E, Goldring MB, Roach HI, Oreffo RO. The epigenetic effect of glucosamine and a nuclear factor-kappa B (NF-kB) inhibitor on primary human chondrocytes--implications for osteoarthritis. Biochem Biophys Res Commun 2011;405(3):362-7. View abstract.

Jackson, C. G. Plaas, A. H. Sandy, J. D. Hua, C. Kim-Rolands, S. Barnhill, J. G. Harris, C. L. and Clegg, D. O. The human pharmacokinetics of oral ingestion of glucosamine and chondroitin sulfate taken separately or in combination. Osteoarthritis Cartilage 2010;18(3):297-302. View abstract.

Ju Y, Hua J, Sakamoto K, Ogawa H, Nagaoka I. Glucosamine, a naturally occurring amino monosaccharide modulates LL-37-induced endothelial cell activation. Int J Mol Med 2008;22(5):657-62. View abstract.

Ju Y, Hua J, Sakamoto K, Ogawa H, Nagaoka I. Modulation of TNF-alpha-induced endothelial cell activation by glucosamine, a naturally occurring amino monosaccharide. Int J Mol Med 2008;22(6):809-15. View abstract.

Kang ES, Han D, Park J, Kwak TK, Oh MA, Lee SA, Choi S, Park ZY, Kim Y, Lee JW. O-GlcNAc modulation at Akt1 Ser473 correlates with apoptosis of murine pancreatic beta cells. Exp Cell Res 2008;314(11-12):2238-48. View abstract.

Kawasaki T, Kurosawa H, Ikeda H, et al. Additive effects of glucosamine or risedronate for the treatment of osteoarthritis of the knee combined with home exercise: a prospective randomized 18-month trial. J Bone Miner Metab 2008;26(3):279-87. View abstract.

Kim DS, Park KS, Jeong KC, Lee BI, Lee CH, Kim SY. Glucosamine is an effective chemo-sensitizer via transglutaminase 2 inhibition. Cancer Lett 2009;273(2):243-9. View abstract.

Kim YB, Zhu JS, Zierath JR, et al. Glucosamine infusion in rats rapidly impairs insulin stimulation of phosphoinositide 3-kinase but does not alter activation of Akt/protein kinase B in skeletal muscle. Diabetes 1999;48:310-20. View abstract.

Knudsen J, Sokol GH. Potential glucosamine-warfarin interaction resulting in increased international normalized ratio: Case report and review of the literature and MedWatch database. Pharmacotherapy 2008;28:540-8. View abstract.

Kuo M, Zilberfarb V, Gangneux N, Christeff N, Issad T. O-GlcNAc modification of FoxO1 increases its transcriptional activity: a role in the glucotoxicity phenomenon? Biochimie 2008;90(5):679-85. View abstract.

Kuo M, Zilberfarb V, Gangneux N, Christeff N, Issad T. O-glycosylation of FoxO1 increases its transcriptional activity towards the glucose 6-phosphatase gene. FEBS Lett 2008;582(5):829-34. View abstract.

Kwoh CK, Roemer FW, Hannon MJ, Moore CE, Jakicic JM, Guermazi A, Green SM, Evans RW, Boudreau R. Effect of oral glucosamine on joint structure in individuals with chronic knee pain: a randomized, placebo-controlled clinical trial. Arthritis Rheumatol. 2014 Apr;66(4):930-9. View abstract.

Leffler CT, Philippi AF, Leffler SG, et al. Glucosamine, chondroitin, and manganese ascorbate for degenerative joint disease of the knee or low back: a randomized, double-blind, placebo-controlled pilot study. Mil Med 1999;164:85-91. View abstract.

Levin RM, Krieger NN, and Winzler RJ. Glucosamine and acetylglucosamine tolerance in man. J Lab Clin Med 1961;58(6):927-932.

Liang CM, Tai MC, Chang YH, Chen YH, Chen CL, Chien MW, Chen JT. Glucosamine inhibits epidermal growth factor-induced proliferation and cell-cycle progression in retinal pigment epithelial cells. Mol Vis 2010;16:2559-71. View abstract.

Lin YC, Liang YC, Sheu MT, Lin YC, Hsieh MS, Chen TF, Chen CH. Chondroprotective effects of glucosamine involving the p38 MAPK and Akt signaling pathways. Rheumatol Int 2008;28(10):1009-16. View abstract.

Liu W, Liu G, Pei F, et al. Kashin-Beck disease in Sichuan, China: report of a pilot open therapeutic trial. J Clin Rheumatol 2012;18(1):8-14. View abstract.

McAlindon T. Why are clinical trials of glucosamine no longer uniformly positive? Rheum Dis Clin North Am 2003;29:789-801. View abstract.

Messier SP, Mihalko S, Loeser RF, et al. Glucosamine/chondroitin combined with exercise for the treatment of knee osteoarthritis: a preliminary study. Osteoarthritis Cartilage 2007;15:1256-66. View abstract.

Meulyzer M, Vachon P, Beaudry F, Vinardell T, Richard H, Beauchamp G, Laverty S. Comparison of pharmacokinetics of glucosamine and synovial fluid levels following administration of glucosamine sulphate or glucosamine hydrochloride. Osteoarthritis Cartilage 2008;16(9):973-9. View abstract.

Monauni T, Zenti MG, Cretti A, et al. Effects of glucosamine infusion on insulin secretion and insulin action in humans. Diabetes 2000;49:926-35. View abstract.

Muniyappa R, Karne RJ, Hall G, et al. Oral glucosamine for 6 weeks at standard doses does not cause or worsen insulin resistance or endothelial dysfunction in lean or obese subjects. Diabetes 2006;55:3142-50. View abstract.

Naito K, Watari T, Furuhata A, Yomogida S, Sakamoto K, Kurosawa H, Kaneko K, Nagaoka I. Evaluation of the effect of glucosamine on an experimental rat osteoarthritis model. Life Sci 2010;86(13-14):538-43. View abstract.

Nakamura H, Masuko K, Yudoh K, et al. Effects of glucosamine administration on patients with rheumatoid arthritis. Rheumatol Int 2007;27:213-8. View abstract.

Nandhakumar J. Efficacy, tolerability, and safety of a multicomponent antiinflammatory with glucosamine hydrochloride vs glucosamine sulfate vs an NSAID in the treatment of knee osteoarthritis--a randomized, prospective, double-blind, comparative study. Integr Med Clin J 2009;8(3):32-38.

Nelson BA, Robinson KA, Buse MG. High glucose and glucosamine induce insulin resistance via different mechanisms in 3T3-L1 adipocytes. Diabetes 2000;49(6):981-91. View abstract.

Nowak A, Szczesniak L, Rychlewski T, et al. Glucosamine levels in people with ischaemic heart disease with and without type II diabetes. Pol Arch Med Wewn 1998;100:419-25. View abstract.

Olszewski AJ, Szostak WB, McCully KS. Plasma glucosamine and galactosamine in ischemic heart disease. Atherosclerosis 1990;82:75-83. View abstract.

Ossendza RA, Grandval P, Chinoune F, Rocher F, Chapel F, Bernardini D. [Acute cholestatic hepatitis due to glucosamine forte]. Gastroenterol Clin Biol. 2007 Apr;31(4):449-50. View abstract.

Park JY, Park JW, Suh SI, Baek WK. D-glucosamine down-regulates HIF-1alpha through inhibition of protein translation in DU145 prostate cancer cells. Biochem Biophys Res Commun 2009;382(1):96-101. View abstract.

Pavelka K, Gatterova J, Olejarova M, et al. Glucosamine sulfate use and delay of progression of knee osteoarthritis: A 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med 2002;162:2113-23. View abstract.

Pham T, Cornea A, Blick KE, et al. Oral glucosamine in doses used to treat osteoarthritis worsens insulin resistance. Am J Med Sci 2007;333:333-9. View abstract.

Pouwels MJ, Jacobs JR, Span PN, et al. Short-term glucosamine infusion does not affect insulin sensitivity in humans. J Clin Endocrinol Metab 2001;86:2099-103. View abstract.

Provenza JR, Shinjo SK, Silva JM, Peron CR, Rocha FA. Combined glucosamine and chondroitin sulfate, once or three times daily, provides clinically relevant analgesia in knee osteoarthritis. Clin Rheumatol 2015;34:1455-62.View abstract.

Qiu GX, Weng XS, Zhang K, et al. [A multi-central, randomized, controlled clinical trial of glucosamine hydrochloride/sulfate in the treatment of knee osteoarthritis]. Zhonghua Yi Xue Za Zhi 2005;85:3067-70. View abstract.

Qiu W, Su Q, Rutledge AC, Zhang J, Adeli K. Glucosamine-induced endoplasmic reticulum stress attenuates apolipoprotein B100 synthesis via PERK signaling. J Lipid Res 2009;50(9):1814-23. View abstract.

Raciti GA, Iadicicco C, Ulianich L, Vind BF, Gaster M, Andreozzi F, Longo M, Teperino R, Ungaro P, Di Jeso B, Formisano P, Beguinot F, Miele C. Glucosamine-induced endoplasmic reticulum stress affects GLUT4 expression via activating transcription factor 6 in rat and human skeletal muscle cells. Diabetologia 2010;53(5):955-65. View abstract.

Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine sulfate on osteoarthritis progression: a randomised, placebo-controlled trial. Lancet 2001;357:251-6. View abstract.

Rossetti L, Hawkins M, Chen W, et al. In vivo glucosamine infusion induces insulin resistance in normoglycemic but not in hyperglycemic conscious rats. J Clin Invest 1995;96:132-40. View abstract.

Rozenfeld V, Crain JL, Callahan AK. Possible augmentation of warfarin effect by glucosamine-chondroitin. Am J Health Syst Pharm 2004;61:306-307. View abstract.

Sakai S, Sugawara T, Kishi T, Yanagimoto K, Hirata T. Effect of glucosamine and related compounds on the degranulation of mast cells and ear swelling induced by dinitrofluorobenzene in mice. Life Sci 2010;86(9-10):337-43. View abstract.

Satia JA, Littman A, Slatore CG, Galanko JA, White E. Associations of herbal and specialty supplements with lung and colorectal cancer risk in the VITamins and Lifestyle study. Cancer Epidemiol Biomarkers Prev 2009;18(5):1419-28. View abstract.

Scotto d'Abusco A, Politi L, Giordano C, Scandurra R. A peptidyl-glucosamine derivative affects IKKalpha kinase activity in human chondrocytes. Arthritis Res Ther 2010;12(1):R18. View abstract.

Scroggie DA, Albright A, Harris MD. The effect of glucosamine-chondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized clinical trial. Arch Intern Med 2003;163:1587-90. View abstract.

Shankar RR, Zhu JS, Baron AD. Glucosamine infusion in rats mimics the beta-cell dysfunction of non-insulin-dependent diabetes mellitus. Metabolism 1998;47:573-7. View abstract.

Shankland WE. The effects of glucosamine and chondroitin sulfate on osteoarthritis of the TMJ: a preliminary report of 50 patients. Cranio 1998;16(4):230-5. View abstract.

Shikhman AR, Brinson DC, Valbracht J, Lotz MK. Differential metabolic effects of glucosamine and N-acetylglucosamine in human articular chondrocytes. Osteoarthritis Cartilage 2009;17(8):1022-8. View abstract.

Stumpf JL, Lin SW. Effect of glucosamine on glucose control. Ann Pharmacother 2006;40:694-8. View abstract.

Tallia AF, Cardone DA. Asthma exacerbation associated with glucosamine-chondroitin supplement. J Am Board Fam Pract 2002;15:481-4. View abstract.

Tannis AJ, Barban J, Conquer JA. Effect of glucosamine supplementation on fasting and non-fasting plasma glucose and serum insulin concentrations in healthy individuals. Osteoarthritis Cartilage 2004;12:506-11. View abstract.

Tannock LR, Kirk EA, King VL, et al. Glucosamine supplementation accelerates early but not late atherosclerosis in LDL receptor-deficient mice. J Nutr 2006;136:2856-61. View abstract.

Toegel S, Wu SQ, Piana C, Unger FM, Wirth M, Goldring MB, Gabor F, Viernstein H. Comparison between chondroprotective effects of glucosamine, curcumin, and diacerein in IL-1beta-stimulated C-28/I2 chondrocytes. Osteoarthritis Cartilage 2008;16(10):1205-12. View abstract.

Tsai CY, Lee TS, Kou YR, Wu YL. Glucosamine inhibits IL-1beta-mediated IL-8 production in prostate cancer cells by MAPK attenuation. J Cell Biochem 2009;108(2):489-98. View abstract.

Uitterlinden EJ, Koevoet JL, Verkoelen CF, Bierma-Zeinstra SM, Jahr H, Weinans H, Verhaar JA, van Osch GJ. Glucosamine increases hyaluronic acid production in human osteoarthritic synovium explants. BMC Musculoskelet Disord 2008;9:120. View abstract.

Weiden S and Wood IJ. The fate of glucosamine hydrochloride injected intravenously in man. J Clin Pathol 1958;11:343-349.

Weimann G, Lubenow N, Selleng K, et al. Glucosamine sulfate does not crossreact with the antibodies of patients with heparin-induced thrombocytopenia. Eur J Haematol 2001;66:195-9. View abstract.

Wu D, Huang Y, Gu Y, Fan W. Efficacies of different preparations of glucosamine for the treatment of osteoarthritis: a meta-analysis of randomised, double-blind, placebo-controlled trials. Int J Clin Pract 2013;67(6):585-94. View abstract.

Wu H, Liu M, Wang S, Zhao H, Yao W, Feng W, Yan M, Tang Y, Wei M. Comparative fasting bioavailability and pharmacokinetic properties of 2 formulations of glucosamine hydrochloride in healthy Chinese adult male volunteers. Arzneimittelforschung. 2012 Aug;62(8):367-71. View abstract.

Wu YL, Kou YR, Ou HL, Chien HY, Chuang KH, Liu HH, Lee TS, Tsai CY, Lu ML. Glucosamine regulation of LPS-mediated inflammation in human bronchial epithelial cells. Eur J Pharmacol 2010;635(1-3):219-26. View abstract.

Yomogida S, Hua J, Sakamoto K, Nagaoka I. Glucosamine suppresses interleukin-8 production and ICAM-1 expression by TNF-alpha-stimulated human colonic epithelial HT-29 cells. Int J Mol Med 2008;22(2):205-11. View abstract.

Yomogida S, Kojima Y, Tsutsumi-Ishii Y, Hua J, Sakamoto K, Nagaoka I. Glucosamine, a naturally occurring amino monosaccharide, suppresses dextran sulfate sodium-induced colitis in rats. Int J Mol Med 2008;22(3):317-23. View abstract.

Yu JG, Boies SM, Olefsky JM. The effect of oral glucosamine sulfate on insulin sensitivity in human subjects. Diabetes Care 2003;26:1941-2. View abstract.

Yue QY, Strandell J, Myrberg O. Concomitant use of glucosamine may potential the effect of warfarin. The Uppsala Monitoring Centre. Available at: www. who-umc. org/graphics/9722.pdf (Accessed 28 April 2008).

Yun J, Tomida A, Nagata K, Tsuruo T. Glucose-regulated stresses confer resistance to VP-16 in human cancer cells through a decreased expression of DNA topoisomerase II. Oncol Res 1995;7:583-90. View abstract.

Glucosamine Hydrochloride Uses, Side Effects, Interactions And Warnings, D-Glucosamin

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GLUCOSAMINE HYDROCHLORIDE

Dudics, V. Kunstar, A. Kovacs, J. Lakatos, T. Geher, P. Gomor, B. Monostori, E. and Uher, F. Chondrogenic potential of mesenchymal stem cells from patients with rheumatoid arthritis and osteoarthritis: measurements in a microculture system. Cells Tissues. Organs 2009;189(5):307-316. View abstract.

Kanzaki, N. Saito, K. Maeda, A. Kitagawa, Y. Kiso, Y. Watanabe, K. Tomonaga, A. Nagaoka, I. and Yamaguchi, H. Effect of a dietary supplement containing glucosamine hydrochloride, chondroitin sulfate and quercetin glycosides on symptomatic knee osteoarthritis: a randomized, double-blind, placebo-controlled study. J. Sci. Food Agric. 3-15-2012;92(4):862-869. View abstract.

Sawitzke, A. D. Shi, H. Finco, M. F. Dunlop, D. D. Harris, C. L. Singer, N. G. Bradley, J. D. Silver, D. Jackson, C. G. Lane, N. E. Oddis, C. V. Wolfe, F. Lisse, J. Furst, D. E. Bingham, C. O. Reda, D. J. Moskowitz, R. W. Williams, H. J. and Clegg, D. O. Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT. Ann. Rheum. Dis. 2010;69(8):1459-1464. View abstract.

Yue, J. Yang, M. Yi, S. Dong, B. Li, W. Yang, Z. Lu, J. Zhang, R. and Yong, J. Chondroitin sulfate and/or glucosamine hydrochloride for Kashin-Beck disease: a cluster-randomized, placebo-controlled study. Osteoarthritis. Cartilage. 2012;20(7):622-629. View abstract.

Adams ME. Hype about glucosamine. Lancet 1999;354:353-4. View abstract.

Adebowale AO, Cox DS, Liang Z, et al. Analysis of glucosamine and chondroitin sulfate content in marketed products and the Caco-2 permeability of chondroitin sulfate raw materials. JANA 2000;3:37-44.

Almada A, Harvey P, Platt K. Effects of chronic oral glucosamine sulfate on fasting insulin resistance index (FIRI) in non-diabetic individuals. FASEB J 2000;14:A750.

Audimoolam VK, Bhandari S. Acute interstitial nephritis induced by glucosamine. Nephrol Dial Transplant 2006;21(7):2031. View abstract.

Balkan B, Dunning BE. Glucosamine inhibits glucokinase in vitro and produces a glucose-specific impairment of in vivo insulin secretion in rats. Diabetes 1994;43:1173-9. View abstract.

Baron AD, Zhu JS, Zhu JH, et al. Glucosamine induces insulin resistance in vivo by affecting GLUT 4 translocation in skeletal muscle. Implications for glucose toxicity. J Clin Invest 1995;96(6):2792-801. View abstract.

Braham R, Dawson B, Goodman C. The effect of glucosamine supplementation on people experiencing regular knee pain. Br J Sports Med 2003;37:45-9. View abstract.

Bush TM, Rayburn KS, Holloway SW, et al. Adverse interactions between herbal and dietary substances and prescription medications: a clinical survey. Altern Ther Health Med 2007;13:30-5. View abstract.

Cerda C, Bruguera M, Pares A. Hepatotoxicity associated with glucosamine and chondroitin sulfate in patients with chronic liver disease. World J Gastroenterol 2013;19(32):5381-4. View abstract.

Chesnokov V, Sun C, Itakura K. Glucosamine suppresses proliferation of human prostate carcinoma DU145 cells through inhibition of STAT3 signaling. Cancer Cell Int 2009;9:25. View abstract.

Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 2006;354:795-808. View abstract.

Danao-Camara T. Potential side effects of treatment with glucosamine and chondroitin. Arthritis Rheum 2000;43:2853. View abstract.

Das A Jr, Hammad TA. Efficacy of a combination of FCHG49 glucosamine hydrochloride, TRH122 low molecular weight sodium chondroitin sulfate and manganese ascorbate in the management of knee osteoarthritis. Osteoarthritis Cartilage 2000;8:343-50. View abstract.

Does glucosamine increase serum lipid levels and blood pressure? Pharmacist's Letter/Prescriber's Letter 2001;17(11):171115.

Du XL, Edelstein D, Dimmeler S, et al. Hyperglycemia inhibits endothelial nitric oxide synthase activity by post-translational modification at the Akt site. J Clin Invest 2001;108:1341-8. View abstract.

Eggertsen R, Andreasson A, Andren L. No changes of cholesterol levels with a commercially available glucosamine product in patients treated with lipid lowering drugs: a controlled, randomised, open cross-over trial. BMCPharmacol Toxicol 2012;13(1):10. View abstract.

Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press, 2002. Available at: www. nap. edu/books/0309072794/html/.

Fox BA, Stephens MM. Glucosamine hydrochloride for the treatment of osteoarthritis symptoms. Clin Interv Aging 2007;2(4):599-604. View abstract.

Giaccari A, Morviducci L, Zorretta D, et al. In vivo effects of glucosamine on insulin secretion and insulin sensitivity in the rat: possible relevance to the maladaptive responses to chronic hyperglycaemia. Diabetologia 1995;38:518-24. View abstract.

Glucosamine for knee osteoarthritis--what's new? Drug Ther Bull. 2008: 46(11):81-4. View abstract.

Gray HC, Hutcheson PS, Slavin RG. Is glucosamine safe in patients with seafood allergy (letter)? J Allergy Clin Immunol 2004;114:459-60. View abstract.

Guillaume MP, Peretz A. Possible association between glucosamine treatment and renal toxicity: comment on the letter by Danao-Camara. Arthritis Rheum 2001;44:2943-4. View abstract.

Hochberg MC, Martel-Pelletier J, Monfort J, Moller I, Castillo JR, Arden N, Berenbaum F, Blanco FJ, Conaghan PG, Domenech G, Henrotin Y, Pap T, Richette P, Sawitzke A, du Souich P, Pelletier JP; on behalf of the MOVES Investigation Group. Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a multicentre, randomised, double-blind, non-inferiority trial versus celecoxib. Ann Rheum Dis 2016;75(1):37-44. View abstract.

Hoffer LJ, Kaplan LN, Hamadeh MJ, et al. Sulfate could mediate the therapeutic effect of glucosamine sulfate. Metabolism 2001;50:767-70. View abstract.

Holmang A, Nilsson C, Niklasson M, et al. Induction of insulin resistance by glucosamine reduces blood flow but not interstitial levels of either glucose or insulin. Diabetes 1999;48:106-11. View abstract.

Hong H, Park YK, Choi MS, Ryu NH, Song DK, Suh SI, Nam KY, Park GY, Jang BC. Differential down-regulation of COX-2 and MMP-13 in human skin fibroblasts by glucosamine-hydrochloride. J Dermatol Sci 2009;56(1):43-50. View abstract.

Houpt JB, McMillan R, Wein C, Paget-Dellio SD. Effect of glucosamine hydrochloride in the treatment of pain of osteoarthritis of the knee. J Rheumatol 1999;26:2423-30. View abstract.

Hwang MS, Baek WK. Glucosamine induces autophagic cell death through the stimulation of ER stress in human glioma cancer cells. Biochem Biophys Res Commun 2010;399(1):111-6. View abstract.

Ilic MZ, Martinac B, Samiric T, Handley CJ. Effects of glucosamine on proteoglycan loss by tendon, ligament and joint capsule explant cultures. Osteoarthritis Cartilage 2008;16(12):1501-8. View abstract.

Imagawa K, de Andres MC, Hashimoto K, Pitt D, Itoi E, Goldring MB, Roach HI, Oreffo RO. The epigenetic effect of glucosamine and a nuclear factor-kappa B (NF-kB) inhibitor on primary human chondrocytes--implications for osteoarthritis. Biochem Biophys Res Commun 2011;405(3):362-7. View abstract.

Jackson, C. G. Plaas, A. H. Sandy, J. D. Hua, C. Kim-Rolands, S. Barnhill, J. G. Harris, C. L. and Clegg, D. O. The human pharmacokinetics of oral ingestion of glucosamine and chondroitin sulfate taken separately or in combination. Osteoarthritis Cartilage 2010;18(3):297-302. View abstract.

Ju Y, Hua J, Sakamoto K, Ogawa H, Nagaoka I. Glucosamine, a naturally occurring amino monosaccharide modulates LL-37-induced endothelial cell activation. Int J Mol Med 2008;22(5):657-62. View abstract.

Ju Y, Hua J, Sakamoto K, Ogawa H, Nagaoka I. Modulation of TNF-alpha-induced endothelial cell activation by glucosamine, a naturally occurring amino monosaccharide. Int J Mol Med 2008;22(6):809-15. View abstract.

Kang ES, Han D, Park J, Kwak TK, Oh MA, Lee SA, Choi S, Park ZY, Kim Y, Lee JW. O-GlcNAc modulation at Akt1 Ser473 correlates with apoptosis of murine pancreatic beta cells. Exp Cell Res 2008;314(11-12):2238-48. View abstract.

Kawasaki T, Kurosawa H, Ikeda H, et al. Additive effects of glucosamine or risedronate for the treatment of osteoarthritis of the knee combined with home exercise: a prospective randomized 18-month trial. J Bone Miner Metab 2008;26(3):279-87. View abstract.

Kim DS, Park KS, Jeong KC, Lee BI, Lee CH, Kim SY. Glucosamine is an effective chemo-sensitizer via transglutaminase 2 inhibition. Cancer Lett 2009;273(2):243-9. View abstract.

Kim YB, Zhu JS, Zierath JR, et al. Glucosamine infusion in rats rapidly impairs insulin stimulation of phosphoinositide 3-kinase but does not alter activation of Akt/protein kinase B in skeletal muscle. Diabetes 1999;48:310-20. View abstract.

Knudsen J, Sokol GH. Potential glucosamine-warfarin interaction resulting in increased international normalized ratio: Case report and review of the literature and MedWatch database. Pharmacotherapy 2008;28:540-8. View abstract.

Kuo M, Zilberfarb V, Gangneux N, Christeff N, Issad T. O-GlcNAc modification of FoxO1 increases its transcriptional activity: a role in the glucotoxicity phenomenon? Biochimie 2008;90(5):679-85. View abstract.

Kuo M, Zilberfarb V, Gangneux N, Christeff N, Issad T. O-glycosylation of FoxO1 increases its transcriptional activity towards the glucose 6-phosphatase gene. FEBS Lett 2008;582(5):829-34. View abstract.

Kwoh CK, Roemer FW, Hannon MJ, Moore CE, Jakicic JM, Guermazi A, Green SM, Evans RW, Boudreau R. Effect of oral glucosamine on joint structure in individuals with chronic knee pain: a randomized, placebo-controlled clinical trial. Arthritis Rheumatol. 2014 Apr;66(4):930-9. View abstract.

Leffler CT, Philippi AF, Leffler SG, et al. Glucosamine, chondroitin, and manganese ascorbate for degenerative joint disease of the knee or low back: a randomized, double-blind, placebo-controlled pilot study. Mil Med 1999;164:85-91. View abstract.

Levin RM, Krieger NN, and Winzler RJ. Glucosamine and acetylglucosamine tolerance in man. J Lab Clin Med 1961;58(6):927-932.

Liang CM, Tai MC, Chang YH, Chen YH, Chen CL, Chien MW, Chen JT. Glucosamine inhibits epidermal growth factor-induced proliferation and cell-cycle progression in retinal pigment epithelial cells. Mol Vis 2010;16:2559-71. View abstract.

Lin YC, Liang YC, Sheu MT, Lin YC, Hsieh MS, Chen TF, Chen CH. Chondroprotective effects of glucosamine involving the p38 MAPK and Akt signaling pathways. Rheumatol Int 2008;28(10):1009-16. View abstract.

Liu W, Liu G, Pei F, et al. Kashin-Beck disease in Sichuan, China: report of a pilot open therapeutic trial. J Clin Rheumatol 2012;18(1):8-14. View abstract.

McAlindon T. Why are clinical trials of glucosamine no longer uniformly positive? Rheum Dis Clin North Am 2003;29:789-801. View abstract.

Messier SP, Mihalko S, Loeser RF, et al. Glucosamine/chondroitin combined with exercise for the treatment of knee osteoarthritis: a preliminary study. Osteoarthritis Cartilage 2007;15:1256-66. View abstract.

Meulyzer M, Vachon P, Beaudry F, Vinardell T, Richard H, Beauchamp G, Laverty S. Comparison of pharmacokinetics of glucosamine and synovial fluid levels following administration of glucosamine sulphate or glucosamine hydrochloride. Osteoarthritis Cartilage 2008;16(9):973-9. View abstract.

Monauni T, Zenti MG, Cretti A, et al. Effects of glucosamine infusion on insulin secretion and insulin action in humans. Diabetes 2000;49:926-35. View abstract.

Muniyappa R, Karne RJ, Hall G, et al. Oral glucosamine for 6 weeks at standard doses does not cause or worsen insulin resistance or endothelial dysfunction in lean or obese subjects. Diabetes 2006;55:3142-50. View abstract.

Naito K, Watari T, Furuhata A, Yomogida S, Sakamoto K, Kurosawa H, Kaneko K, Nagaoka I. Evaluation of the effect of glucosamine on an experimental rat osteoarthritis model. Life Sci 2010;86(13-14):538-43. View abstract.

Nakamura H, Masuko K, Yudoh K, et al. Effects of glucosamine administration on patients with rheumatoid arthritis. Rheumatol Int 2007;27:213-8. View abstract.

Nandhakumar J. Efficacy, tolerability, and safety of a multicomponent antiinflammatory with glucosamine hydrochloride vs glucosamine sulfate vs an NSAID in the treatment of knee osteoarthritis--a randomized, prospective, double-blind, comparative study. Integr Med Clin J 2009;8(3):32-38.

Nelson BA, Robinson KA, Buse MG. High glucose and glucosamine induce insulin resistance via different mechanisms in 3T3-L1 adipocytes. Diabetes 2000;49(6):981-91. View abstract.

Nowak A, Szczesniak L, Rychlewski T, et al. Glucosamine levels in people with ischaemic heart disease with and without type II diabetes. Pol Arch Med Wewn 1998;100:419-25. View abstract.

Olszewski AJ, Szostak WB, McCully KS. Plasma glucosamine and galactosamine in ischemic heart disease. Atherosclerosis 1990;82:75-83. View abstract.

Ossendza RA, Grandval P, Chinoune F, Rocher F, Chapel F, Bernardini D. [Acute cholestatic hepatitis due to glucosamine forte]. Gastroenterol Clin Biol. 2007 Apr;31(4):449-50. View abstract.

Park JY, Park JW, Suh SI, Baek WK. D-glucosamine down-regulates HIF-1alpha through inhibition of protein translation in DU145 prostate cancer cells. Biochem Biophys Res Commun 2009;382(1):96-101. View abstract.

Pavelka K, Gatterova J, Olejarova M, et al. Glucosamine sulfate use and delay of progression of knee osteoarthritis: A 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med 2002;162:2113-23. View abstract.

Pham T, Cornea A, Blick KE, et al. Oral glucosamine in doses used to treat osteoarthritis worsens insulin resistance. Am J Med Sci 2007;333:333-9. View abstract.

Pouwels MJ, Jacobs JR, Span PN, et al. Short-term glucosamine infusion does not affect insulin sensitivity in humans. J Clin Endocrinol Metab 2001;86:2099-103. View abstract.

Provenza JR, Shinjo SK, Silva JM, Peron CR, Rocha FA. Combined glucosamine and chondroitin sulfate, once or three times daily, provides clinically relevant analgesia in knee osteoarthritis. Clin Rheumatol 2015;34:1455-62.View abstract.

Qiu GX, Weng XS, Zhang K, et al. [A multi-central, randomized, controlled clinical trial of glucosamine hydrochloride/sulfate in the treatment of knee osteoarthritis]. Zhonghua Yi Xue Za Zhi 2005;85:3067-70. View abstract.

Qiu W, Su Q, Rutledge AC, Zhang J, Adeli K. Glucosamine-induced endoplasmic reticulum stress attenuates apolipoprotein B100 synthesis via PERK signaling. J Lipid Res 2009;50(9):1814-23. View abstract.

Raciti GA, Iadicicco C, Ulianich L, Vind BF, Gaster M, Andreozzi F, Longo M, Teperino R, Ungaro P, Di Jeso B, Formisano P, Beguinot F, Miele C. Glucosamine-induced endoplasmic reticulum stress affects GLUT4 expression via activating transcription factor 6 in rat and human skeletal muscle cells. Diabetologia 2010;53(5):955-65. View abstract.

Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine sulfate on osteoarthritis progression: a randomised, placebo-controlled trial. Lancet 2001;357:251-6. View abstract.

Rossetti L, Hawkins M, Chen W, et al. In vivo glucosamine infusion induces insulin resistance in normoglycemic but not in hyperglycemic conscious rats. J Clin Invest 1995;96:132-40. View abstract.

Rozenfeld V, Crain JL, Callahan AK. Possible augmentation of warfarin effect by glucosamine-chondroitin. Am J Health Syst Pharm 2004;61:306-307. View abstract.

Sakai S, Sugawara T, Kishi T, Yanagimoto K, Hirata T. Effect of glucosamine and related compounds on the degranulation of mast cells and ear swelling induced by dinitrofluorobenzene in mice. Life Sci 2010;86(9-10):337-43. View abstract.

Satia JA, Littman A, Slatore CG, Galanko JA, White E. Associations of herbal and specialty supplements with lung and colorectal cancer risk in the VITamins and Lifestyle study. Cancer Epidemiol Biomarkers Prev 2009;18(5):1419-28. View abstract.

Scotto d'Abusco A, Politi L, Giordano C, Scandurra R. A peptidyl-glucosamine derivative affects IKKalpha kinase activity in human chondrocytes. Arthritis Res Ther 2010;12(1):R18. View abstract.

Scroggie DA, Albright A, Harris MD. The effect of glucosamine-chondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized clinical trial. Arch Intern Med 2003;163:1587-90. View abstract.

Shankar RR, Zhu JS, Baron AD. Glucosamine infusion in rats mimics the beta-cell dysfunction of non-insulin-dependent diabetes mellitus. Metabolism 1998;47:573-7. View abstract.

Shankland WE. The effects of glucosamine and chondroitin sulfate on osteoarthritis of the TMJ: a preliminary report of 50 patients. Cranio 1998;16(4):230-5. View abstract.

Shikhman AR, Brinson DC, Valbracht J, Lotz MK. Differential metabolic effects of glucosamine and N-acetylglucosamine in human articular chondrocytes. Osteoarthritis Cartilage 2009;17(8):1022-8. View abstract.

Stumpf JL, Lin SW. Effect of glucosamine on glucose control. Ann Pharmacother 2006;40:694-8. View abstract.

Tallia AF, Cardone DA. Asthma exacerbation associated with glucosamine-chondroitin supplement. J Am Board Fam Pract 2002;15:481-4. View abstract.

Tannis AJ, Barban J, Conquer JA. Effect of glucosamine supplementation on fasting and non-fasting plasma glucose and serum insulin concentrations in healthy individuals. Osteoarthritis Cartilage 2004;12:506-11. View abstract.

Tannock LR, Kirk EA, King VL, et al. Glucosamine supplementation accelerates early but not late atherosclerosis in LDL receptor-deficient mice. J Nutr 2006;136:2856-61. View abstract.

Toegel S, Wu SQ, Piana C, Unger FM, Wirth M, Goldring MB, Gabor F, Viernstein H. Comparison between chondroprotective effects of glucosamine, curcumin, and diacerein in IL-1beta-stimulated C-28/I2 chondrocytes. Osteoarthritis Cartilage 2008;16(10):1205-12. View abstract.

Tsai CY, Lee TS, Kou YR, Wu YL. Glucosamine inhibits IL-1beta-mediated IL-8 production in prostate cancer cells by MAPK attenuation. J Cell Biochem 2009;108(2):489-98. View abstract.

Uitterlinden EJ, Koevoet JL, Verkoelen CF, Bierma-Zeinstra SM, Jahr H, Weinans H, Verhaar JA, van Osch GJ. Glucosamine increases hyaluronic acid production in human osteoarthritic synovium explants. BMC Musculoskelet Disord 2008;9:120. View abstract.

Weiden S and Wood IJ. The fate of glucosamine hydrochloride injected intravenously in man. J Clin Pathol 1958;11:343-349.

Weimann G, Lubenow N, Selleng K, et al. Glucosamine sulfate does not crossreact with the antibodies of patients with heparin-induced thrombocytopenia. Eur J Haematol 2001;66:195-9. View abstract.

Wu D, Huang Y, Gu Y, Fan W. Efficacies of different preparations of glucosamine for the treatment of osteoarthritis: a meta-analysis of randomised, double-blind, placebo-controlled trials. Int J Clin Pract 2013;67(6):585-94. View abstract.

Wu H, Liu M, Wang S, Zhao H, Yao W, Feng W, Yan M, Tang Y, Wei M. Comparative fasting bioavailability and pharmacokinetic properties of 2 formulations of glucosamine hydrochloride in healthy Chinese adult male volunteers. Arzneimittelforschung. 2012 Aug;62(8):367-71. View abstract.

Wu YL, Kou YR, Ou HL, Chien HY, Chuang KH, Liu HH, Lee TS, Tsai CY, Lu ML. Glucosamine regulation of LPS-mediated inflammation in human bronchial epithelial cells. Eur J Pharmacol 2010;635(1-3):219-26. View abstract.

Yomogida S, Hua J, Sakamoto K, Nagaoka I. Glucosamine suppresses interleukin-8 production and ICAM-1 expression by TNF-alpha-stimulated human colonic epithelial HT-29 cells. Int J Mol Med 2008;22(2):205-11. View abstract.

Yomogida S, Kojima Y, Tsutsumi-Ishii Y, Hua J, Sakamoto K, Nagaoka I. Glucosamine, a naturally occurring amino monosaccharide, suppresses dextran sulfate sodium-induced colitis in rats. Int J Mol Med 2008;22(3):317-23. View abstract.

Yu JG, Boies SM, Olefsky JM. The effect of oral glucosamine sulfate on insulin sensitivity in human subjects. Diabetes Care 2003;26:1941-2. View abstract.

Yue QY, Strandell J, Myrberg O. Concomitant use of glucosamine may potential the effect of warfarin. The Uppsala Monitoring Centre. Available at: www. who-umc. org/graphics/9722.pdf (Accessed 28 April 2008).

Yun J, Tomida A, Nagata K, Tsuruo T. Glucose-regulated stresses confer resistance to VP-16 in human cancer cells through a decreased expression of DNA topoisomerase II. Oncol Res 1995;7:583-90. View abstract.

Glucosamine Hydrochloride Uses, Side Effects, Interactions And Warnings, Glucosamil

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GLUCOSAMINE HYDROCHLORIDE

Dudics, V. Kunstar, A. Kovacs, J. Lakatos, T. Geher, P. Gomor, B. Monostori, E. and Uher, F. Chondrogenic potential of mesenchymal stem cells from patients with rheumatoid arthritis and osteoarthritis: measurements in a microculture system. Cells Tissues. Organs 2009;189(5):307-316. View abstract.

Kanzaki, N. Saito, K. Maeda, A. Kitagawa, Y. Kiso, Y. Watanabe, K. Tomonaga, A. Nagaoka, I. and Yamaguchi, H. Effect of a dietary supplement containing glucosamine hydrochloride, chondroitin sulfate and quercetin glycosides on symptomatic knee osteoarthritis: a randomized, double-blind, placebo-controlled study. J. Sci. Food Agric. 3-15-2012;92(4):862-869. View abstract.

Sawitzke, A. D. Shi, H. Finco, M. F. Dunlop, D. D. Harris, C. L. Singer, N. G. Bradley, J. D. Silver, D. Jackson, C. G. Lane, N. E. Oddis, C. V. Wolfe, F. Lisse, J. Furst, D. E. Bingham, C. O. Reda, D. J. Moskowitz, R. W. Williams, H. J. and Clegg, D. O. Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT. Ann. Rheum. Dis. 2010;69(8):1459-1464. View abstract.

Yue, J. Yang, M. Yi, S. Dong, B. Li, W. Yang, Z. Lu, J. Zhang, R. and Yong, J. Chondroitin sulfate and/or glucosamine hydrochloride for Kashin-Beck disease: a cluster-randomized, placebo-controlled study. Osteoarthritis. Cartilage. 2012;20(7):622-629. View abstract.

Adams ME. Hype about glucosamine. Lancet 1999;354:353-4. View abstract.

Adebowale AO, Cox DS, Liang Z, et al. Analysis of glucosamine and chondroitin sulfate content in marketed products and the Caco-2 permeability of chondroitin sulfate raw materials. JANA 2000;3:37-44.

Almada A, Harvey P, Platt K. Effects of chronic oral glucosamine sulfate on fasting insulin resistance index (FIRI) in non-diabetic individuals. FASEB J 2000;14:A750.

Audimoolam VK, Bhandari S. Acute interstitial nephritis induced by glucosamine. Nephrol Dial Transplant 2006;21(7):2031. View abstract.

Balkan B, Dunning BE. Glucosamine inhibits glucokinase in vitro and produces a glucose-specific impairment of in vivo insulin secretion in rats. Diabetes 1994;43:1173-9. View abstract.

Baron AD, Zhu JS, Zhu JH, et al. Glucosamine induces insulin resistance in vivo by affecting GLUT 4 translocation in skeletal muscle. Implications for glucose toxicity. J Clin Invest 1995;96(6):2792-801. View abstract.

Braham R, Dawson B, Goodman C. The effect of glucosamine supplementation on people experiencing regular knee pain. Br J Sports Med 2003;37:45-9. View abstract.

Bush TM, Rayburn KS, Holloway SW, et al. Adverse interactions between herbal and dietary substances and prescription medications: a clinical survey. Altern Ther Health Med 2007;13:30-5. View abstract.

Cerda C, Bruguera M, Pares A. Hepatotoxicity associated with glucosamine and chondroitin sulfate in patients with chronic liver disease. World J Gastroenterol 2013;19(32):5381-4. View abstract.

Chesnokov V, Sun C, Itakura K. Glucosamine suppresses proliferation of human prostate carcinoma DU145 cells through inhibition of STAT3 signaling. Cancer Cell Int 2009;9:25. View abstract.

Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 2006;354:795-808. View abstract.

Danao-Camara T. Potential side effects of treatment with glucosamine and chondroitin. Arthritis Rheum 2000;43:2853. View abstract.

Das A Jr, Hammad TA. Efficacy of a combination of FCHG49 glucosamine hydrochloride, TRH122 low molecular weight sodium chondroitin sulfate and manganese ascorbate in the management of knee osteoarthritis. Osteoarthritis Cartilage 2000;8:343-50. View abstract.

Does glucosamine increase serum lipid levels and blood pressure? Pharmacist's Letter/Prescriber's Letter 2001;17(11):171115.

Du XL, Edelstein D, Dimmeler S, et al. Hyperglycemia inhibits endothelial nitric oxide synthase activity by post-translational modification at the Akt site. J Clin Invest 2001;108:1341-8. View abstract.

Eggertsen R, Andreasson A, Andren L. No changes of cholesterol levels with a commercially available glucosamine product in patients treated with lipid lowering drugs: a controlled, randomised, open cross-over trial. BMCPharmacol Toxicol 2012;13(1):10. View abstract.

Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press, 2002. Available at: www. nap. edu/books/0309072794/html/.

Fox BA, Stephens MM. Glucosamine hydrochloride for the treatment of osteoarthritis symptoms. Clin Interv Aging 2007;2(4):599-604. View abstract.

Giaccari A, Morviducci L, Zorretta D, et al. In vivo effects of glucosamine on insulin secretion and insulin sensitivity in the rat: possible relevance to the maladaptive responses to chronic hyperglycaemia. Diabetologia 1995;38:518-24. View abstract.

Glucosamine for knee osteoarthritis--what's new? Drug Ther Bull. 2008: 46(11):81-4. View abstract.

Gray HC, Hutcheson PS, Slavin RG. Is glucosamine safe in patients with seafood allergy (letter)? J Allergy Clin Immunol 2004;114:459-60. View abstract.

Guillaume MP, Peretz A. Possible association between glucosamine treatment and renal toxicity: comment on the letter by Danao-Camara. Arthritis Rheum 2001;44:2943-4. View abstract.

Hochberg MC, Martel-Pelletier J, Monfort J, Moller I, Castillo JR, Arden N, Berenbaum F, Blanco FJ, Conaghan PG, Domenech G, Henrotin Y, Pap T, Richette P, Sawitzke A, du Souich P, Pelletier JP; on behalf of the MOVES Investigation Group. Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a multicentre, randomised, double-blind, non-inferiority trial versus celecoxib. Ann Rheum Dis 2016;75(1):37-44. View abstract.

Hoffer LJ, Kaplan LN, Hamadeh MJ, et al. Sulfate could mediate the therapeutic effect of glucosamine sulfate. Metabolism 2001;50:767-70. View abstract.

Holmang A, Nilsson C, Niklasson M, et al. Induction of insulin resistance by glucosamine reduces blood flow but not interstitial levels of either glucose or insulin. Diabetes 1999;48:106-11. View abstract.

Hong H, Park YK, Choi MS, Ryu NH, Song DK, Suh SI, Nam KY, Park GY, Jang BC. Differential down-regulation of COX-2 and MMP-13 in human skin fibroblasts by glucosamine-hydrochloride. J Dermatol Sci 2009;56(1):43-50. View abstract.

Houpt JB, McMillan R, Wein C, Paget-Dellio SD. Effect of glucosamine hydrochloride in the treatment of pain of osteoarthritis of the knee. J Rheumatol 1999;26:2423-30. View abstract.

Hwang MS, Baek WK. Glucosamine induces autophagic cell death through the stimulation of ER stress in human glioma cancer cells. Biochem Biophys Res Commun 2010;399(1):111-6. View abstract.

Ilic MZ, Martinac B, Samiric T, Handley CJ. Effects of glucosamine on proteoglycan loss by tendon, ligament and joint capsule explant cultures. Osteoarthritis Cartilage 2008;16(12):1501-8. View abstract.

Imagawa K, de Andres MC, Hashimoto K, Pitt D, Itoi E, Goldring MB, Roach HI, Oreffo RO. The epigenetic effect of glucosamine and a nuclear factor-kappa B (NF-kB) inhibitor on primary human chondrocytes--implications for osteoarthritis. Biochem Biophys Res Commun 2011;405(3):362-7. View abstract.

Jackson, C. G. Plaas, A. H. Sandy, J. D. Hua, C. Kim-Rolands, S. Barnhill, J. G. Harris, C. L. and Clegg, D. O. The human pharmacokinetics of oral ingestion of glucosamine and chondroitin sulfate taken separately or in combination. Osteoarthritis Cartilage 2010;18(3):297-302. View abstract.

Ju Y, Hua J, Sakamoto K, Ogawa H, Nagaoka I. Glucosamine, a naturally occurring amino monosaccharide modulates LL-37-induced endothelial cell activation. Int J Mol Med 2008;22(5):657-62. View abstract.

Ju Y, Hua J, Sakamoto K, Ogawa H, Nagaoka I. Modulation of TNF-alpha-induced endothelial cell activation by glucosamine, a naturally occurring amino monosaccharide. Int J Mol Med 2008;22(6):809-15. View abstract.

Kang ES, Han D, Park J, Kwak TK, Oh MA, Lee SA, Choi S, Park ZY, Kim Y, Lee JW. O-GlcNAc modulation at Akt1 Ser473 correlates with apoptosis of murine pancreatic beta cells. Exp Cell Res 2008;314(11-12):2238-48. View abstract.

Kawasaki T, Kurosawa H, Ikeda H, et al. Additive effects of glucosamine or risedronate for the treatment of osteoarthritis of the knee combined with home exercise: a prospective randomized 18-month trial. J Bone Miner Metab 2008;26(3):279-87. View abstract.

Kim DS, Park KS, Jeong KC, Lee BI, Lee CH, Kim SY. Glucosamine is an effective chemo-sensitizer via transglutaminase 2 inhibition. Cancer Lett 2009;273(2):243-9. View abstract.

Kim YB, Zhu JS, Zierath JR, et al. Glucosamine infusion in rats rapidly impairs insulin stimulation of phosphoinositide 3-kinase but does not alter activation of Akt/protein kinase B in skeletal muscle. Diabetes 1999;48:310-20. View abstract.

Knudsen J, Sokol GH. Potential glucosamine-warfarin interaction resulting in increased international normalized ratio: Case report and review of the literature and MedWatch database. Pharmacotherapy 2008;28:540-8. View abstract.

Kuo M, Zilberfarb V, Gangneux N, Christeff N, Issad T. O-GlcNAc modification of FoxO1 increases its transcriptional activity: a role in the glucotoxicity phenomenon? Biochimie 2008;90(5):679-85. View abstract.

Kuo M, Zilberfarb V, Gangneux N, Christeff N, Issad T. O-glycosylation of FoxO1 increases its transcriptional activity towards the glucose 6-phosphatase gene. FEBS Lett 2008;582(5):829-34. View abstract.

Kwoh CK, Roemer FW, Hannon MJ, Moore CE, Jakicic JM, Guermazi A, Green SM, Evans RW, Boudreau R. Effect of oral glucosamine on joint structure in individuals with chronic knee pain: a randomized, placebo-controlled clinical trial. Arthritis Rheumatol. 2014 Apr;66(4):930-9. View abstract.

Leffler CT, Philippi AF, Leffler SG, et al. Glucosamine, chondroitin, and manganese ascorbate for degenerative joint disease of the knee or low back: a randomized, double-blind, placebo-controlled pilot study. Mil Med 1999;164:85-91. View abstract.

Levin RM, Krieger NN, and Winzler RJ. Glucosamine and acetylglucosamine tolerance in man. J Lab Clin Med 1961;58(6):927-932.

Liang CM, Tai MC, Chang YH, Chen YH, Chen CL, Chien MW, Chen JT. Glucosamine inhibits epidermal growth factor-induced proliferation and cell-cycle progression in retinal pigment epithelial cells. Mol Vis 2010;16:2559-71. View abstract.

Lin YC, Liang YC, Sheu MT, Lin YC, Hsieh MS, Chen TF, Chen CH. Chondroprotective effects of glucosamine involving the p38 MAPK and Akt signaling pathways. Rheumatol Int 2008;28(10):1009-16. View abstract.

Liu W, Liu G, Pei F, et al. Kashin-Beck disease in Sichuan, China: report of a pilot open therapeutic trial. J Clin Rheumatol 2012;18(1):8-14. View abstract.

McAlindon T. Why are clinical trials of glucosamine no longer uniformly positive? Rheum Dis Clin North Am 2003;29:789-801. View abstract.

Messier SP, Mihalko S, Loeser RF, et al. Glucosamine/chondroitin combined with exercise for the treatment of knee osteoarthritis: a preliminary study. Osteoarthritis Cartilage 2007;15:1256-66. View abstract.

Meulyzer M, Vachon P, Beaudry F, Vinardell T, Richard H, Beauchamp G, Laverty S. Comparison of pharmacokinetics of glucosamine and synovial fluid levels following administration of glucosamine sulphate or glucosamine hydrochloride. Osteoarthritis Cartilage 2008;16(9):973-9. View abstract.

Monauni T, Zenti MG, Cretti A, et al. Effects of glucosamine infusion on insulin secretion and insulin action in humans. Diabetes 2000;49:926-35. View abstract.

Muniyappa R, Karne RJ, Hall G, et al. Oral glucosamine for 6 weeks at standard doses does not cause or worsen insulin resistance or endothelial dysfunction in lean or obese subjects. Diabetes 2006;55:3142-50. View abstract.

Naito K, Watari T, Furuhata A, Yomogida S, Sakamoto K, Kurosawa H, Kaneko K, Nagaoka I. Evaluation of the effect of glucosamine on an experimental rat osteoarthritis model. Life Sci 2010;86(13-14):538-43. View abstract.

Nakamura H, Masuko K, Yudoh K, et al. Effects of glucosamine administration on patients with rheumatoid arthritis. Rheumatol Int 2007;27:213-8. View abstract.

Nandhakumar J. Efficacy, tolerability, and safety of a multicomponent antiinflammatory with glucosamine hydrochloride vs glucosamine sulfate vs an NSAID in the treatment of knee osteoarthritis--a randomized, prospective, double-blind, comparative study. Integr Med Clin J 2009;8(3):32-38.

Nelson BA, Robinson KA, Buse MG. High glucose and glucosamine induce insulin resistance via different mechanisms in 3T3-L1 adipocytes. Diabetes 2000;49(6):981-91. View abstract.

Nowak A, Szczesniak L, Rychlewski T, et al. Glucosamine levels in people with ischaemic heart disease with and without type II diabetes. Pol Arch Med Wewn 1998;100:419-25. View abstract.

Olszewski AJ, Szostak WB, McCully KS. Plasma glucosamine and galactosamine in ischemic heart disease. Atherosclerosis 1990;82:75-83. View abstract.

Ossendza RA, Grandval P, Chinoune F, Rocher F, Chapel F, Bernardini D. [Acute cholestatic hepatitis due to glucosamine forte]. Gastroenterol Clin Biol. 2007 Apr;31(4):449-50. View abstract.

Park JY, Park JW, Suh SI, Baek WK. D-glucosamine down-regulates HIF-1alpha through inhibition of protein translation in DU145 prostate cancer cells. Biochem Biophys Res Commun 2009;382(1):96-101. View abstract.

Pavelka K, Gatterova J, Olejarova M, et al. Glucosamine sulfate use and delay of progression of knee osteoarthritis: A 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med 2002;162:2113-23. View abstract.

Pham T, Cornea A, Blick KE, et al. Oral glucosamine in doses used to treat osteoarthritis worsens insulin resistance. Am J Med Sci 2007;333:333-9. View abstract.

Pouwels MJ, Jacobs JR, Span PN, et al. Short-term glucosamine infusion does not affect insulin sensitivity in humans. J Clin Endocrinol Metab 2001;86:2099-103. View abstract.

Provenza JR, Shinjo SK, Silva JM, Peron CR, Rocha FA. Combined glucosamine and chondroitin sulfate, once or three times daily, provides clinically relevant analgesia in knee osteoarthritis. Clin Rheumatol 2015;34:1455-62.View abstract.

Qiu GX, Weng XS, Zhang K, et al. [A multi-central, randomized, controlled clinical trial of glucosamine hydrochloride/sulfate in the treatment of knee osteoarthritis]. Zhonghua Yi Xue Za Zhi 2005;85:3067-70. View abstract.

Qiu W, Su Q, Rutledge AC, Zhang J, Adeli K. Glucosamine-induced endoplasmic reticulum stress attenuates apolipoprotein B100 synthesis via PERK signaling. J Lipid Res 2009;50(9):1814-23. View abstract.

Raciti GA, Iadicicco C, Ulianich L, Vind BF, Gaster M, Andreozzi F, Longo M, Teperino R, Ungaro P, Di Jeso B, Formisano P, Beguinot F, Miele C. Glucosamine-induced endoplasmic reticulum stress affects GLUT4 expression via activating transcription factor 6 in rat and human skeletal muscle cells. Diabetologia 2010;53(5):955-65. View abstract.

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Migraine Headache Practice Essentials, Background, Pathophysiology, Migr‰Nerton

Migraine Headache

Practice Essentials

Migraine is a complex disorder characterized by recurrent episodes of headache, most often unilateral and in some cases associated with visual or sensory symptoms—collectively known as an aura—that arise most often before the head pain but that may occur during or afterward (see the image below). Migraine is most common in women and has a strong genetic component.

Migraine headache. Example of a visual migraine aura as described by a person who experiences migraines. This patient reported that these visual auras preceded her headache by 20-30 minutes.

Signs and symptoms

Typical symptoms of migraine include the following:

Throbbing or pulsatile headache, with moderate to severe pain that intensifies with movement or physical activity

Unilateral and localized pain in the frontotemporal and ocular area, but the pain may be felt anywhere around the head or neck

Pain builds up over a period of 1-2 hours, progressing posteriorly and becoming diffuse

Headache lasts 4-72 hours

Nausea (80%) and vomiting (50%), including anorexia and food intolerance, and light-headedness

Sensitivity to light and sound

Features of migraine aura are as follows:

May precede or accompany the headache phase or may occur in isolation

Usually develops over 5-20 minutes and lasts less than 60 minutes

Most commonly visual but can be sensory, motor, or any combination of these

Visual symptoms may be positive or negative

The most common positive visual phenomenon is the scintillating scotoma, an arc or band of absent vision with a shimmering or glittering zigzag border

Physical findings during a migraine headache may include the following:

Cranial/cervical muscle tenderness

Horner syndrome (ie, relative miosis with 1-2 mm of ptosis on the same side as the headache)

Tachycardia or bradycardia

Hypertension or hypotension

Hemisensory or hemiparetic neurologic deficits (ie, complicated migraine)

Adie-type pupil (ie, poor light reactivity, with near dissociation from light)

Diagnosis

The diagnosis of migraine is based on patient history. International Headache Society diagnostic criteria are that patients must have had at least 5 headache attacks that lasted 4-72 hours (untreated or unsuccessfully treated) and that the headache must have had at least 2 of the following characteristics [1] :

Moderate or severe pain intensity

Aggravation by or causing avoidance of routine physical activity (eg, walking or climbing stairs)

In addition, during the headache the patient must have had at least 1 of the following:

Nausea and/or vomiting

Photophobia and phonophobia

Finally, these features must not have been attributable to another disorder. Classification of migraine is as follows:

Migraine without aura (formerly, common migraine)

Probable migraine without aura

Migraine with aura (formerly, classic migraine)

Probable migraine with aura

Chronic migraine associated with analgesic overuse

Childhood periodic syndromes that may not be precursors to or associated with migraine

Complications of migraine

Migrainous disorder not fulfilling above criteria

Migraine variants include the following:

Childhood periodic syndromes

Late-life migrainous accompaniments

A migraine variant may be suggested by focal neurologic findings, such as the following, that occur with the headache and persist temporarily after the pain resolves:

Unilateral paralysis or weakness - Hemiplegic migraine

Aphasia, syncope, and balance problems - Basilar-type migraine

Third nerve palsy with ocular muscle paralysis and ptosis, including or sparing the pupillary response - Ophthalmoplegic migraine

Testing and imaging studies

Selection of laboratory and/or imaging studies to rule out conditions other than migraine headache is determined by the individual presentation (eg, erythrocyte sedimentation rate and C-reactive protein levels may be appropriate to exclude temporal/giant cell arteritis). Neuroimaging is not necessary in patients with a history of recurrent migraine headaches and a normal neurologic examination.

The American Headache Society released a list of 5 commonly performed tests or procedures that are not always necessary in the treatment of migraine and headache, as part of the American Board of Internal Medicine (ABIM) Foundation's Choosing Wisely campaign. The recommendations include [2, 3] :

Don't perform neuroimaging studies in patients with stable headaches that meet criteria for migraine.

Don't perform computed tomography imaging for headache when magnetic resonance imaging is available, except in emergency settings.

Don't recommend surgical deactivation of migraine trigger points outside of a clinical trial.

Don't prescribe opioid or butalbital-containing medications as first-line treatment for recurrent headache disorders.

Don't recommend prolonged or frequent use of over-the-counter pain medications for headache.

See Workup for more detail.

Management

Pharmacologic agents used for the treatment of migraine can be classified as abortive (ie, for alleviating the acute phase) or prophylactic (ie, preventive).

Acute treatment aims to reverse, or at least stop the progression of, a headache. It is most effective when given within 15 minutes of pain onset and when pain is mild. [4]

Abortive medications include the following:

Selective serotonin receptor (5-hydroxytryptamine–1, or 5-HT1) agonists (triptans)

Ergot alkaloids (eg, ergotamine, dihydroergotamine [DHE])

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Background

Migraine headache is a complex, recurrent headache disorder that is one of the most common complaints in medicine. In the United States, more than 30 million people have 1 or more migraine headaches per year. Approximately 75% of all persons who experience migraines are women (see Epidemiology).

The term migraine is derived from the Greek word hemikrania. This term was corrupted into low Latin as hemigranea, the French translation of which was migraine.

Causes of migraine

Migraine was previously considered to be a vascular phenomenon that resulted from intracranial vasoconstriction followed by rebound vasodilation. Currently, however, the neurovascular theory describes migraine as primarily a neurogenic process with secondary changes in cerebral perfusion associated with a sterile neurogenic inflammation (see Pathophysiology).

A genetic component to migraine is indicated by the fact that approximately 70% of patients have a first-degree relative with a history of migraine. In addition, a variety of environmental and behavioral factors may precipitate migraine attacks in persons with a predisposition to migraine (see Etiology).

Migraine characteristics and treatment

Migraine is characterized most often by unilateral head pain that is moderate to severe, throbbing, and aggravated by activity. It may also be associated with various visual or sensory symptoms, which occur most often before the headache component but which may occur during or after the headache; these are collectively known as an aura. Most commonly, the aura consists of visual manifestations, such as scotomas, photophobia, or visual scintillations (eg, bright zigzag lines) (see Presentation).

The head pain may also be associated with weakness. This form of migraine is termed hemiplegic migraine.

In practice, however, migraine headaches may be unilateral or bilateral and may occur with or without an aura. In the current International Headache Society categorization, the headache previously described as classic migraine is now known as migraine with aura, and the headache that was described as common migraine is now termed migraine without aura. Migraines without aura are the most common, accounting for more than 80% of all migraines.

The diagnosis of migraine is clinical in nature, based on criteria established by the International Headache Society. A full neurologic examination should be performed during the first visit, to exclude other disorders; the findings are usually normal in patients with migraine. Neuroimaging is not necessary in a typical case, but other diagnostic investigations may be indicated to guide management.

A screening tool called the ID-CM may be useful in diagnosis. The ID-CM is a 12-item screening tool for chronic migraine that has a sensitivity of 82% and a specificity of 87% compared with semi-structured clinical interviews. [6]

Migraine treatment involves acute (abortive) and preventive (prophylactic) therapy. Patients with frequent attacks usually require both. Measures directed toward reducing migraine triggers are also generally advisable.

Acute treatment aims to eliminate, or at least prevent the progression of, a headache. Preventive treatment, which is given even in the absence of a headache, aims to reduce the frequency and severity of migraine attacks, to make acute attacks more responsive to abortive therapy, and perhaps also to improve the patient's quality of life (see Treatment).

Migraine classification

The second edition of the International Classification of Headache Disorders (ICHD) [7] lists the following types of migraine:

Migraine without aura (formerly, common migraine)

Probable migraine without aura

Migraine with aura (formerly, classic migraine)

Pathophysiology

The mechanisms of migraine remain incompletely understood. However, new technologies have allowed formulation of current concepts that may explain parts of the migraine syndrome.

Vascular theory

In the 1940s and 1950s, the vascular theory was proposed to explain the pathophysiology of migraine headache. Wolff et al believed that ischemia induced by intracranial vasoconstriction is responsible for the aura of migraine and that the subsequent rebound vasodilation and activation of perivascular nociceptive nerves resulted in headache.

This theory was based on the following 3 observations:

Extracranial vessels become distended and pulsatile during a migraine attack

Stimulation of intracranial vessels in an awake person induces headache

Vasoconstrictors (eg, ergots) improve the headache, whereas vasodilators (eg, nitroglycerin) provoke an attack

However, this theory did not explain the prodrome and associated features. Nor did it explain the efficacy of some drugs used to treat migraines that have no effect on blood vessels and the fact that most patients do not have an aura. Moreover, with the advent of newer imaging technologies, researchers found that intracranial blood flow patterns were inconsistent with the vascular theory.

No consistent flow changes have been identified in patients suffering from migraine headache without aura. Regional cerebral blood flow (rCBF) remains normal in the majority of patients. However, bilateral decrease in rCBF, beginning at the occipital cortex and spreading anteriorly, has been reported. More recently, Perciaccante has shown that migraine is characterized by a cardiac autonomic dysfunction. [11]

As a result of these anomalous findings, the vascular theory was supplanted by the neurovascular theory.

Neurovascular theory

The neurovascular theory holds that a complex series of neural and vascular events initiates migraine. [12] According to this theory, migraine is primarily a neurogenic process with secondary changes in cerebral perfusion. [13]

At baseline, a migraineur who is not having any headache has a state of neuronal hyperexcitability in the cerebral cortex, especially in the occipital cortex. [14] This finding has been demonstrated in studies of transcranial magnetic stimulation and with functional magnetic resonance imaging (MRI).

This observation explains the special susceptibility of the migrainous brain to headaches. [15] One can draw a parallel with the patient with epilepsy who similarly has interictal neuronal irritability.

Cortical spreading depression

In 1944, Leao proposed the theory of cortical spreading depression (CSD) to explain the mechanism of migraine with aura. CSD is a well-defined wave of neuronal excitation in the cortical gray matter that spreads from its site of origin at the rate of 2-6 mm/min.

This cellular depolarization causes the primary cortical phenomenon or aura phase; in turn, it activates trigeminal fibers, causing the headache phase. The neurochemical basis of the CSD is the release of potassium or the excitatory amino acid glutamate from neural tissue. This release depolarizes the adjacent tissue, which, in turn, releases more neurotransmitters, propagating the spreading depression.

Positron emission tomography (PET) scanning demonstrates that blood flow is moderately reduced during a migrainous aura, but the spreading oligemia does not correspond to vascular territories. The oligemia itself is insufficient to impair function. Instead, the flow is reduced because the spreading depression reduces metabolism.

Although CSD is the disturbance that presumably results in the clinical manifestation of migraine aura, this spreading oligemia can be clinically silent (ie, migraine without aura). Perhaps a certain threshold is required to produce symptoms in patients having aura but not in those without aura. A study of the novel agent tonabersat, which inhibits CSD, found that the agent helped to prevent migraine attacks with aura only, suggesting that CSD may but not be involved in attacks without aura. [16]

Activation of the trigeminovascular system by CSD stimulates nociceptive neurons on dural blood vessels to release plasma proteins and pain-generating substances such as calcitonin gene-related peptide, substance P, vasoactive intestinal peptide, and neurokinin A. The resultant state of sterile inflammation is accompanied by further vasodilation, producing pain.

The initial cortical hyperperfusion in CSD is partly mediated by the release of trigeminal and parasympathetic neurotransmitters from perivascular nerve fibers, whereas delayed meningeal blood flow increase is mediated by a trigeminal-parasympathetic brainstem connection. According to Moulton et al, altered descending modulation in the brainstem has been postulated to contribute to the headache phase of migraine; this leads to loss of inhibition or enhanced facilitation, resulting in trigeminovascular neuron hyperexcitability. [17]

In addition, through a variety of molecular mechanisms, CSD upregulates genes, such as those encoding for cyclo-oxygenase 2 (COX-2), tumor necrosis factor alpha (TNF-alpha), interleukin-1beta, galanin, and metalloproteinases. The activation of metalloproteinases leads to leakage of the blood-brain barrier, allowing potassium, nitric oxide, adenosine, and other products released by CSD to reach and sensitize the dural perivascular trigeminal afferent endings. [18]

Increased net activity of matrix metalloproteinase–2 (MMP-2) has been demonstrated in migraineurs. Patients who have migraine without aura seem to have an increased ratio of matrix metalloproteinase–9 (MMP-9) to tissue inhibitors of metalloproteinase–1 (TIMP-1), in contrast to a lower MMP-9/TIMP-1 ratio in patients who have migraine with aura. [19] Measured levels of MMP-9 alone are the same for migraine patients with or without aura. [20]

In an experimental study, acute hypoxia was induced by a single episode of CSD. This was accompanied by dramatic failure of brain ion homeostasis and prolonged impairment of neurovascular and neurometabolic coupling. [21]

Vasoactive substances and neurotransmitters

Perivascular nerve activity also results in release of substances such as substance P, neurokinin A, calcitonin gene-related peptide, and nitric oxide, which interact with the blood vessel wall to produce dilation, protein extravasation, and sterile inflammation. This stimulates the trigeminocervical complex, as shown by induction of c-fos antigen by PET scan. Information then is relayed to the thalamus and cortex for registering of pain. Involvement of other centers may explain the associated autonomic symptoms and affective aspects of this pain.

Neurogenically induced plasma extravasation may play a role in the expression of pain in migraine, but it may not be sufficient by itself to cause pain. The presence of other stimulators may be required.

Although some drugs that are effective for migraine inhibit neurogenic plasma extravasation, substance P antagonists and the endothelin antagonist bosentan inhibit neurogenic plasma extravasation but are ineffective as antimigraine drugs. Also, the pain process requires not only the activation of nociceptors of pain-producing intracranial structures but also reduction in the normal functioning of endogenous pain-control pathways that gate the pain.

Migraine center

A potential "migraine center" in the brainstem has been proposed, based on PET-scan results showing persistently elevated rCBF in the brainstem (ie, periaqueductal gray, midbrain reticular formation, locus ceruleus) even after sumatriptan-produced resolution of headache and related symptoms. These were the findings in 9 patients who had experienced spontaneous attack of migraine without aura. The increased rCBF was not observed outside of the attack, suggesting that this activation was not due to pain perception or increased activity of the endogenous antinociceptive system.

The fact that sumatriptan reversed the concomitant increased rCBF in the cerebral cortex but not the brainstem centers suggests dysfunction in the regulation involved in antinociception and vascular control of these centers. Thalamic processing of pain is known to be gated by ascending serotonergic fibers from the dorsal raphe nucleus and from aminergic nuclei in the pontine tegmentum and locus ceruleus; the latter can alter brain flow and blood-brain barrier permeability.

Because of the set periodicity of migraine, linkage to the suprachiasmatic nucleus of the hypothalamus that governs circadian rhythm has been proposed. Discovering the central trigger for migraine would help to identify better prophylactic agents.

Brainstem activation

PET scanning in patients having an acute migraine headache demonstrates activation of the contralateral pons, even after medications abort the pain. Weiler et al proposed that brainstem activation may be the initiating factor of migraine.

Once the CSD occurs on the surface of the brain, H + and K + ions diffuse to the pia mater and activate C-fiber meningeal nociceptors, releasing a proinflammatory soup of neurochemicals (eg, calcitonin gene–related peptide) and causing plasma extravasation to occur. Therefore, a sterile, neurogenic inflammation of the trigeminovascular complex is present.

Once the trigeminal system is activated, it stimulates the cranial vessels to dilate. The final common pathway to the throbbing headache is the dilatation of blood vessels.

Cutaneous allodynia

Burstein et al described the phenomenon of cutaneous allodynia, in which secondary pain pathways of the trigeminothalamic system become sensitized during a migrainous episode. [22] This observation demonstrates that, along with the previously described neurovascular events, sensitization of central pathways in the brain mediates the pain of migraine.

Dopamine pathway

Some authors have proposed a dopaminergic basis for migraine. [23] In 1977, Sicuteri postulated that a state of dopaminergic hypersensitivity is present in patients with migraine. Interest in this theory has recently been renewed.

Some of the symptoms associated with migraine headaches, such as nausea, vomiting, yawning, irritability, hypotension, and hyperactivity, can be attributed to relative dopaminergic stimulation. Dopamine receptor hypersensitivity has been shown experimentally with dopamine agonists (eg, apomorphine). Dopamine antagonists (eg, prochlorperazine) completely relieve almost 75% of acute migraine attacks.

Magnesium deficiency

Another theory proposes that deficiency of magnesium in the brain triggers a chain of events, starting with platelet aggregation and glutamate release and finally resulting in the release of 5-hydroxytryptamine, which is a vasoconstrictor. In clinical studies, oral magnesium has shown benefit for preventive treatment and intravenous magnesium may be effective for acute treatment, particularly in certain subsets of migraine patients. [24]

Endothelial dysfunction

Vascular smooth muscle cell dysfunction may involve impaired cyclic guanosine monophosphate and hemodynamic response to nitric oxide. [25] Nitric oxide released by microglia is a potentially cytotoxic proinflammatory mediator, initiating and maintaining brain inflammation through activation of the trigeminal neuron system.

Nitric oxide levels continue to be increased even in the headache-free period in migraineurs. [26] In premenopausal women with migraine, particularly in those with migraine aura, increased endothelial activation, which is a component of endothelial dysfunction, is evident. [27]

Serotonin and migraine

The serotonin receptor (5-hydroxytryptamine [5-HT]) is believed to be the most important receptor in the headache pathway. Immunohistochemical studies have detected 5-hydroxytryptamine–1D (5-HT1D) receptors in trigeminal sensory neurons, including peripheral projections to the dura and within the trigeminal nucleus caudalis (TNC) and solitary tract, while 5-HT1B receptors are present on smooth muscle cells in meningeal vessels; however, both can be found in both tissues to some extent and even in coronary vessels.

All the currently available triptans (see Medication) are selective 5-HT1B/D full agonists. These agents may decrease headache by abolishing neuropeptide release in the periphery and blocking neurotransmission by acting on second-order neurons in the trigeminocervical complex.

Migraine risk factors

Predisposing vascular risk factors for migraine include the following [28] :

Increased levels of C-reactive protein

Increased levels of interleukins

Increased levels of TNF-alpha and adhesion molecules (systemic inflammation markers)

Oxidative stress and thrombosis

Etiology

Migraine has a strong genetic component. Approximately 70% of migraine patients have a first-degree relative with a history of migraine. The risk of migraine is increased 4-fold in relatives of people who have migraine with aura. [30]

Nonsyndromic migraine headache with or without aura generally shows a multifactorial inheritance pattern, but the specific nature of the genetic influence is not yet completely understood. Certain rarer syndromes with migraine as a clinical feature generally show an autosomal dominant inheritance pattern. [31]

However, recent genome-wide association studies have suggested 4 regions in which single-nucleotide polymorphisms influence the risk of developing migraine headache. [32, 33, 34] Other associations have been found in individual studies but could not be replicated in other populations.

Familial hemiplegic migraine

Familial hemiplegic migraine (FHM) is a rare type of migraine with aura that is preceded or followed by hemiplegia, which typically resolves. FHM may be associated with cerebellar ataxia, which is also linked to the 19p locus. Evidence suggests that the 19p locus for FHM may also be involved in patients with other forms of migraine. Three genes have thus far been identified as being causative for FHM.

FHM type 1 is characterized clinically by episodes that commonly include nystagmus and cerebellar signs. This disorder is caused by mutations in the CACNA1A gene located on 19p13, which codes for a brain-specific calcium channel. Mutations in CACNA1A were previously thought to account for 50% of cases of FHM, [35] but a Danish study showed that only 7% of patients with a clinical diagnosis of FHM had a mutation in that gene. [36]

FHM type 2 occurs in patients who also have a seizure disorder. This condition has been attributed to mutations in the ATP1A2 gene, located on 1q21q23, which encodes a sodium/potassium pump. [37, 38] However, the Danish study found mutations in ATP1A2 in only 7% of patients with a clinical diagnosis of FHM. [36]

FHM type 3 is caused by mutations in the SCN1A gene, located on 2q24. Mutations in SCN1A are also known to cause familial febrile seizure disorders and infantile epileptic encephalopathy. [39] Although SCN1A mutation has been reported in several unrelated families, it is felt to be a rare cause of FHM. [40]

Migraine in other inherited disorders

Migraine occurs with increased frequency in patients with mitochondrial disorders, such as MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes). CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a genetic disorder that causes migraine with aura, strokes before the age of 60, progressive cognitive dysfunction, and behavioral changes.

CADASIL is inherited in an autosomal dominant fashion, and most patients with the disorder have an affected parent. Approximately 90% of cases result from mutations of the <INOTCH3< I>gene, located on chromosome 19. Patients with CADASIL have significant morbidity from their ailment, and life expectancy is approximately 68 years. [41]

Migraine is also a common symptom in other genetic vasculopathies, including 2 autosomal dominant disorders: (1) RVCL (retinal vasculopathy with cerebral leukodystrophy), which is caused by mutations in the TREX1 gene, [42] and (2) HIHRATL (hereditary infantile hemiparesis, retinal arteriolar tortuosity, and leukoencephalopathy), which is suggested to be caused by mutations in the COL4A1 gene. [43] The mechanisms by which these genetic vasculopathies give rise to migraine are still unclear. [44]

Migraine precipitants

Various precipitants of migraine events have been identified, as follows:

Hormonal changes, such as those accompanying menstruation (common), [45] pregnancy, and ovulation

Excessive or insufficient sleep

Monosodium glutamate (MSG)

Foods containing tyramine (eg, aged cheese)

Meats with nitrites

However, large epidemiologic studies have failed to substantiate most of these as triggers, [47] and no diets have been shown to help migraine. Nevertheless, patients who identify particular foods as triggers should avoid these foods.

Although chocolate has been considered a migraine trigger, data from the PAMINA study do not support this contention. [47] Instead, it has been hypothesized that ingestion of chocolate may be in response to a craving brought on at the start of a migraine, as a result of hypothalamic activation.

Migraine and other vascular disease

People who suffer from migraine headaches are more likely to also have cardiovascular or cerebrovascular disease (ie, stroke, myocardial infarction). [48] Reliable evidence comes from the Women's Health Study, which found that migraine with aura raised the risk of myocardial infarction by 91% and ischemic stroke by 108% and that migraine without aura raised both risks by approximately 25%. [49] Migraines during pregnancy are also linked to stroke and vascular diseases. [50]

Migraine with aura for women in midlife has a statistically significant association with late-life vascular disease (infarcts) in the cerebellum. This association is not seen in migraine without aura. [51]

Results of a large, prospective cohort study in women indicate a consistent link between migraine and cardiovascular disease events, including cardiovascular mortality. Researchers analyzed data from more than 115,000 women, 15.2% (17,531) of whom reported a diagnosis of migraine. Over 20 years of follow-up, 1329 major cardiovascular disease events occurred and 223 women died from cardiovascular disease. After adjusting for the known risk factors, women with migraine had a significantly elevated risk for developing major cardiovascular disease (hazard ratio 1.50, 95% CI 1.33-1.69). The greatest increase in risk was for stroke (HR 1.62) and for angina/coronary revascularizations (HR 1.73). [52]

Migraine and iron

In a population-based MRI study by Kruit et al, migraineurs had increased local iron deposits in the putamen, globus pallidus, and red nucleus, compared with controls. [53] This increase in iron deposits may be explained as a physiologic response induced by repeated activation of nuclei involved in central pain processing or by damage to these structures secondary to the formation of free radicals in oxidative stress (possibly the cause of the disease becoming chronic). [54]

Migraine and sensory perception

In a study by Nguyen et al, quantitative sensory testing found significant differences in the perception of vibrotactile stimulation in patients with migraine compared with controls, including stimulus amplitude discrimination, temporal order judgment, and duration discrimination. [55]

Epidemiology

In the United States, more than 30 million people have 1 or more migraine headaches per year. This corresponds to approximately 18% of females and 6% of males. [56] Migraine accounts for 64% of severe headaches in females and 43% of severe headaches in males.

Approximately 75% of all persons who experience migraines are women. Currently, 1 in 6 American women has migraine headaches. (The reported incidence of migraine in females of reproductive age has increased over the last 20 years, but this change probably reflects greater awareness of the condition.)

The incidence of migraine with aura peaks in boys at around age 5 years and in girls at around age 12-13 years. The incidence of migraine without aura peaks in boys at age 10-11 years and in girls at age 14-17 years. [57]

Before puberty, the prevalence and incidence of migraine are higher in boys than in girls. After age 12 years, the prevalence increases in males and females, reaching a peak at age 30-40 years. The female-to-male ratio increases from 2.5:1 at puberty to 3.5:1 at age 40 years. Attacks usually decrease in severity and frequency after age 40 years, except for women in perimenopause. A study by Hsu et al suggests that women aged 40-50 years are also more susceptible to migrainous vertigo. [58] Onset of migraine after age 50 years is rare.

Race-related differences in prevalence

The prevalence of migraine appears to be lower among African Americans and Asian Americans than among whites. One study showed that among women, 20.4% of whites, 16.2% of African Americans, and 9.2% of Asian Americans met International Classification of Headache Disorders (ICHD) criteria for migraine. Similarly, in males, 8.6% of whites, 7.2% of African Americans, and 4.8% of Asian Americans were considered to have migraine.

Economic impact of migraine

The economic cost resulting from migraine-related loss of productive time in the US workforce is more than $13 billion per year, most of which is in the form of reduced work productivity. In the American Migraine Study, more than 85% of women and 82% of men with severe migraine had some headache-related disability. Migraineur men required 3.8 bed-rest days per year, whereas women required 5.6 bed-rest days per year. [59]

International statistics

The World Health Organization (WHO) estimates the worldwide prevalence of current migraine to be 10% and the lifetime prevalence to be 14%. The adjusted prevalence of migraine is highest in North America, followed by South and Central America, Europe, Asia, and Africa. [24]

Approximately 3000 migraine attacks per million persons worldwide occur every day. According to the WHO, migraine is 19th among all causes of years lived with disability.

In the United States, migraine prevalence is inversely correlated with household income and level of education. Internationally, however, a relationship between migraine and socioeconomic status is not present.

Prognosis

Migraine is a chronic condition, but prolonged remissions are common. One study showed that among persons who had migraine during childhood, 62% were migraine free for more than 2 years during puberty and as young adults but that only 40% were still migraine free at age 30 years. [60]

The severity and frequency of migraine attacks tend to diminish with increasing age. After 15 years of suffering migraines, approximately 30% of men and 40% of women no longer have migraine attacks.

Migraine and vascular disorders

Migraine and ischemic strokes reportedly occur in 1.4-3.3 per 100,000 population and account for 0.8% of total strokes. Milhaud et al showed that in young patients (< 45 y) with active migraine who had suffered ischemic stroke, risk factors such as patent foramen ovale, female gender, and oral contraceptive use were much more likely to be present; posterior circulation stroke was characteristic. Surprisingly, older patients characteristically lacked vascular risk factors (ie, previous hypertension, ischemic heart disease, cigarette smoking). [61]

Even in patients older than 45 years, women with migraine are more likely to suffer from ischemic stroke.

Migraineurs, male and female, have a 2.5-fold increased risk of subclinical cerebellar stroke and those with migraines with aura and increased headache frequency are at the highest risk. [62]

Migraineurs also have a higher incidence of adverse cardiovascular profiles (including diabetes and hypertension), and they are more likely to be smokers, have a family history of early heart attacks, and have an unfavorable cholesterol profile. The odds of an elevated Framingham risk score of coronary artery disease are doubled with migraine with aura, and women who have migraine with aura are more likely to be using oral contraceptives. [63, 64]

The Women's Health Study, which included professional women older than 45 years, showed that any history of migraine is associated with a higher incidence of major cardiovascular disease and that the highest risk is associated with migraine with aura, with a 2.3-fold risk of cardiovascular death and a 1.3-fold risk of coronary vascularization. [65] However, those who have migraine without aura have the same risks as the general population.

These findings have been confirmed in a population-based study by Bigal et al. [66] Similarly, a study by Gudmundsson et al found that men and women who have migraine with aura are at a higher risk for cardiovascular and all-cause mortality than are those without headache. [67]

Jasvinder Chawla, MD, MBA Chief of Neurology, Hines Veterans Affairs Hospital; Professor of Neurology, Loyola University Medical Center

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Patent Ca2490341a1 - Composition Pharmaceutique Solide Contenant Un Principe Actif Lipophile, Son, N

Composition pharmaceutique solide contenant un principe actif lipophile, son procede de preparation CA 2490341 A1

La présente Invention se rapporte à une composition pharmaceutique solide, destinée à une administration par voie orale, comprenant au sein d'une seule et même phase, un principe actif lipophile, un agent tensioactif, une polymère cationique insoluble dans l'eau à pH supérieur ou égal à 5 et un acide minéral ou organique, ainsi qu'à son procédé de préparation.

Патентная формула (32)

1. Composition pharmaceutique solide, destinée à l'administration par voie orale, caractérisée par le fait qu'elle contient au sein d'une seule et même phase (phase interne) : - au moins un principe actif lipophile solide et micronisé, - au moins un agent tensioactif, - au moins un polymère cationique insoluble dans l'eau à pH supérieur ou égal à 5, et - au moins un acide organique ou minéral.

2. Composition selon la revendication 1, caractérisée par le fait que le principe actif lipophile est choisi parmi les hypolipidémiants, les hormones stéroïdiennes, les antifongiques, les rétinoïdes, les anti-inflammatoires stéroïdiens, les anti-inflammatoires non stéroïdiens, les anti-rétroviraux, les inhibiteurs de protéases, les antiacides, les inhibiteurs de la pompe à protons, les antiémétiques, les vitamines liposolubles, les médicaments du système cardiovasculaire, les antiagrégants plaquettaires, les anticancéreux, certains extraits végétaux et leurs principes actifs isolés ou dérivés, les immunosuppresseurs, Ies médicaments du système nerveux central, les antimigraineux, les antibiotiques et les antiparasitaires.

3. Composition selon la revendication 2, caractérisée par le fait que les hypolipidémiants sont choisis parmi le 1-méthyléthyl ester de l'acide 2-(4-(4-chlorobenzoyl)phénoxy)-2-méthyl-propanoïque (fénofibrate), le bézafibrate, le ciprofibrate, le gemfibrozil, le probucol, le tiadénol, la simvastatine, la mévastatine, la lovastatine, l'atorvastatine, la pravastatine, la fluvastatine, la cerivastatine et le mélinamide.

4. Composition selon la revendication 2, caractérisée par le fait que les hormones stéroïdiennes sont choisies parmi citer les oestrogènes dérivés et esters de l'estradiol, la progestérone, le danazol, la testostérone et les esters et dérivés de testostérone, les anti-androgènes, les inhibiteurs de la 5.alpha.-réductase, les inhibiteurs compétitifs de la testostérone, les dérivés de la quinazoline et les agonistes/antagonistes non stéroïdiens des récepteurs oestrogéniques.

5. Composition selon la revendication 2, caractérisée par le fait que les antifongiques sont choisis parmi l'itraconazole, le miconazole, le kétoconazole, le fluconazole, la griséofulvine, l'amphotéricine B et la terbinafine.

6. Composition selon l'une quelconque des revendications précédentes, caractérisée par le fait que le principe actif lipophile est le fénofibrate, la progestérone ou l'itraconazole.

7. Composition selon l'une quelconque des revendications précédentes, caractérisée par le fait que le principe actif représente de 10 à 90 % en poids du poids total de la composition pharmaceutique.

8. Composition selon l'une quelconque des revendications précédentes, caractérisée par le fait que l'agent tensioactif est choisi parmi les composés présentant une valeur de la balance hydrophile-lipophile (HLB) supérieure ou égale à 15.

9. Composition selon la revendication 8, caractérisée par le fait que l'agent tensioactif est choisi parmi le laurylsulfate de sodium (HLB 40), les poloxamers (HLB 16-29), les macrogol éthers d'alcools organiques (HLB 15-18), et les sucrose-esters d'acides organiques (HLB 15-16).

10. Composition selon la revendication 9, caractérisée par le fait que l'agent tensioactif est le laurylsulfate de sodium.

11. Composition selon l'une quelconque des revendications précédentes, caractérisée par le fait que l'agent tensioactif représente de 1 à 10 % en poids du poids total de ladite composition.

12. Composition selon l'une quelconque des revendications précédentes, caractérisée par le fait que l'agent tensioactif se présente sous forme solide.

13. Composition selon la revendication 12, caractérisée par le fait que l'agent tensioactif est co-micronisé avec le principe actif.

14. Composition selon l'une quelconque des revendications précédentes, caractérisée par le fait que le rapport pondéral principe actif/agent tensioactif est compris entre 100/1 et 5/1.

15. Composition selon l'une quelconque des revendications précédentes, caractérisée par le fait que les polymères cationiques insolubles dans l'eau à pH supérieur ou égal à 5 sont choisis parmi les polymères acryliques contenant un groupe amine tertiaire.

16. Composition selon la revendication 15, caractérisée par le fait que lesdits polymères sont choisis parmi les polymères de type méthacrylate aminoalkyle solubles à pH inférieur à 5.

17. Composition selon la revendication 16, caractérisée par le fait que lesdits polymères sont choisis parmi le terpolymère de poly(diméthylaminoéthyl)méthacrylate, de méthyl méthacrylate et de butyl méthacrylate et le terpolymère de poly(diéthylaminoéthyl)méthacrylate, de méthyl méthacrylate et de butyl méthacrylate.

18. Composition selon l'une quelconque des revendications précédentes, caractérisée par le fait que le ou les polymères cationiques insolubles dans l'eau à pH supérieur ou égal à 5 représentent de 0,5 à 15 % en poids par rapport au poids total de la composition pharmaceutique.

19. Composition selon l'une quelconque des revendications précédentes, caractérisée par le fait que le rapport pondéral polymère cationique insoluble dans l'eau à pH supérieur ou égal à 5 / principe actif est compris entre 1/5 et 1/30.

20. Composition selon l'une quelconque des revendications précédentes, caractérisée par le fait que l'acide organique ou minéral est choisi parmi l'acide citrique, l'acide succinique, l'acide fumarique, l'acide acétique, l'acide phosphorique, l'acide sulfurique et l'acide chlorhydrique.

21. Composition selon l'une quelconque des revendications précédentes, caractérisée par le fait que l'acide organique ou minéral représente de 1 à % en poids par rapport au poids total de la composition.

22. Composition selon l'une quelconque des revendications précédentes, caractérisée par le fait que le rapport pondéral acide organique ou minérallpolymère cationique insoluble dans l'eau à pH supérieur ou égal à 5 est compris entre 6/1 et 0,25/1.

23. Composition selon l'une quelconque des revendications précédentes, caractérisée par le fait que le ratio principe actif lipophile/acide minéral ou organique est compris entre 1/1 et 30/l.

24. Composition selon l'une quelconque des revendications précédentes, caractérisée par le fait qu'elle comprend, en poids par rapport au poids total de la composition : - 40 à 80 % de fénofibrate à titre de principe actif lipophile, - 2 à 10 % d'agent tensioactif, - 2 à 10 % d'un terpolymère de poly(diméthylaminoéthyl)-méthacrylate, de méthyl méthacrylate et de butyl méthacrylate, et - de 2,5 à 5 % d'un acide minéral ou organique.

25. Composition selon l'une quelconque des revendications précédentes, caractérisée par le fait qu'elle renferme du fénofibrate à titre de principe actif lipophile et qu'elle présente une dissolution d'au moins 50 % en 15 minutes, supérieure à 80 % en 30 minutes, supérieure à 85 % en 45 minutes et supérieure à 90 % en 60 minutes, telle que mesurée conformément à la méthode de la palette tournante à 75 tours/min selon la Pharmacopée Européenne, dans un milieu de dissolution constitué de laurylsulfate de sodium 0,1 M en solution aqueuse portée à 37°C.

26. Composition selon l'une quelconque des revendications précédentes, caractérisée par le fait que la phase interne renferme un ou plusieurs excipients choisis parmi les agents diluants et/ou liants, les agents désintégrants et les adjuvants de pulvérisation, de compression, de lubrification et d'écoulement des poudres.

27. Composition selon l'une quelconque des revendications précédentes, caractérisée par le fait qu'elle comprend en outre une phase externe comprenant un ou plusieurs excipients.

28. Procédé de préparation d'une composition pharmaceutique telle que définie à l'une quelconque des revendications 1 à 27, caractérisé par le fait qu'il comprend les étapes suivantes : a) le mélange d'au moins un principe actif lipophile solide et micronisé, d'au moins un agent tensioactif, d'au moins un polymère cationique insoluble dans l'eau à pH supérieur ou égal à 5 et d'au moins un acide organique ou minéral, b) la granulation ou l'atomisation du mélange obtenu ci-dessus à l'étape a), c) l'addition éventuelle d'une phase externe comprenant un ou plusieurs excipients, puis d) la compression ou la répartition en gélules du mélange obtenu à l'issue de l'étape b) ou c) lorsque cette dernière est réalisée.

29. Procédé selon la revendication 28, caractérisé par le fait qu'il comprend une étape préliminaire de co-micronisation du principe actif avec le ou les agents tensioactifs.

30. Procédé selon la revendication 28 ou 29, caractérisé par le fait que l'étape b) est réalisée par granulation et que le mélange des constituants lors de l'étape a) comprend les sous-étapes suivantes : a1) la préparation d'une solution ou d'une suspension comprenant au moins acide organique ou minéral et au moins un polymère cationique insoluble dans l'eau à pH supérieur ou égal à 5, dans un liquide de granulation, a2) la pulvérisation du mélange préparé ci-dessus à l'étape a1) sur le principe actif micronisé et préalablement mélangé à l'agent tensioactif solide ou co-micronisé avec ledit principe actif, à une température compatible avec la stabilité physique des substances engagées dans la formulation, a3) la récupération des granulés fluidisés ainsi obtenus, a4) le calibrage, des granulés fluidisés, et a5) le séchage des granulés fluidisés.

31. Procédé selon la revendication 30, caractérisé par le fait que ledit polymère est un terpolymère de poly(diméthylaminoéthyl)méthacrylate, de méthyl méthacrylate et de butyl méthacrylate et que le liquide de granulation est un mélange propanol/acétone.

32. Procédé selon la revendication 28 ou 29, caractérisé par le fait que l'étape b) est réalisée par atomisation et que l'étape a) comprend les sous-étapes suivantes : a'1) la préparation d'une solution acide ou tampon contenant un acide minéral ou organique et une base forte, ladite solution présentant un pH inférieur à 5, a'2) la préparation d'une suspension, par addition à cette solution tampon, d'au moins un principe actif lipophile solide et micronisé, d'au moins un agent tensioactif éventuellement co-micronisé avec ledit principe actif et d'au moins un polymère cationique insoluble dans l'eau à pH supérieur ou égal à 5, sous agitation, a'3) l'atomisation de ladite suspension, a'4) la récupération du produit atomisé.

Описание (текст распознан автоматически, поэтому в нем могут быть ошибки)

COMPOSITION PHARMACEUTIQUE SOLIDE CONTENANT UN PRINCIPE ACTIF LIPOPHILE, SON PROCÉDÉ DE PRÉPARATION La présente Invention se rapporte à une composition pharmaceutique solide, destinée à une administration par voie orale, comprenant au sein d'une seule et même phase, un principe actif lipophile, un agent tensioactif, un polymère cationique insoluble dans l'eau à pH neutre ou alcalin et un acide minéral ou organique, ainsi qu'à son procédé de préparation. Une telle composition permet en particulier de conférer à ce type de principe actif, lorsqu'il est absorbé par la voie orale, une biodisponibilité significativement améliorée du fait d'une dissolution favorisée en milieu aqueux. II existe un grand nombre de principes actifs lipophiles présentant une faible hydrosolubilité et dont la formulation, pour une administration par la voie orale, pose un certain nombre de problèmes majeurs, notamment en termes de biodisponibilité. Parmi ces principes actifs lipophiles figurent notamment la famille des hypolipidémiants à laquelle appartiennent en particulier les fibrates tels que le fénofibrate (DCI). Le fénofibrate a été mis sur le marché pour la première fois en France en 1975, sous la forme de gélules dosées à 100 mg de principe actif (Lipanthyl

100) et avec une posologie de 3 ou 4 gélules par jour à prendre en cours des différents repas, correspondant donc à une administration quotidienne de 300 à 400 mg de principe actif. Cette spécialité pharmaceutique est toujours commercialisée à ce jour en France mais sous le nom Sécalip

100. Depuis cette première mise sur le marché, les formulateurs n'ont pas cessé de chercher à améliorer la formulation des principes actifs lipophiles et en particulier celle du fénofibrate. En 1986, un deuxième dosage, destiné à offrir aux patients ne nécessitant que 300 mg de fénofibrate par jour une meilleure observance thérapeutique, a été commercialisé sous la forme de gélules renfermant 300 mg de principe actif (Lipanthyl

300), la posologie étant alors d'une seule gélule par jour. Une telle posologie est rendue possible par la longue durée d'action du fénofibrate dont la demi-vie d'élimination est, en effet, d'environ 20 heures. Cette spécialité pharmaceutique est toujours disponible en France, mais sous le nom Sécalip0 300. Toutefois, cette forme galénïque conduit à une faible biodisponibilité du principe actif (Desager et al. J. Clin. Pharmacol. 1978, 26, 570-574 ; Weil et al. Drug Metabolism, 1980, 18, 115-120) ; Strolin Benedetti et al. (Acta Pharmacol. Toxicol. 1986, 59, suppl. 5, 1967). En effet, du fait de sa faible hydrosolubilité, le fénofibrate, et de façon plus générale, les principes actifs lipophiles, très peu solubles, voire insolubles dans l'eau, sont mal absorbés au niveau du tube digestif et présentent par conséquent une biodisponibilité incomplète. Pour améliorer la dissolution du fénofibrate et sa biodisponibilité et réduire ainsi la dose devant être administrée, la demande de brevet FR-A-2 627 propose notamment une composition pharmaceutique dans laquelle le fénofibrate est utilisé sous la forme d'une poudre co-micronisée avec un tensioactif solide, par exemple du laurylsulfate de sodium. La poudre de fénofibrate co-micronisée ainsi obtenue est mélangée avec des excipients classiques tels que le lactose, l'amidon, la polyvinylpyrrolidone (PVP) et le stéarate de magnésium puis mise en gélule. Ce brevet enseigne en particulier que la co-micronisation du fénofibrate avec un tensioactif solide permet d'améliorer la biodisponibilité du fénofibrate de façon significativement plus importante que l'amélioration que l'on obtiendrait soit par addition d'un agent tensioactif, soit en micronisant uniquement le fénofibrate, soit encore en mélangeant intimement le fénofibrate et le tensioactif micronisés séparément. Ce procédé conduit à une nouvelle forme galénique où le produit actif, co-micronisé avec un tensioactif solide, présente une dissolution du fénofibrate améliorée, donc une biodisponibilité augmentée, ce qui permet, à efficacité égale, une diminution de la dose quotidienne de médicament. respectivement 67 mg (Lipanthyl

) et 200 mg (Lipanthyl

200 M ou TricorC

) au lieu de 100 mg et 300 mg. Ainsi le patient a pu disposer d'une forme galénique ne nécessitant qu'une seule prise par jour qui produit un effet identique à celui obtenu à l'aide de prises multiples. Cependant, le procédé de préparation selon ce brevet n'est pas totalement satisfaisant dans la mesure où il ne conduit pas à une dissolution et à une biodisponibilité complète du principe actif.

La demande de brevet EP 0 793 958 décrit un procédé de préparation d'une composition pharmaceutique mettant en oeuvre du fénofibrate, un agent tensioactif et de la PVP. Selon ce document, les particules de fénofibrate sont mélangées avec une solution de PVP. Le mélange obtenu est ensuite granulé avec une solution de un ou plusieurs tensioactifs. Le granulé ainsi produit est alors séché. La demande de brevet FR-A-2 783 421 montre que l'on peut aussi améliorer la biodisponibilité du fénofibrate à l'aide d'un procédé de préparation consistant à procéder à la micronisation du fénofibrate, puis à sa granulation en présence d'un milieu liquide comprenant un agent tensioactif, de l'eau et un alcool hydromiscible et enfin à sécher le granulé ainsi obtenu. Selon la demande de brevet EP 1 048 295, la dissolution d'une composition de ce principe actif peut également être améliorée lorsque l'on réalise la co-micronisation du fénofibrate avec un excipient solide autre qu'un agent tensioactif, tel que le lactose, la cellulose microcristalline ou l'amidon. Ire même, la demande internationale WO 02/11699 décrit une formulation galénique comprenant du fénofibrate micronisé, intimement mélangé à des excipients inertes tels que le lactose et la cellulose microcristalline dont la taille des particules (inférieure à 50 gym) est sélectionnée de sorte à éviter l'agrégation des particules de fénofibrate et à optimiser leur dispersion. Ainsi, la dissolution du fénofibrate est améliorée et la biodisponibilité de la composition ainsi préparée est supérieure à celle de la spécialité pharmaceutique Tricor

dosée à 200 mg et 67 mg. Toutefois, la dissolution du fénofibrate à 30 minutes n'est pas proche de 100 %. Le brevet US 6,180,13 8 décrit un procédé de préparation d'une formule solide d'agent de régulation des lipides incluant le fénofibrate dont Ies caractéristiques de dissolution et d'absorption sont améliorées. Le procédé décrit dans ce brevet consiste en un mélange de fénofibrate co-micronisé avec éventuellement un ou plusieurs excipients tels que le lactose que l'on met en suspension dans une solution de tensioactif. Un électrolyte du type chlorure de sodium peut étre ajouté à la solution de tensioactif de manière à éviter l'agglomération des particules de fénofibrate par force électrostatique. La suspension est ensuite séchée par atomisation ou en lit d'air fluidisé (LAF) et optionnellement granulée et mise sous forme de gélule ou de comprimé.

Le brevet US 6,368,622 se rapporte à un autre procédé de préparation d'une formule solide de fénofibrate consistant à fondre et à mélanger du fénofibrate et un tensioactif avec éventuellement un autre excipient. Le mélange congelé, broyé et réduit en poudre ou petits granulés est ensuite mis en gélules. Ce procédé permet d'obtenir de très petites particules de fénofibrate de manière à augmenter la surface spécifique et donc la dissolution. Les résultats de dissolution montrent une équivalence entre les compositions pharmaceutiques obtenues selon le procédé dans ce brevet et la spécialité Lipanthyl

67 M. Le brevet US 6,368,620 concerne un procédé de préparation d'une formulation galénique comprenant un agent de régulation du métabolisme lipidique incluant le fénofibrate, dissout dans du C02 supercritique et dont la solution est pulvérisée à travers une buse pour former de petites particules (nanoparticules ou nanocristaux) facilement dissoutes. L'ajout d'un agent de revêtement de surface, avant ou après l'étape de formation des nanoparticules, permet d'éviter l'agglomération des particules entre elles. Une suspension est ensuite formée pour collecter les particules et les sécher. La dissolution des formulations galéniques des nanoparticules ou nanocristaux ainsi générées est comparée à celle du Lipanthyl

Une autre méthode pour améliorer la dissolution du fénofibrate est décrite dans la demande de brevet EP 0 904 781. Il s'agit d'un procédé de préparation de granulés de fénofibrate, à partir d'une dispersion solide, lequel procédé comprend le mélange d'un agent désintégrant solide avec du fénofibrate fondu, le refroidissement et la solidification du mélange et la production de granulés par tamisage. Les désintégrants utilisés sont des polymères tels que l'amidon, la croscarmellose sodique, le glycolate d'amidon sodique et la PVP réticulée (crospovidone). Le granulé est ensuite introduit dans les compositions pharmaceutiques. Cependant, un désintégrant comme la crospovidone ne se dissout pas uniformément dans le fénofibrate fondu et présente des problèmes de compatibilité de phases. Ces phénomènes ont été mis en évidence par Sheu, M T et al. Int. J. Pharm 1994, 103 (2), 137-146 en utilisant des mesures calorimétriques différentielles. Ces derniers ont aussi découvert que le fénofibrate est incompatible avec la PVP. Ainsi, la préparation de mélanges de matière pharmaceutique par fusion suivie d'une solidification conduit à une répartition et à une composition non uniforme dans le granulé final pouvant entraîner des effets indésirables sur la biodisponibilité du principe actif. De plus, le procédé de "co-fusion" nécessite l'utilisation d'équipements spécifïques. La demande de brevet FR-A-2 722 984 décrit une dispersion solide 5 de principes actifs assurant une meilleure solubilité dans les milieux aqueux et une meilleure résorption dans le tube digestïf. La dispersion solide est préparée en dissolvant le principe actif dans un solvant organique volatil contenant un polymère très hydrophile tel qu'un amide cyclique, et éventuellement un tensioactif puis en évaporant à sec la solution organique. Le co-précipité du principe actif et du polymère ainsi formé est ensuite broyé, tamisé et dilué avec un excipient ou un véhicule pharmaceutiquement acceptable, ou bien utilisé tel quel. Il s'agit d'une composition comprenant un tensioactif, un principe actif dispersé dans un excipient hydrophile du type pyrrolidone. La demande internationale WO 00/72829 décrit une composition pharmaceutique comprenant un agent de régulation lipidique incluant le fénofibrate et un excipient. Dans cette composition pharmaceutique, le fénofibrate et ledit excipient, par exemple l'acide succinique ou le polyéthylèneglycol (PEG) forment un mélange eutectique. Toutefois, ces dispersions solides ne présentent pas un profil de dissolution proche de 100 % et demandent des équipements spécifiques pour leur préparation. La demande de brevet FR-A-2 758 459 décrit une composition pharmaceutique solide de fënofibrate ayant une biodisponibilité élevée ainsi que son procédé de préparation. Ce document décrit en particulier une composition de fénofibrate à libération immédiate comprenant un support inerte hydrosoluble enrobé d'une couche de fénofibrate micronisé dont la taille de particules est de moins de 20 gym, d'un polymère hydrophile tel que la PVP et éventuellement d'un agent tensioactif. Le microgranule comprend ensuite une phase externe ou un enrobage externe supplémentaire tel que par exemple de la PVP réticulée. La composition ainsi préparée montre une augmentation signif cative de la dissolution du fénofibrate. Même si l'augmentation du taux de dissolution i

vitYO ne signifie pas directement une augmentation de biodisponibilité ifa vivo, l'enseignement de ce document réside dans l'utilisation d'un polymère hydrophile et d'un support inerte hydrosoluble permettant d'organiser les particules de fénofibrate autour d'un support de manière à offrir au milieu de dissolution une plus grande surface spécifique. Dans ce cas de figure les profils de dissolution sont proches de 100 % puisque l'on obtient la dissolution suivante pour le comprimé à libération modifiée, dosé à 160 mg. 83 % de fénofibrate dissous en 15 minutes et 96 % en 30 minutes contre respectivement 16,5 % et 55 pour le Lipanthyl

200 M. Cette nouvelle composition pharmaceutique est actuellement commercialisée en France sous le nom Lipanthyl

160 mg. Cependant, le procédé de mise en oeuvre est complexe, coûteux et demande des équipements spécifiques. Il existe donc un besoin pour améliorer la dissolution et la biodisponibilité des principes lipophiles, très peu solubles, voire insolubles dans l'eau, et en particulier, celle des hypolipidémiants tels que le fénofibrate, sous forme solide, afin d'atteindre dans des temps très courts un niveau proche de 100 %, en tout cas supérieur à 80 % en 30 minutes, sans avoir recours à des procédés complexes et coûteux comme par exemple la réalisation de microgranules hydrosolubles ou de dispersions solides. La demanderesse a mis en évidence de façon surprenante qu'il est possible de résoudre ce problème grâce à une composition pharmaceutique solide monophasique comprenant un principe actif lipophile, solide et micronisé, un agent tensioactif, un polymère cationique insoluble dans l'eau à pH supérieur ou égal à 5, par exemple de type polyméthacrylate, et un acide organique ou minéral. La présente Invention concerne aussi le procédé de préparation d'une telle composition. On connaît des compositions pharmaceutiques à base de principes actifs lipophiles comprenant des polyrnéthacrylates. Ces formulations sont généralement utilisées pour retarder ou contrôler la libération du principe actif dans l' organisme. La demande internationale WO 82/01649 décrit une formulation de microgranules à base de fénofibrate comprenant un noyau neutre constitué d'amidon et de saccharose. Le noyau neutre est recouvert d'une solution de fénofibrate avec éventuellement un ou plusieurs excipients et d'une seconde couche microporeuse constituée d'un polymère compatible avec une administration orale, notamment la gomme arabique, les éthers et esters de cellulose, les polyméthacrylates, etc. Cette formulation permet de réaliser un médicament ayant un effet retard contrôlé par le mélange de granules ayant différentes vitesses de libération de fénofibrate. Par exemple, les granules neutres non enrobés de polymère permettent d'obtenir une concentration prédéterminée en fénofibrate. La demande de brevet FR-A-2 602 423 se rapporte à une composition pharmaceutique comprenant des granules de fénofibrate à libération contrôlée. Chaque granule est constitué d'un noyau inerte, d'une couche de fénofibrate et d'une couche de protection à base de polymères méthacryliques, de PVP, de dérivés de la cellulose ou de polyéthylènes glycols. Dans la couche de base, le fénofibrate est présent sous forme de particules microcristallines de dimension inférieure ou égale à 50 microns (

m). L'utilisation de tels cristaux permet d'obtenir une absorption régulière du fénofibrate contrairement à celle qui est obtenue en suïvant l'enseignement de la demande internationale WO 82/01649. La demande internationale WO 96/36318 se rapporte à une forme pharmaceutique à 3 phases, à libération constante et lente d'un ingrédient actif amorphe pour une administration quotidienne unique. La première phase consiste en un noyau contenant en particulier du fénofibrate amorphe, de la PVP, un éther de cellulose comme excipient et inhibiteur de cristallisation, et un agent tensioactif qui améliore la solubilisation et l'absorption du principe actif amorphe dans le tractus gastro-intestinal. La seconde phase contient un éther de cellulose et un mélange de mono-, di - et triglycérides pour modifier la cinétique de libération du principe actif. La troisième phase est constituée d'un film enrobant faiblement soluble constitué de polymère gastro-résistant, notamment l'Eudragit

L100-55 qui est un copolymère d'acide méthacrylique et d'acrylate d'éthyle (polymère non-cationique). La demande de brevet FR-A-2 772 615 concerne un comprimé multicouche (bi-couche) pour la libération instantanée puis prolongée de substances actives comprenant au moins deux couches superposées. La première couche permet la libération immédiate du principe actif. La deuxième couche est constituée d'une matrice polyrnérique poreuse inerte, non biodégradable dans laquelle est dispersée une seconde substance active, pouvant être identique à celle présente dans la première couche. Les substances actives peuvent être notamment hypolipidémiants et la matrice polymérique est par exemple un copolymère non cationique d'acide méthacrylique et d'acrylate d'éthyle ou bien un copolymère cationique tel qu'un copolymère de méthacrylate d'éthylammonium et de méthacrylate d'éthyle (Eudragit

RL, RS, L). Cette seconde couche matricielle est responsable de la libération contrôlée du principe actif. Enfin, la demande internationale WO 00/72825 traite d'une formulation solide comprenant du fénofibrate ou une statine dispersé dans un polymère hydrophile amorphe. Le fénofibrate est présent dans la formulation sous forme métastable amorphe. Parmi les polymères amorphes sont désignés, entre autres, les polyrnéthacrylates de la marque Eudragit

Selon ce document, l'amélioration de la dissolution est espérée car les principes actifs et les polyméthacrylates se présentent sous une forme amorphe. Toutefois, rien ne démontre une amélioration de la dissolution telle qu'elle est annoncée par les auteurs, d'autant plus que les résultats rapportés démontrent une perte de biodisponibilité et un effet retard. L'ensemble de ces documents démontre que les polymères de type Eudragit

sont généralement utilisés comme film d'enrobage afin de retarder la libération d'un principe actif. Ainsi, les valeurs de dissolution ne peuvent étre supérieures à 80 % en 30 minutes. Selon Lehmann I

ylie polynzers. A review of pha

fnaceutical applications'; STP Pharma Sciences, 1997, 403-437, les polymères ou copolymères polyméthacryliques, notamment les polymères de type Eudragit

peuvent être utilisés dans les formes pharmaceutiques pour agir sur la libération de principes actifs dans le tractus gastro-intestinal de manière - soit immédiate, - soit retardée ("lag-time'

- soit prolongée. Les principaux polymères acryliques sont les carbomères (Carbopol

), les copolymères de chlorure de triméthyl ammonioéthyl/méthacrylate (Eudragit

RS/RL), d'acide méthacrylique/méthylméthacrylate (Eudragit

L100, S 100, L100-55), de poly(diméthylaminoéthyl)méthacrylate, de méthylméthacrylate et de butylméthacrylate (Eudragit

E100). Selon la demande de brevet EP 0 436 370, on peut préparer des formulations à libération "pulsée" caractérisées par une période de latence ou "lag-time" comprenant un noyau de principe actif et un acide organique, en particulier l'acide succinique, et un film d'enrobage à base d'Eudragit

RS ou RL ayant un groupe ammonium quaternaire. Le film d'enrobage étant légèrement perméable à l'eau, la substance pharmaceutique n'est dissoute ou libérée qu'au bout d'une durée prédéterminée (fonction de l'épaisseur de l'enrobage) mais lorsque le suc digestif a pénétré graduellement dans la préparation et ainsi dissous l'acide organique, la perméabilité du polymère en est augmentée, d'oü une dissolution et une libération rapides du principe actif. Le mécanisme probable d'un tel schéma unique de dissolution et de libération du principe actif pourrait s'expliquer par le fait que l'acide organique dissous réagit avec le groupement éthyltriéthylamrnonium contenu dans Ie film d'enrobage formé par la dispersion aqueuse et qu'ainsi le polymère très légèrement perméable à l'eau est transformé en un polymère perméable à l'eau. Les polymères de type Eudragit

comportant un groupe amine tertiaire, en particulier l'Eudragit

E, sont principalement utilisés comme film d'enrobage des formes pharmaceutiques finales pour en masquer le goût. Ces films sont insolubles dans des conditions de pH quasi neutre (pH 5 à 7) du milieu buccal, mais sont très solubles dans un environnement acide comme l'estomac. Ils se dissolvent rapidement à pH inférieur à 5 grâce à une concentration importante des groupes amines tertiaires du monomère N-N-diméthylaminoéthylméthacrylate (50% en poids du polymère). Par contre, ce polymère gonfle à un pH supérieur à 5 à cause des groupes amines très hydrophobes. Ce polymère peut aussi être utilisé dans les formulations à libération lente. En effet, selon Lis P. et al. Drug. Dev. Ind. Pharm. 1989, 15, 1999-2016, quand l'Eudragit

E recouvre des granulés de théophylline, la cinétique de libération est d'ordre zéro. Dans de rares cas, l'Eudragit

E peut fournir des formes galéniques à libération immédiate. Selon Suzuki H. et al. Chem. Pharm. Bull, 1996, 44, 371, le chlorhydrate de bénidipine, qui est un antagoniste calcique, est légèrement soluble dans un acide faible, si bien que sa biodisponibilité est influencée par la variabilité de l'acidité gastrique des patients. Par contre, la molécule est peu soluble dans les solvants organiques généralement utilisés dans les préparations de dispersions solides. Selon le solvant utilisé, les auteurs ont montré que l'Eudragit

E était capable de solubiliser le chlorhydrate de bénidipine grâce à des interactions moléculaires entre le principe actif et le film. Ainsi, des dispersions solides de bénidipine ont pu être préparées et ont montré un taux de dissolution amélioré (pH 6). Toutefois, la bénidipine sous forme de chlorhydrate est une espëce ionisée qui ne se comporte pas cornine le fénofibrate. Le fénofibrate n'étant pas un sel, il n'y a pas d'interaction 5 ionique directe possible avec le film d'Eudragit

Ainsi, la présente Invention a pour objet une composition pharmaceutique solide, destinée à l'administration par voie orale, caractérisée par le fait qu'elle contient au sein d'une seule et même phase (phase interne) - au moins un principe actif lipophile solide et micronisé, 10 - au moins un agent tensioactif, - au moins un polymère cationique insoluble dans l'eau à pH supérieur ou égal à 5, et - au moins un acide organique ou minéral. LTne telle composition pharmaceutique ne se présente pas sous forme de comprimé multicouche mais sous la forme d'une composition homogène constituée d'une seule phase au sein de laquelle tous les ingrédients décrits ci-dessus sont intimement mélangés. De plus, le polymère cationique insoluble ne confère pas d'effet retard à la composition pharmaceutique. Selon la prësente Invention, le terme "principe actif lipophile" recouvre toute substance lipophile très peu soluble, voire insoluble dans l'eau présentant une activité pharmacologique, thérapeutique etc. Par "trës peu soluble" dans l'eau, on entend selon l'Invention, une solubilité inférieure ou égale à 0,1 mg/ml ou un coefficient de partage (P) octanol/eau, exprimé par le log P, supérieur à 2 et de préférence supérieur ou égal à 4. En effet, la lipophilie d'un principe actif (PA) peut être déterminée en fonction de son coefficient de partage (P) entre foctanol et l'eau qui correspond au rapport concentration du PA dans l'octanol (Co

t.)/concentration du PA dans l'eau (CEau). Lorsque le rapport P est supérieur à l, cela signifie que Co

t est supérieure à CEau et que par conséquent le PA est lipophile (log P > 0). On peut donc en déduire que plus le log P d'un PA est élevé et plus celui-ci présente un caractère lipophile prononcé. Ces principes actifs se retrouvent en pratique dans les classes 2 et 4 de la classification biopharmaceutique proposée en 1995 par Amidon et al. Pharm. Res. 1995,12, 413-420.

Ces principes actifs lïpophiles peuvent notamment être choisis parmi les hypolipidémiants, les hormones stéroïdiennes, les antifongiques, les rétinoïdes, les anti-inflammatoires stéroïdiens, les anti-inflammatoires non stéroïdiens (A. LN. S.), les anti-rétroviraux, les inhibiteurs de protéases ("navirs"), les antiacides, les inhibiteurs de la pompe à protons, les antiémétiques, les vitamines liposolubles, les médicaments du système cardiovasculaire, les antiagrégants plaquettaires, les anticancéreux, certains extraits végétaux et leurs principes actifs isolés ou dérivés, les immunosuppresseurs, les médicaments du système nerveux central, les antimigraineux, les antibiotiques et les antiparasitaires. Panni les hypolipidémiants, on peut notamment citer les fibrates comme le 1-méthyléthyl ester de l'acide 2-(4-(4-chlorobenzoyl)phénoxy)-2-méthyl-propanoïque également dénommé fénofibrate et les produits apparentés de la classe des fibrates tels que le bézafibrate, le ciprofibrate et le gemfibrozil. On peut également citer, parmi les autres hypolipidémiants, les bisthioéthers, dont le probucol et le tiadénol, la classe des inhibiteurs de la HMG Co-A réductase (statines) tels que par exemple la simvastatine, la mévastatine, la lovastatine, fatorvastatine, la pravastatine, la fluvastatine, la cerivastatine, ainsi que la classe des inhibiteurs de l'ACAT tels que le mélinamide et ses analogues structuraux. A titre d'hormones stéroïdiennes, on peut notamment citer les oestrogènes dérivés et esters de l'estradiol, la progestérone, le danazol, la testostérone et les esters et dérivés de testostérone. On peut également citer les anti-androgènes dont le flutamide, la nilutamide ; les inhibiteurs de la 5 a-réductase, les inhibiteurs compétitifs de la testostérone tels que le finastéride ; les dérivés de la quinazoline tels que falfuzosine ; les agonistes/antagonistes non stéroïdiens des récepteurs oestrogéniques tels que le tamoxifène et le raloxifène. Parmi les antifongiques, on peut notamment citer les antifongiques azolés (conazoles) dont fitraconazole, le miconazole, le kétoconazole et le fluconazole, ainsi que la griséofulvine, l'amphotéricine B et la terbinafme. Parmi les rétinoïdes, on peut citer, en premier lieu, les rétinoïdes dérivés de la vitamine A comme la trétinoïne, encore connue sous le nom d'acide tout trans rétinoïque ou d'acide tout-trans vitamine A, fisotrétinoïne qui correspond à l'isomère 13-cis de la trétinoïne, et qui, de ce fait, est également appelée acide 13-cis rétinoïque ou acide 13-cis vitamine A, l'acide 9-cis rétinoïque ou acide 9-cis vitamine A, l'acitrétine, l'étrétinate, mais également les rétinoïdes acétyléniques comme le tazarotène, les rétinoïdes dérivés du naphtalène comme le lonapalène et l'acide 2-(5,6,+,8-tétrahydrométhyl-2-anthryl)-4-thiophénocarboxylique, et les rétinoïdes à cycle adamantyle tels que l'adapalène, l'acide 6-[3-(1-adasnantyl)-4-hydroxyphényl]-2-naphtoïque et l'acide 4-[3-(1-adamantyl)-4-méthoxybenzamido]-benzoïque et leurs esters. A titre d'ami-inflammatoires stéroïdiens, on peut notamment citer les glucocorticoïdes tels que la prednisolone, la cortisone, ses esters et dérivés. A titre d'A. LN. S. on peut notamment citer l'acide méfénamique, le naproxëne, le nabumétone, I'ibuprofène et les inhibiteurs de la COX-2 tels que le celecoxib, le rofecoxib, le parecoxib et le valdecoxib. Les antirétroviraux et les inhibiteurs des protéases sont des composés très peu solubles dans l'eau, dont les coefficients de partage peuvent être calculés ou déterminés par voie analytique, parmi lesquels on peut citer l'amprenavir (solubilité 0,04 mg/I), le saquinavir et le saquinavir mésylate (solubilité 2,22 mg/ml) et le ritonavir (presque insoluble dans l'eau). A titre d'antiacides et d'inhibiteurs de la pompe à protons, on peut notamment citer l'oméprazole, le pantoprazole, le rabéprazole (ou pariprazole), la lansoprazole et le timoprazole. A titre d'antiémétiques, on peut notamment citer la dompéridone, les antagonistes de la sérotonine ("setrons") tels que fondansetron, le granisetron et fazasetron. A titre de vitamines liposolubles, on peut notamment citer les vitamines A ou rétinol, D dont le calcitriol, E ou tocophérols, I

ou ménadione. Parmi les médicaments du système cardiovasculaire, on peut notamment citer les antagonistes de l'angiotensine II (sartans) tels que le valsartan, le losartan, firbésartan, le candesartan, le tasosartan, Ie telmisartan ; les a-et /3-bloquants tels que le carvédilol, le celiprolol ; les inhibiteurs calciques (dihydropyridines) tels que le verapamil, le diltiazem, la nifédipine et la nitrendipine. On peut également citer d'autres composés, anti-hypertenseurs, tels que les peptides inhibiteurs de la rénine, les dérivés d'oxazolidinone ou glycol peptides substitués par des restes aminés et/ou des noyaux hétérocycliques azotés ou thiazolés. A titre d'antiagrégants plaquettaires, on peut notamment citer la ticlopidine et l'hydrogénosulfate de clopidogrel ; les anticoagulants coumariniques dont la warfarine et les composés du groupe de l'indan-dione, dont la phényl indan-dione. A titre d'anticancéreux, on peut notamment citer le paclitaxel et le docétaxel qui sont des composés insolubles dans l'eau ; les extraits et alcaloïdes de T

inca zzziyzof° tels que la vincristine, la vincaleucoblastine ou vinblastine, la vincamine et leurs dérivés ; les alcaloïdes d'Ochrosia elliptica dont fellipticine. Parmi les extraits végétaux et leurs principes actifs isolés ou dérivés, on peut notamment citer les alcaloïdes tels que la yohimbine, les flavonoïdes dont la diosmine, la rutine et ses dérivés tels que la troxérutine ; les extraits de Pygeum afi°icayzmzz ou de Se

epezzs. A titre d'immunosuppresseurs, on peut en particulier citer la ciclosporine et le tacrolimus. Parmi les divers médicaments du système nerveux central, figurent les tranquillisants, les sédatifs, les hypnotiques et anesthésiques. A titre d'exemple, on peut citer les barbituriques tels que les thiobarbituriques ; les anxiolytiques tels que les benzodiazépines ; les antihistaminiques tels que la terfénadine, la loratadine, la desloratadine et la cétirizine ; les antidépresseurs tricycliques et sérotoninergiques tels que la fluoxétine, la paroxétine, la sertraline et le citalopram. Parmi les antimigraineux, on peut citer les composés du groupe des "triptans" sérotoninergiques tels que foxitriptan, le sumatriptan et l'almotriptan. Parmi les antibiotiques, on peut notamment citer les céphalosporines de troisième génération telles que le céfixime trihydrate et le cefpodoxime proxétil ; les macrolides tels que fazithromycine, la clarithromycine, la roxithromycine, la josamycine, la spiramycine ; les synergistines telles que la pristinamycine ; les quinolones et les quinoxalines, dont le carbadox. Parmi les antiparasitaires on peut citer les antipaludiques tels que l'halofantrine, la méfloquine, le proguanil, la pyriméthamine, les extraits d'A

tenzisia spp et les substances isolées de ces extraits et leurs dérivés tels que fartémisine, l'artémisinine ; la série des avermectines, dont l'ivermectine pratiquement insoluble dans l'eau ; les anthelminthiques dérivés du benzimidazole à usage vétérinaire tels que par exemple le tiabendazole, falbendazole, le mébendazole, le fenbendazole et le triclabendazole ; la classe des salicylanilides à usage vétérinaire, utilisés dans les fascioloses (douvicides) et autres parasitoses comprenant notamment le bromoxanide, le brotianide, le clioxanide, le closantel, l'oxyclozanide, le rafoxanide ainsi que le dibromosalan et le tribromosalan. Selon l'Invention, le ou les principes actifs sont de préférence choisis parmi les hypolipidémiants parmi lesquels le fénofibrate est tout particulièrement préféré, les hormones stéroïdiennes parmi lesquelles la progestérone est tout particulièrement préférée et les antifongiques parmi lesquels fitraconazole est tout particulièrement préféré. Le ou les principes actifs représentent de préférence de 10 à 90 % en poids du poids total de la composition pharmaceutique, ces pôurcentages étant bien évidemment modulés selon les besoins de la formulation eu égard aux doses efficaces du principe actif considéré. Selon une forme de réalisation avantageuse de l'Invention, le principe actif micronisé se présente, avant son mélange avec les autres constituants de la présente composition pharmaceutique, sous la forme d'une poudre dont les particules ont une dimension homogène de taille inférieure ou égale à 45

m et, si besoin, inférieure ou égale à 10

m. Ainsi qu'on fa vu précédemment, la présence d'un agent tensioactif est l'une des caractéristiques essentielles de la composition pharmaceutique conforme à l'Invention. Cet agent tensioactif est de préférence choisi parmi les composés présentant une valeur de la balance hydrophile-lipophile (HLB) élevée, de préférence supérieure ou égale à 15. Parmi de tels agents tensioactifs, on peut en particulier citer le laurylsulfate de sodium (HLB 40), les poloxamers (HLB 16-29), les macrogol éthers d'alcools organiques (HLB 15-1S), et les sucrose-esters d'acides organiques (HLB 15-16). Selon un mode de réalisation préféré de l'Invention, l'agent tensioactif est le laurylsulfate de sodium.

Le ou les agents tensioactifs utilisables dans la composition pharmaceutique conforme à l'Invention représentent de préférence de 1 à 10 % en poids du poids total de ladite composition et encore plus préférentiellement de 5 à 10 % en poids. 5 Selon une forme de réalisation particulière de l'Invention, l'agent tensioactif se présente sous forme solide. Dans ce cas, il peut étre co-micronisé avec le principe actif. Les techniques de micronisation de principes actifs (en présence ou non d'un agent tensioactif solide) sont bien connues de l'homme de l'art et peuvent notamment être réalisées au moyen de broyeurs à jet d'air ou de broyeurs à jet liquide 10 (Microfluidizer

). On peut notamment utiliser un principe actif co-micronisé avec du laurylsulfate de sodium. Le rapport pondéral principe actif/agent tensioactif est de préférence compris entre 10011 et 5/1. Parmi les polymères cationiques insolubles dans l'eau à pH

15 supérieur ou égal à 5 utilisables conformément à la présente Invention, on peut citer les polymères acryliques contenant un groupe amine tertiaire tels que les polymères de type méthacrylate aminoalkyle solubles en milieu acide, c'est à dire à pH inférieur à 5. Parmi ces polymères, on peut par exemple citer le terpolymère de poly(diméthylaminoéthyl)méthacrylate, de méthyl méthacrylate et de butyl méthacrylate et le terpolymère de poly(diéthylaminoéthyl)méthacrylate, de méthyl méthacrylate et de butyl méthacrylate. Selon l'Invention, le polymère cationique préféré est un terpolymére de poly(diméthylaminoéthyl)méthacrylate, de méthyl méthacrylate et de butyl méthacrylate tel que celui vendu sous Ia dénomination Eudragit

E par la société Rôhm Pharma. Selon l'Invention, Ie ou les polymères cationiques insolubles représentent de préférence de 0,5 à 15 % en poids par rapport au poids total de la composition pharmaceutique et encore plus particulièrement de 1 à 10 %. Par ailleurs, selon un mode de réalisation préféré de la composition pharmaceutique conforme à l'Invention, le rapport pondéral polymère cationique insoluble / principe actif est compris entre 1/5 et 1/30.

L'acide organique ou minéral présent dans la composition pharmaceutique conforme à l'Invention peut notamment étre choisi parmi l'acide citrique, l'acide succinique, l'acide fumarique, l'acide acétique, l'acide phosphorique, l'acide sulfurique et l'acide chlorhydrique. L'utilisation d'acide succinique est particulièrement préférée selon l'Invention. Cet acide organique ou minéral représente de préférence de 1 à % en poids par rapport au poids total de la composition pharmaceutique conforme à l'Invention, et encore plus préférentiellement de 2 à 7 % en poids. 10 L'utilisation d'un acide organique ou minéral permet de créer un micro-pH favorisant la solubilisation du polymère cationique insoluble dans l'eau à pH supérieur ou égal à 5. En effet, le polymère devient soluble dans l'eau en formant un sel en présence de restes acides. Selon une forme de réalisation préférée de l'Invention, le rapport pondéral acide organique ou minéral/polyrnère cationique insoluble dont dépend aussi, de façon surprenante, la dissolution du principe actif, est compris entre 6/1 et 0,25/1 et encore plus préférentiellement entre 2/1 et 0,5/1. Par ailleurs, le ratio principe actif lipophile/acide minéral ou organique au sein de la composition pharmaceutique conforme à l'Invention est de préférence compris entre 1/1 et 30/1 et encore plus préférentiellement, il est égal à 20/ 1. Une composition pharmaceutique particulièrement préférée selon flnvention comprend (en poids par rapport au poids total de ladite composition) - 40 à

0 % environ de fénofibrate à titre de principe actif lipophile, - 2 à 10 % environ d'agent tensioactif, - 2 à 10 % environ d'un terpolymère de poly(diméthylaminoéthyl)-méthacrylate, de méthyl méthacrylate et de butyl méthacrylate (Eudragit E

), et - de 2,5 à 5 % environ d'un acide minéral ou organique, la teneur de 5 environ étant particulièrement préférée.

Par ailleurs, la composition pharmaceutique particulièrement préférée et telle que décrite ci-dessus peut être diluée si besoin par incorporation de divers agents d'écoulement des poudres et ce, dans une proportion voisine de 40 à 50 %. La composition pharmaceutique conforme à l'Invention et telle que décrite de façon générale ci-dessus permet d'améliorer la dissolution des principes actifs lipophiles très peu solubles, voire insolubles dans Peau, et en particulier celle du fénofibrate et d'accroître ainsi leur absorption intestinale. L'Invention fournit donc une composition pharmaceutique comprenant un principe actif lipophile présentant, dans le cas particulier du fénofibrate, une dissolution d'au moins 50 % en 15 minutes, supérieure à 80 % en 30 minutes, supérieure à 85 % en 45 minutes et supérieure à 90 % en 60 minutes, telle que mesurée conformément à la méthode de la palette tournante à 75 tours/min selon la Pharmacopée Européenne, dans un milieu de dissolution constitué de laurylsulfate de sodium 0,1 M en solution aqueuse portée à 37°C. Sans vouloir être lié à une quelconque théorie, l'amélioration de la dissolution des principes actifs lipophiles et en particulier de celle du fénofibrate pourrait être facilitée par le micro-pH acide créé par l'acide organique ou minéral au contact du polymère cationique insoluble dans l'eau, la dissolution de celui-ci entraînant une meilleure mouillabilité de l'agent tensioactif d'où une amélioration de la dissolution du principe actif. La phase interne de la composition pharmaceutique conforme à l'Invention peut également renfermer, selon les besoins de la formulation, un ou plusieurs excipients choisis parmi les agents diluants et/ou liants, les agents désintégrants et les adjuvants classiques de pulvérisation, de compression, de lubrification et d'écoulement des poudres connus de l'homme de l'art, à condition, toutefois, que la présence d'un tel excipient ne dénature pas le caractère homogène et monophasique de ladite phase interne. Parmi de tels excipients, on peut plus particulièrement citer les agents d'écoulement des poudres tels que le talc, la silice, (acide stéarique, le stéarate de magnésium et ses dérivés, les agents liants tels que les celluloses telles que la cellulose microcristalline, les dextrines et maltodextrines, et les agents désintégrants tels que l'amidon modifié comme le carboxyméthyl amidon vendu par exemple sous la dénomination Primogel

et leurs mélanges.

Lorsqu'ils sont utilisés dans la phase interne de la composition pharmaceutique conforme à l'Invention, les agents d'écoulement des poudres représentent alors de préférence de 40 à 50 % en poids environ par rapport au poids total de la composition pharmaceutique conforme à l'Invention. La composition pharmaceutique conforme à la présente Invention et telle que décrite précédemment peut être incorporée, parmi d'autres ingrédients de formulation, dans la mise en forme d'un produit fini médicamenteux. La forme pharmaceutique finale ainsi obtenue comporte, outre la composition pharmaceutique décrite ci-dessus, d'autres composants constituant une phase externe comprenant un ou plusieurs excipients. Dans le cadre de la présente Invention, on entend par "phase externe", tout revêtement présent sur la composition pharmaceutique telle que décrite précédemment, sur un produit semi-ouvré, sur le principe actif modifié ou sur un produit intermédiaire. Selon l'Invention, on entend par "produit semi-ouvré" ou par principe actif modifié ou encore par produit intermédiaire, toute composition intermédiaire entre la matière première constituée par le principe actif lipophile micronisé et le produit fini. Ce dernier correspond au médicament sous une forme galénique achevée telle que comprimé, gélule ou encore sachet. Ce produit semi-ouvré peut se présenter sous différentes formes physiques, en particulier atomisat ou granulé, avant d'être incorporé dans la forme galénique finale. Cette phase externe peut notamment comprendre un ou plusieurs excipients classiques tels que ceux utilisés dans le domaine pharmaceutique et chimiquement compatibles avec le principe actif mis en oeuvre conformément à l'Invention. Parmi de tels excipients, on peut notamment citer les agents diluants et/ou liants, les agents de désintégration, les charges, les pigments, les agents mouillants, les tampons, ainsi qu'un ou plusieurs adjuvants susceptibles de faciliter l'écoulement des poudres tels que les agents d'écoulement ou lubrifiants (talc, silice, acide stéarique, le stéarate de magnésium et ses dérivés), couramment employés pour améliorer les caractéristiques rhéologiques des produits pulvérulents et leur mise en forme pharmaceutique finale (ensachage, répartition en gélules, compression).

Parmi les agents liants pouvant être utilisés dans la composition pharmaceutique conforme à l'Invention, on peut notamment citer les celluloses telles que la cellulose microcristalline, les dextrines, les maltodextrines, les cyclodextrines, le mannitol et leurs mélanges. Les agents liants facilitent les opérations de compressions nécessaires à l'obtention de comprimés et confèrent une dureté adéquate à ces derniers. Lorsqu'ils sont utilisés, ces agents liants représentent de préférence de 5 à 60% du poids total de la formulation galénique finale ou forme pharmaceutique. Parmi les agents de désintégration pouvant être utilisés dans la composition pharmaceutique conforme à l'Invention, on peut notamment citer la carboxyméthylcellulose de sodium réticulée (croscarmellose sodique), l'amidon modifié tel que le carboxyméthyl amidon vendu par exemple sous la dénomination Primogel

et leurs mélanges. Parmi les agents d'écoulement ou lubrifiants pouvant être utilisés dans la composition pharmaceutique conforme à l'Invention, on peut notamment citer la silice colloïdale anhydre telle que le produit vendu sous la dénomination Aerosil

le dioxyde de silice précipitée, le talc, le stéarate de magnésium, l'acide stéarique, le polyéthylèneglycol (PEG), et leurs mélanges ; la silice colloïdale anhydre étant particulièrement préférée. Ces agents d'écoulement sont utilisés pour empêcher les composants des comprimés ou des granulés de former des agrégats au cours de la préparation de ces comprimés ou granulés et pour réduire également les frictions pendant les opérations de compression. Lorsqu'ils sont utilisés, ils sont généralement présents dans des proportions comprises entre 0,1 et 3 % du poids total de la forme galénique finale. La phase externe peut également renfermer un acide organique ou minéral tels ceux définis ci-dessus. Lorsqu'elle est présente, la phase externe peut représenter jusqu'à 60 % en poids du poids total de la forme galénique finale, de préférence jusqu'à 45 %. Selon un mode de réalisation préféré, la composition pharmaceutique selon la présente Invention se présente sous forme de comprimés. Selon un autre mode de réalisation, la composition pharmaceutique selon la présente Invention se présente sous forme de granulés répartis en gélules.

La présente Invention a également pour objet un procédé de préparation d'une telle composition pharmaceutique comprenant les étapes suivantes a) le mélange d'au moins un principe actif lipophile solide et micronisé, d'au moins un agent tensioactif, d'au moins un polymère cationique 5 insoluble dans l'eau à pH supér

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