Pharmacodynamic and pharmacokinetic profile of S 17092, a new orally active prolyl endopeptidase inhibitor, in elderly healthy volunteers. A phase I study.

AIMS: The aim of this study was to characterize the pharmacodynamics and the pharmacokinetics of S 17092, a new orally active prolyl endopeptidase inhibitor following single and repeated administration in elderly healthy volunteers. METHODS: This was a double-blind, randomized, placebo-controlled, single and multiple dose study in elderly healthy male and female volunteers (n = 36). Four doses were investigated in sequential order: 100, 400, 800 and 1200 mg. Each dose was administered orally once a day in single administration and then, after a 1 week washout period, during 7 days. Pharmacodynamics were assessed by measurement of plasmatic prolyl endopeptidase (PEP) activity, quantitative electroencephalogram (EEG) and psychometric tests. S 17092 concentrations in plasma were quantified by high performance liquid chromatography with tandem mass spectrometric detection. RESULTS: PEP activity in plasma was dose-dependently inhibited both after administration of a single dose and after repeated doses of S 17092. The mean maximal inhibition was obtained within 0.5-2 h after dosing, while inhibition lasted at least 12 h after dose administration. S 17092 appeared to be a centrally active substance as it induced statistically significant modifications in EEG compared with placebo. S 17092 at 100 mg exerted an acute increase in alpha band following single administration at 4 h and 8 h postdosing. When administered repeatedly over 7 days S 17092 did not appear to induce significant lasting central nervous system (CNS) effects. In psychometric tests, response times in the numeric working memory were significantly reduced compared with placebo, following the 800 mg dose. There were some beneficial residual effects of the 1200 mg dose on day 13: delayed word recall and word recognition sensitivity improved compared with the declines noted under placebo. Maximum measured concentration (Cmax) and area under the curve (AUC) parameters increased in proportion to the dose. The terminal half-life (t(1/2)) values ranged between 9 and 31 h on day 1 and between 7 and 18 h on day 14. A high interindividual variability was observed at all dose levels. S 17092 was well tolerated with no clinically significant changes in laboratory or physical parameters observed at any dose. CONCLUSIONS: S 17092 had a potent, dose-dependent inhibitory effect on plasmatic PEP, increased alpha band EEG at the 100 mg dose and improved performance in two verbal memory tests at the 1200 mg dose while there were disruption to the vigilance task. The results obtained in elderly healthy subjects indicated that S 17092 is suitable for once-daily dosing without any serious adverse events.

Large scale safety study of ketoprofen 25 mg (Toprec) in febrile and painful conditions.

OBJECTIVE: To assess the safety, tolerability and efficacy of low-dose ketoprofen (75-150 mg daily for 5 to 15 days) in a general practice setting. DESIGN: Open label, non-controlled study of ketoprofen 25 mg tablets in the treatment of pain in ENT diseases, dysmenorrhoea, and musculoskeletal disorders. SETTING: General practice, 600 investigators SUBJECTS: Four thousand and sixty-eight patients, aged 13-93 years, mean 42.3 years, 1009 with ENT diseases (mean age 38.8 (13-83) years, 53% female), 978 with dysmenorrhoea (mean age 30.3 (13-60) years, 100% female), 2081 with musculoskeletal disorders (mean age 49.6 (16-93) years, 54% female). MAIN OUTCOME MEASURES: Occurrence of adverse events, on patient and physician evaluation; dose and duration of treatment prescribed/taken (diary); global evaluation of efficacy by patient and physician. RESULT: Twenty-two patients were lost to follow-up (<1%); dose effectively taken was lower than prescribed (3.3 versus 3.6 tablets/day); treatment was stopped prematurely in 3.3% of patients because of adverse events, in 17.1% because of early success of therapy. Gastrointestinal adverse events (AE) were the most frequent (76%) of AE), occurring in 10% of patients. They were more frequent in patients with musculoskeletal pain, who were older and had more associated diseases. Five patients were hospitalized, two for preplanned hospitalizations, the others for one asthma attack, one worsening of low back pain, and one angina attack, none attributed to treatment by the GP. None of the AE was life-threatening. Identified risk factors for AE were age and previous medical history, especially of gastrointestinal disorders. CONCLUSIONS: Good quality large scale studies with little or no loss to follow-up can be done in a general practice setting. At the dose used, ketoprofen was generally well tolerated, and used at a lower dose than prescribed, it was not associated with severe or new side-effects. The results of this study could justify its use in self-medication in these indications.

Multicentric double-blind study comparing efficacy and safety of minaprine and imipramine in dysthymic disorders.

This multicentre study compares the therapeutic efficacy and safety of minaprine (200 mg) to that of imipramine (50, 75, 100 mg) in the treatment of patients over 40 years suffering from dysthymic disorders as diagnosed according to DSM III. After 4-7 days on placebo, 67 patients were randomly assigned to receive either drug for a period of 6 weeks in a double-blind manner. As rated by the Hamilton Depression Rating Scale and evaluated by exploratory statistics, minaprine showed similar efficacy to imipramine in these patients. Minaprine was better tolerated than imipramine according to the physicians' tolerance rating (p < 0.05) and produced significantly fewer symptoms of the autonomic nervous system as compared to imipramine (p < 0.01).

Penta- and hexadienoic acid derivatives: a novel series of 5-lipoxygenase inhibitors.

The synthesis of a series of pentadienoic and hexadienoic acid derivatives is reported. These compounds were tested as inhibitors of 5-lipoxygenase (5 LO) and cyclooxygenase (CO) in vitro and as inhibitors of arachidonic acid (AA) induced ear edema in mice in vivo. Their potency is compared with that of the standard inhibitors nafazatrom, BW 755C, NDGA, KME4, quercetine, and L 652,243. The most potent compound in vivo, diethyl 2-hydroxy-5-(ethylthio)-2(Z),4(Z)-hexadienedioate (20) inhibited AA-induced ear edema when administered topically or orally, with an ED50 value of 0.01 mg/ear and 20 mg/kg, respectively. Among the standard compounds tested, L 652,243 was the most active compound in this test with an ED50 value of 0.01 mg/ear and 1 mg/kg po, but unlike this compound, 20 is a selective inhibitor of 5-LO (IC50 = 2 microM) without any significant activity against CO (IC50 greater than 50 microM). Most of the other compounds in this series are also selective 5-LO inhibitors.

The effects of N-3 polyunsaturated fatty acids on the generation of platelet-activating factor-acether by human monocytes.

Human leukocytes generate platelet-activating factor (PAF-acether), a lipid mediator of inflammation, from membrane alkyl phospholipids through the release of arachidonic acid or other fatty acids at the 2-position and subsequent acetylation. Because it was previously demonstrated that fish oil fatty acids suppress human leukocyte arachidonic acid release and metabolism, separate experiments were conducted to investigate the effects of dietary fish oil supplementation and in vitro incubation with fish oil fatty acids on calcium ionophore-stimulated PAF-acether generation in human monocytes. In subjects on their regular diets, a 4-hr incubation of monocyte monolayers with an optimally effective concentration of arachidonic acid of 1 micrograms/ml resulted in a 64% increase of calcium ionophore-induced net PAF-acether generation from 7.75 +/- 0.78 ng/10(6) cells for untreated monolayers to 12.70 +/- 1.21 ng/10(6) cells (mean +/- SEM). Treatment of monolayers with eicosapentaenoic acid (EPA) at the optimal concentration of 1 micrograms/ml decreased net PAF-acether generation by 28%. However, treatment of monocyte monolayers with docosahexaenoic acid did not appreciably affect net PAF-acether generation. The changes in PAF-acether release with each fatty acid added in vitro paralleled those in total PAF-acether generation; the percentage PAF-acether release remained unaffected. Three weeks of dietary supplementation with 18 g MaxEPA daily, providing 3.2 g EPA did not affect the PAF-acether generation of calcium ionophore-stimulated human monocyte monolayers. However, 6 weeks of dietary supplementation resulted in a 47% decrease of net total PAF-acether generation and a concomitant 59% decline in net PAF-acether release; the percentage release of PAF-acether was not affected. Thus, whether added to the diet or introduced in vitro, fish oil-derived fatty acids suppress PAF-acether generation by human monocyte monolayers.

Differential effects of calcium channel blockers on leukotriene C4- and D4-induced contractions in guinea pig pulmonary parenchymal strips.

Leukotriene (LT)C4 and LTD4-induced contractile effects in guinea pig pulmonary parenchyma were distinguished by their sensitivity to calcium channel blockers. LTC4-induced contractions were inhibited in a noncompetitive manner in the presence of calcium channel blockers, whereas LTD4 contractions were unaffected. In the presence of diltiazem, maximum LTC4-induced (1 X 10(-7) M) contractions were reduced by 24% and the concentration-effect curve was shifted to the right in a nonparallel manner; diltiazem had no significant effect on the LTD4 response. We used this differential sensitivity to calcium channel blockade to permit pharmacological characterization in guinea pig pulmonary parenchyma of the interaction of the competitive LT blocker FPL55712 and the putative LTD4 receptor, LTRd. We showed, using [3H]LTC4, that at least 15% of LTC4 is converted to LTD4 under our experimental conditions. We performed a Schild analysis of the inhibition of LTD4-induced contractions by FPL55712 in the presence of the calcium channel blocker diltiazem (0.67 mM). The Kb derived from this analysis (3.2 X 10(-7) M) agrees closely with the Ki derived for the interaction of FPL55712 and specific LTD4 binding in lung membranes. A Schild analysis of the interaction of FPL55712 and LTC4 in the presence of diltiazem resulted in competitive inhibition with a Kb of 4.7 X 10(-7) M. This apparent competitive inhibition, combined with the similarity of these binding constants, suggests that diltiazem is effective in blocking LTC4-mediated responses and that when these effects are blocked, LTC4 induced contractions are mediated through LTRd. The differential effects of calcium blockade on these two agonists provides evidence for distinct coupling mechanisms for LT receptors in this tissue.

[Potential value of eicosapentaenoic acid]. / Intérêt potentiel de l'acide eicosapentaénoïque.

The arachidonic acid substitution by an alternative fatty acid, substrate for the 5-lipoxygenase and the cyclo-oxygenase pathway constitutes a novel therapeutic approach or a complement for other therapeutics in the inflammation area. Eicosapentaenoic acid (EPA), one of the fish oil components, is a substrate for both enzymes and an inhibitor for several enzymes of arachidonic acid cascade, in vitro and in vivo. The EPA-generated metabolites have less pro-inflammatory effects than those produced by arachidonic acid metabolism.

Effects of dietary supplementation with marine fish oil on leukocyte lipid mediator generation and function in rheumatoid arthritis.

Twelve patients with active rheumatoid arthritis supplemented their usual diet with 20 gm of Max-EPA fish oil, daily, for 6 weeks. Following this supplementation, the ratio of arachidonic acid to eicosapentaenoic acid in the patients' neutrophil cellular lipids decreased from 81:1 to 2.7:1, and the mean generation of leukotriene B4 (with calcium ionophore stimulation) significantly declined by 33%. The mean neutrophil chemotaxis to both leukotriene B4 and FMLP significantly increased toward the normal range at week 6. The generation of 5-lipoxygenase products by calcium ionophore-stimulated monocytes was not significantly suppressed, but a significant decline (37%) in platelet-activating factor generation was noted at week 6. The modulation of these measures of leukocyte inflammatory potential suggests that fish oil supplementation may have an antiinflammatory effect.

Generation of leukotrienes by human monocytes pretreated with cytochalasin B and stimulated with formyl-methionyl-leucyl-phenylalanine.

The N-formylated tripeptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) initiated the generation of immunoreactive C-6 sulfidopeptide leukotrienes and of leukotriene B4 (LTB4) in a dose-dependent manner from monolayers of human monocytes pretreated for 10 min with 5 micrograms/ml of cytochalasin B. The EC50 for the immunoreactive C-6 sulfidopeptide leukotrienes was 10(-8) M FMLP and for immunoreactive LTB4 was 5 X 10(-8) M FMLP. The maximal response to FMLP occurred within 10 min, and the sum of the two classes of leukotrienes generated was about 1/6 that obtained from monocytes stimulated with calcium ionophore A23187. The requirement for cytochalasin B in order for FMLP, but not the calcium ionophore, to stimulate leukotriene generation is compatible with the ability of cytochalasin B to augment in other cells certain stimulus-specific transmembrane responses that are not dependent on the integrity of the cytoskeleton. Resolution by reverse phase high performance liquid chromatography of the products released from monocytes pretreated with cytochalasin B and stimulated with FMLP or calcium ionophore yielded a single peak of immunoreactive LTB4 eluting at the same retention time as the synthetic standard; immunoreactive C-6 sulfidopeptide leukotrienes eluted at the retention times of leukotriene C4 (LTC4) and leukotriene D4 (LTD4). [3H]LTB4 was not metabolically altered by monocytes pretreated with cytochalasin B and activated with FMLP in comparison with cells treated with buffer alone, whereas [3H]LTC4 was partially converted to [3H]LTD4. The leukotriene-generating response of monolayers of human monocytes pretreated with cytochalasin B to FMLP is receptor-mediated, as indicated by the inactivity of the structural analog N-acetyl-methionyl-leucyl-phenylalanine and by the capacity of the FMLP receptor antagonist carbobenzoxyphenylalanyl-methionine to inhibit the agonist action of FMLP in a dose-response fashion.

Regulation of mediator release from mouse bone marrow-derived mast cells by glucocorticoids.

Mouse bone marrow-derived mast cells (BMMC), which were differentiated from their bone marrow precursors during 14 days of culture in the presence of a T cell lymphokine, were cultured in the absence or in the presence of 0.01 to 5 microM dexamethasone (DEX) for periods of 6 to 96 hr to assess the effects of steroid treatment on stimulus-dependent mediator release. Preincubation of the BMMC for 24 hr with DEX inhibited the subsequent immunoglobulin (Ig) E-dependent release of beta-hexosaminidase in a dose-dependent manner by up to 38% (mean, n = 7) at 1 microM DEX, and the decrease was statistically significant at DEX concentrations greater than or equal to 0.5 microM. DEX (1 microM) inhibited granule secretion from BMMC in a time-dependent manner; the decrease was statistically significant after a preincubation period of 6 hr, was maximal after preincubation times greater than or equal to 24 hr, and was reversible by 24 hr of incubation in medium lacking the steroid. Preincubation for 24 hr with DEX also inhibited the IgE-dependent biosynthesis and release of the immunoreactive leukotrienes (LT)C4 and LTB4 in a dose-dependent manner by up to 56% (n = 7) and 54% (n = 7), respectively, at 1 microM DEX, and the decrease was statistically significant for each product at DEX concentrations greater than or equal to 0.1 microM. In contrast, BMMC preincubated with DEX for 24 hr before sensitization and antigen challenge demonstrated a statistically significant increase in the release of immunoreactive prostaglandin (PG) D2 at DEX concentrations greater than or equal to 0.1 microM and a maximal enhancement of 188% (n = 3) at 1 microM DEX. The effect of 1 microM DEX on the enhancement of IgE-dependent PGD2 generation was significant after 6 hr, and was maximal by 72 hr. The inhibitory effects of DEX on the antigen-induced release of 5-lipoxygenase pathway products were confirmed by the physical measurements of 5-hydroxy-eicosatetraenoic acid (5-HETE) and LTC4, and by isotopic measurement of [3H]LTC4 after reverse-phase high performance liquid chromatography (RP-HPLC). As assessed by fluorescence cytofluorography of IgE-sensitized BMMC that were interacted with F(ab')2 rabbit anti-mouse epsilon and fluorescein isothiocyanate-labeled F(ab')2 goat anti-rabbit IgG-F(ab')2, the number of IgE-Fc receptors on the cell surface decreased by more than 55% after treatment for 24 hr with 1 microM DEX.+

Arachidonic acid derivatives as mediators of asthma.

Arachidonic acid metabolites generated by the cyclooxygenase pathway and by the various lipoxygenase pathways are produced by both resident pulmonary cells and infiltrating cells from the vascular compartment. The various proinflammatory biologic activities of these naturally occurring compounds include bronchoconstriction, increased vascular permeability, alterations in vasomotor tone, enhanced mucus secretion, and granulocyte adherence and chemotaxis. The leukotrienes derived from the 5-lipoxygenase pathway are particularly potent as mediators of inflammation, requiring only nanomolar concentrations for the evocation of their effects. Thus, although a variety of potent cyclooxygenase inhibitors are currently available for anti-inflammatory therapy, therapeutic modalities for the downregulation of leukotriene biosynthesis or efficacy would be highly desirable. Current concepts about the enzymatic cascade in leukotriene generation, the prospects for dietary modification as an adjunct to pharmacotherapeutic intervention, and the implications of specific receptors in leukotriene-mediated events are therefore considered.

Pharmacologic regulation of mediator generation and release from the murine bone marrow derived mast cell.

Mucosal mast cells constitute the subclass of IgE-FcR-bearing cells for which the murine bone marrow derived mast cell (BMMC) is an in vitro model. BMMC can be induced by an IgE-dependent mechanism to biosynthesize prostaglandin D2, several 5-lipoxygenase products, and an alkyl-ether phospholipid metabolite, as well as to degranulate. By introduction of selective enzyme inhibitors, it was determined that the bioavailability of each mediator class occurred without regulatory effects on the others. Additionally, since BMMC divide in culture, cell responsiveness for secretion of each mediator class was shown to be independent of the state of proliferation by employing three different nontoxic inhibitors of cell division.

Extramucosal method in rhinoplasty.

Principles, history, terminology and technique of the extramucosal method in rhinoplasty are presented. The advantages of preserving the mucosa are reviewed: less bleeding, less swelling, fewer nasal breathing troubles, prevention of parrot's beaked nose, support for skeletal grafts, easier method for secondary rhinoplasty if it is needed, facility in measuring the skeletal resections.

The preplanned rhinoplasty.

In aesthetic rhinoplasty performed by the extramucosal method, the "skeletization" of the nose that is obtained allowsmeasurements during the operation. Thereby, it is possible and useful to preplan the rhinoplasty with more accuracy and to inform the patient about the choice to be made. This new approach to rhinoplasty is safer and more precise and provides for (1) a choice of preplanned result (based on artistic technique and psychological reasons), (2) measurements for the plan, and (3) transfer of this plan to the patient during the operation.