Autoradiography in brain of Macaca fascicularis monkeys after injection of acetyl-DL-leucine [2-14C] (Tanganil).

Acetyl-DL-leucine [2-14C]: Tanganil a antivertigal drug has been injected intravenously in two macaca monkeys which have been sacrificed 2 and 5 minutes later. Radioactivity distribution has been studied by autoradiography in the brain. An important uptake of radioactivity is localized in the cortical structures and in several tisses such as nuclei of the vestibular system, including the inner ear.

Biochemical basis of the pharmacologic action of chondroitin sulfates on the osteoarticular system.

BACKGROUND: Chondroitin sulfates (CS) are involved in articular metabolism and could be used as therapeutic agents in degenerative articular diseases. OBJECTIVES: To review the published reports describing both the metabolism of glycosaminoglycans (GAG) and their involvement in osteoarticular pathophysiology. METHODS: MEDLINE search for relevant articles and review of cited references. RESULTS: 1) CS are formed of disaccharide units; sulfated galactosamine residues in position 4 or 6 are found in various ratios, depending on the age and the type of tissue. Binding to the core protein through N- and O-linkages leads to aggregates of monomers with high molecular weights. The proteoglycan aggregate exhibits viscoelastic and hydration properties and an ability to interact with the surrounding tissue through electric charges leading to protection of the cartilaginous tissues. 2) CS are synthesized both in chondrocytes and in bone cells by the action of specific glycosyl-transferases; their catabolism occurs in the matrix and involves numerous matrix (metalloproteinases) and lysosomal enzymes. 3) CS are inhibitors of extracellular proteases involved in the metabolism of connective tissues. In addition to their anti-inflammatory effects, CS in vitro stimulate proteoglycan production by chondrocytes; they also inhibit cartilage cytokine production and induce apoptosis of articular chondrocytes. CS increase the intrinsic viscosity of the synovial liquid. 4) In vivo in experimental arthritis, the number and severity of articular symptoms decreases after CS administration. In bones, CS accelerate the mineralization process and bone repair. CONCLUSIONS: All these data suggest that CS play a role in articular and bone metabolism by controlling cartilaginous matrix integrity and bone mineralization.

Effects of hyperprolactinemia on rat prostate growth: evidence of androgeno-dependence.

The effects of the polypeptide hormone prolactin (PRL) in the development and regulation of benign prostate hyperplasia (BPH) and also in prostate cancer are not very well characterized. This study examines the action of PRL, either alone or in association with androgens [testosterone (T) or dihydrotestosterone (DHT)], in the rat prostate gland. The effects of PRL and androgens were investigated after 30 and 60 days in control, castrated, castrated with a substitutive implant of T or DHT, and sham-operated Wistar rats. To enhance PRL release, we induced hyperprolactinemia by administering chronic injections of sulpiride (40 mg. kg(-1). day(-1)). Chronic hyperprolactinemia induces enlargement and inflammation of the lateral rat prostate without any histological changes on ventral and dorsal lobes. We also demonstrate that hyperprolactinemia induces Bcl-2 overexpression in the lateral rat prostate and that this could inhibit the level of apoptosis. The in vivo model established here is a useful in vivo approach for studying the hormonal regulation of normal and pathological prostate development.

Pharmacological effects of the lipidosterolic extract of Serenoa repens (Permixon) on rat prostate hyperplasia induced by hyperprolactinemia: comparison with finasteride.

BACKGROUND: The growth of the prostate gland is mainly dependent on androgens. Other hormones, like prolactin (PRL), also influence prostate development. Our purpose was to analyze and compare the effects of two drugs (5alpha-reductase inhibitor) used in the therapy of benign prostatic hyperplasia: lipidosterolic extract of Serenoa repens (LSESR), and finasteride in an in vivo model of rat prostate hyperplasia induced by hyperprolactinemia. METHODS: Hyperprolactinemia was induced by 30 daily injections of sulpiride. Wistar rats received daily gavages of LSESR or finasteride. We used the following groups: control, castrated, castrated with a substitute testosterone (T), or 5alpha-dihydrotestosterone (DHT) implant. RESULTS: Hyperprolactinemia increases the wet weight and induces hyperplasia in the lateral prostate (LP). Unlike finasteride, LSESR significantly reduced LP growth and hyperplasia in castrated, DHT-implanted, and sulpiride-treated rats. CONCLUSIONS: Finasteride was only capable of inhibiting the effect of androgens on rat prostate enlargement. LSESR inhibited not only the androgenic but also the trophic effect of PRL in rat LP hyperplasia.

Calcium and bicarbonate ions mediate the inhibition of mast cell histamine release by Avène spa water.

Avène spa water (ASW) inhibits the histamine release induced in mast cells by substance P; the inhibition is reversed by EDTA and by EGTA. Calcium and magnesium ions, the major cations present in ASW, were experimented in simple saline solutions in the presence of various counter-ions. Only calcium salts inhibited the peptidergic stimulation, with different potencies ruled by the nature of the counter-anion (HCO3- > Cl- > SO4(2)). On a Ca2+ concentration basis, ASW was, however, more inhibitory, suggesting that other compounds present in ASW potentiate the effect of calcium.

Effect of the lipidosterolic extract of Serenoa repens (Permixon) and its major components on basic fibroblast growth factor-induced proliferation of cultures of human prostate biopsies.

OBJECTIVE: To assess the effect of the lipidosterolic extract of Serenoa repens (LSESr) on in vitro cell proliferation in biopsies of human prostate MATERIAL AND METHODS: Cell proliferation was assessed by incorporation of [3H]thymidine followed by historadiography. RESULTS: Basic fibroblast growth factor (b-FGF) induced a considerable increase in human prostate cell proliferation (from +100 to +250%); the glandular epithelium was mainly affected, minimal labeling being recorded in the other regions of the prostate. Similar results were observed with epidermal growth factor (EGF), although the increase in cell proliferation was not recorded in some cases. Lovastatin, an inhibitor of hydroxymethylglutaryl coenzyme A, antagonized both the basal proliferation and the growth factor-stimulated proliferation of human prostate epithelium (EGF, mean inhibition approximately 80-95%; b-FGF, mean inhibition approximately 40-90%). Geraniol, a precursor of both farnesyl pyrophosphate and geranylgeranyl pyrophosphate, and farnesol, the precursor of farnesyl pyrophosphate, increased cell proliferation only in some prostate specimens, this effect being antagonized by lovastatin. LSESr did not affect basal prostate cell proliferation, with the exception of two prostate specimens in which a significant inhibition of basal proliferation was observed with the highest concentration of LSESr (30 micrograms/ ml). In contrast, LSESr inhibited b-FGF-induced proliferation of human prostate cell cultures; this effect was significant for the highest concentration of LSESr (30 micrograms/ml). In some prostate samples, a similar inhibition was also noted with lower concentrations. Unsaturated fatty acids (UFA), in the range 1-30 ng/ml), did not affect the basal prostate cell proliferation, only a slight increase in cell proliferation was noted in 1 prostate specimen. UFA (1, 10 or 30 micrograms/ml) markedly inhibited the b-FGF-induced cell proliferation down to the basal value. Lupenone, hexacosanol and the unsaponified fraction of LSESr markedly inhibited the b-FGF-induced cell proliferation, whereas a minimal effect on basal cell proliferation was noted. CONCLUSIONS: Despite the large variability in the response of the prostate samples to b-FGF, these results indicate that LSESr and its components affect the proliferative response of prostate cells to b-FGF more than their basal proliferation.

Effect of the lipidic lipidosterolic extract of Serenoa repens (Permixon) on the ionophore A23187-stimulated production of leukotriene B4 (LTB4) from human polymorphonuclear neutrophils.

Although the lipidic extract of Serenoa repens (LESSr, Permixon, Sereprostat) is widely used in patients suffering from benign prostatic hypertrophy (BPH), its mechanism of action is not fully elucidated. It has been demonstrated that infiltration of the prostate by inflammatory cells is one of the aetiologic factors involved in the development of BPH. These inflammatory cell types, such as polymorphonuclear neutrophils (PMNs), produce chemotactic mediators and contribute to the development of the disease. Among the chemotactic factors generated by inflammatory cell types, the derivatives of arachidonic acid have been extensively studied. For instance, leukotriene (LT) B4 is one of the most potent chemotactic factors for PMNs and also exhibits a wide range of biological activities. In order to investigate the potential action of LESSr on arachidonate metabolism, and particularly on the synthesis of LTB4, the effect of this extract on the in vitro synthesis of LT by human PMNs stimulated with the calcium ionophore A23187 was investigated. LESSr significantly inhibits the production of 5-lipoxygenase metabolites (5-HETE, 20-COOH LTB4, LTB4 and 20-OH LTB4) at concentrations as low as 5 microg/ml. Such an effect of LESSr was also observed in the presence of exogenous arachidonic acid (20 microg/ml) and when f-MLP was used as the agonist, suggesting that inhibition of LTB4 production by the extract was unrelated to phospholipase A2 blockade and independent of the stimulating agent. The capability of LESSr to antagonize 5-lipoxygenase metabolites production may contribute, at least partly, to the understanding of its therapeutic activity on the inflammatory component of BPH.

Distribution study of radioactivity in rats after oral administration of the lipido/sterolic extract of Serenoa repens (Permixon) supplemented with [1-14C]-lauric acid, [1-14C]-oleic acid or [4-14C]-beta-sitosterol.

The study carried out on rats given orally the n-hexane lipido/sterolic extract of Serenoa repens (LSESR), supplemented with [14C]-labelled oleic or lauric acids or beta-sitosterol, demonstrated that radioactivity uptake in prostatic tissues shows the highest level in the case of administration of LSESR supplemented with [14C]-labelled oleic acid. This was clearly demonstrated on a rat with an induced fibro-muscular hyperplasia of the prostate and by quantitative measurements of radioactivity. Ratios of radioactivity in tissues compared to plasma show an uptake of radioactivity greater in prostate as compared to other genital organs, i.e. the seminal vesicles or to other organs such as liver.

[Effects of an hydrosoluble fraction from bovine bone (Ossopan) on murine osteoblasts in culture]. / Effets de la fraction hydrosoluble d'un extrait d'os bovin (Ossopan) sur des ostéoblastes murins en culture.

The effects of an hydrosoluble fraction of the bovine bone extract Ossopan on cultured murine osteoblasts were assessed in this study. The hydrosoluble fraction from Ossopan, obtained by acid/ethanol extraction, contained significant amounts of TGF-beta 1. Calvariae from new-born rats were cultured for 1 month in synthetic medium (DMEM) supplemented with 10% fetal calf serum to allow cell proliferation; immunocytochemistry studies performed with a rabbit serum raised against alkaline phosphatase indicated that only osteoblasts were present in cell cultures. Using an XTT-based colorimetric cell proliferation assay, we showed that the hydrosoluble fraction of the bovine bone extract dose-dependently reduced the proliferation of cultured osteoblasts. A similar inhibition was obtained with a recombinant TGF-beta 1. Thus, the inhibitory effect of the hydrosoluble fraction of Ossopan on osteoblast proliferation should be due to the cytokines contained in this preparation.

Comparison of the metabolism and pharmacokinetics of metbufen and itanoxone and their analogues in rats.

Metbufen, II, itanoxone, I, and two other derivatives of gamma-aryl-gamma-keto-substituted butyric acids labelled with 14C in their carbonyl group were synthesized for a metabolic investigation in rats. Profound changes in pharmacokinetic parameters, most specifically in the distribution, elimination, and metabolic pathways, were induced by substitution in the aromatic nucleus or changes in saturation of the aliphatic chain. The metabolites isolated from plasma and urine were identified by gas chromatography and mass spectrometry, by comparison with chemical controls, revealing the processes of metabolism of these structural analogues. This difference in metabolism further understanding of the diversity of biological effects inherent in these compounds.

1-Aryl-2-(aminomethyl)cyclopropanecarboxylic acid derivatives. A new series of potential antidepressants.

A series of 1-aryl-2-(aminomethyl)cyclopropanecarboxylic acid derivatives were synthesized and evaluated as potential antidepressants. Compounds with the Z configuration were synthesized from 1-aryl-2-oxo-3-oxabicyclo[3.1.0]hexane and those with the E configuration from (E)-1-phenyl-2-(hydroxymethyl)cyclopropanecarboxylic acid. The compounds were evaluated in animal tests designed to reveal potential antidepressant activity and the existence of undesirable side effects. Several derivatives were more active than imipramine and desipramine. On the basis of its activity in pharmacological animal tests of antidepressant activity and its potential lack of side effects, 1-phenyl-1-[(diethylamino)carbonyl]-2- (aminomethyl)cyclopropane hydrochloride, midalcipran (INN), was selected for further development. This compound is currently in phase III clinical evaluation.

Studies of arylthiazole oxamates in relation to oral antiallergic activity.

25 arylthiazole oxamate derivatives were synthesized and examined for antiallergic activity in the rat passive cutaneous anaphylaxis assay. These compounds were prepared by treatment of the appropriate bromoacetophenone with thioureas to give arylaminothiazoles. Further condensation with alkyloxalyl chloride gave the arylthiazolyl oxamates. Several derivatives showed a 70% inhibition at 5 mg/kg p.o. p-Alkoxy substitution on the phenyl ring resulted in enhanced activity while N-alkyl substitution on the nitrogen amide function inhibited the activity. Ethyl-N-(4-p-methoxyphenyl)-2-thiazolyl oxamate (tioxamast, F-1865) was selected for clinical studies.

[Contribution of stereochemistry to the study of the spatial organization of pharmacological receptors]. / Apport de la stéréochimie à l'étude de l'organisation spatiale des récepteurs pharmacologiques.

The important discovery by Pasteur of optical isomerism and the recent developments of stereochemistry showed that a complementarity exist between the geometry of molecules and their pharmacological receptors. The stereochemical bases and the principal configurational nomenclatures are briefly overviewed. The stereospecificity of the biological response and theories leading to an approach to stereochemical structures of main pharmacological receptors are developed. So, the biological activity of steroids is due to junctional modes of cycles and alpha or beta configurations of substituents. Acetylcholine has a skew conformation but it react by an anticlinal/anti-planar conformation with muscarinic receptor. To explain the difference in activity of adrenaline enantiomers, Easson and Stedman proposed a "three points" fixation to the adrenergic receptor. Dopaminergic receptor present a good degree of stereoselectivity: dopamine act by an anti-planar conformation in which the N-O distance is the same as in apomorphine (N-O10). The analgesic activity of morphinans is due to a cis junction of B and C cycles and to the stereoelectronic effect of the unshared lone pair on nitrogen. In the cyclamate sweeteners, some authors proposed for the sweet taste receptor a model with two points fixation (one acceptor and one donor) and two spatial barriers located at precise distances from this two sites. The stereoselectivity of molecules acting as substrates or inhibitors of enzymes is described. For example some oxazolidinone derivatives showed a selective inhibition toward monoamine oxidase A. Finally, the pharmacological activity falls often when molecules are administrated in racemic form. It seems that xenobiotics need to be dissymmetric for chiral recognition by biological systems.

GLC determination of itanoxone in biological fluids.

A sensitive and reliable method for the quantitative determination of itanoxone, 4-[4'-(2-chlorophenyl)phenyl]-4-oxo-2-methylenebutanoic acid, in biological fluids is described. A quantitative ethyl acetate extraction of the plasma samples is followed by reduction and methylation of itanoxone. Quantification is achieved by GLC using electron-capture detection and an internal standard. The minimum concentration of itanoxone detected in plasma is 0.1 microgram/ml. Recovery of the titrated compound added to human plasma averaged 100.9 +/- 2.92% (RSD).

Absorption and elimination of (14C) hesperidin methylchalcone in the rat.

Hesperidin methylchalcone resorption and excretion were studied in rats, using 14C-labelling. The level of radioactivity in the blood showed a peak 1-2 hours after oral administration of the labelled compound, at a dose of 10 mg/kg body weight. The blood kinetics pattern suggested an entero-hepatic cycle, which was demonstrated by i.v. administration of the compound at the same dose. The blood profiles for both administration routes, demonstrated that the bioavailability of the active principle was good. Urinary excretion was lower than faecal excretion after oral ingestion, and both were comparable after administration via the i.v. route. Moreover, excretion mainly occurred within the first 24 hours following administration. When hesperidin methylchalcone was given in a therapeutic, pharmaceutical formulation, its bioavailability was greatly improved. (This was not due to the alcoholic ingredient in the formula).