The pharmacology of VA21B7: an atypical 5-HT3 receptor antagonist with anxiolytic-like properties in animal models

VA21B7 (3-[2-(4-piperonylpiperazinyl) indolyl] carboxaldehyde) was synthesized as a potential 5-HT₃ receptor antagonist. Even though VA21B7 showed a higher affinity towards 5-HT₃ receptors as compared to other receptors studied, it was not a potent 5-HT₃ receptor antagonist either in the periphery or in the brain. In a simple animal model of anxiety such as the two-compartment box in mice, a remarkable anxiolytic-like effect was found at doses of 2–500 µg/kg IP and also at low oral doses, in the microgram range. These drug doses did not produce any significant effect on spontaneous motor activity of mice. The anxiolytic profile of VA21B7 was further explored using other models of anxiety in rats such as the elevated plus-maze and punished-drinking. VA21B7 was compared with standard 5-HT₃ receptor antagonists such as ondansetron, tropisetron and granisetron, with the 5-HT_1A agent buspirone and with diazepam. In the plus-maze, VA21B7 showed an anxiolytic-like profile after doses of 0.25–0.5 mg/kg IP or 2–4 mg/kg PO which did not modify the number of total entries into the open and closed arms of the maze. Diazepam, granisetron and tropisetron were also effective in this test but not ondansetron and buspirone. VA21B7 was also able to release suppressed behaviour in the punished-drinking test. The dose-response curve was bell-shaped with a peak at 2–4 mg/kg. At variance with other studies, 5-HT₃ receptor antagonists also increased the number of shocks taken in this test and the dose-response curve was also bell-shaped. VA21B7 was not anticonvulsant like diazepam, its anxiolytic action in the light/dark test was not flumazenil-sensitive and there was no rebound anxiogenic effect on withdrawal from chronic VA21B7 treatment for 15 consecutive days. Moreover, VA21B7 was not amnesic like the benzodiazepines but low doses of 2–4 mg/kg reduced the memory deficits induced in rats by scopolamine. Much higher doses were necessary to decrease spontaneous motor activity in rats. Since VA21B7 appears to be well tolerated in rodents at high doses, we think that it is of potential interest as an anxiolytic in humans.     

Characterization and prediction of IVF cycles generating “slow-cleaving” embryos

Purpose To characterize and predict cycles generating slowcleaving embryos in in vitro fertilization, 86 cycles were retrospectively divided into two groups (slow, n=41, and fast, n=45 according to whether the number of blastomeres per embryo on day 3 was or > than the mean of the distribution, respectively.Results Cycles generating slowcleaving embryos were treated with luteinizing hormonereleasing hormone agonist before ovarian stimulation for a shorter period (12.1±0.5 versus 15.6±1.1 days; P0.01) and had higher immaturity grade of oocyte-corona-cumulus complexes which resulted in embryos (1.6±0.1 vs 1.3±0.1; P0.05) when compared to cycles producing fastcleaving embryos. Both variables entered in a logistic regression model applied in order to predict the probability of a cycle generating slowcleaving embryos (goodness-of-fit chisquare=180.0, degrees of freedom (df)=80, P=0.4786. This model predicted correctly 86.7% (13 of 15) of cycles generating slowcleaving embryos and 83.3% (10 of 12) of cycles producing fastcleaving embryos when the estimated probability of a cycle producing slowcleaving embryos was 0.7 or 0.3, respectively.Conclusion Shorter treatment with hormone-releasing hormone agonist before ovarian stimulation and higher immaturity grade of oocyte-corona-cumulus complexes which result in embryos are predictive characteristics of in vitro fertilization cycles generating slow-cleaving embryos.     

Characterization of membrane melatonin receptor in mouse peritoneal macrophages: inhibition of adenylyl cyclase by a pertussis toxin-sensitive G protein

Melatonin binding sites were characterized in mouse peritoneal macrophages. Binding of 2-[125I]melatonin by macrophages fulfills all criteria for binding to a receptor site. Thus, binding was dependent on time, temperature and cell concentration, stable, reversible, saturable and specific. Stoichiometric studies showed a high-affinity binding site with a Kd of 0.58-0.71 nM. These data are in close agreement with data obtained from kinetic studies (Kd = 0.29 nM). The affinity of these binding sites suggests that they may recognize the physiological concentrations of melatonin in serum. Moreover, binding experiments using macrophage crude membranes showed that melatonin bound specifically to the membranes. Additionally, in competition studies we observed a low-affinity binding site (Kd = 2.02 microM). Melatonin inhibited significantly forskolin-stimulated cyclic AMP accumulation in a dose-dependent manner. This effect was blocked by luzindole, an antagonist of the melatonin membrane receptor. Pretreatment of macrophages with pertussis toxin blocked the inhibitory effect of melatonin. Pertussis toxin ADP-rybosilation and Western blot experiments demonstrated both alpha(i1/2) and alpha(i3/o) G protein subunits expression in mouse peritoneal macrophages membranes. Our results demonstrate the existence of melatonin receptors in mouse peritoneal macrophages, and a pertussis toxin-sensitive melatonin signal transduction pathway that involves the inhibition of adenylyl cyclase.     

Antibiotic-induced endotoxemia in a patient with endogenous endophthalmitis

PURPOSE: The aim of the study is to describe a case of suspected endotoxin-induced uveitis associated with septic endogenous endophthalmitis followed by antibiotic-induced endotoxemia. METHODS: The human leukocyte antigen (HLA) typing of peripheral leukocytes was studied by lymphocytotoxicity technique. Histological and immunohistochemical studies of paraffin embedded specimen were conducted. RESULTS: Findings of HLA typing revealed positive reaction for B 51, Cw 3, DR 8, DR 11, DQ 3. The vitreous body of an eviscerated eye was occupied by the non-specific granulomatous tissue, composed of fibroblast, plasma cells, and Sudan black staining positive foamy cells, including melaniferous phagocytes, identified as CD 68 positive macrophage. CONCLUSION: It is suggested that antibiotic-induced endotoxemia of a patient with septic endogenous endophthalmitis produced endotoxin-induced uveitis under an upregulation of HLA and endotoxin activated macrophages may release cytokines, followed by fibrin formation and subsequent granuloma.     

Ajoene in the topical short-term treatment of tinea cruris and tinea corporis in humans. Randomized comparative study with terbinafine.

Ajoene (CAS 92284-99-6), an organic trisulphur originally isolated from garlic, has an antimycotic activity which has been widely demonstrated both in vitro and in vivo. The objective of this work was to compare the safety and effectiveness of ajoene (0.6%, gel) with terbinafine (CAS 91161-71-6) (1%, cream) for the treatment of tinea corporis and tinea cruris. The patients selected were 60 soldiers with clinical and mycological diagnosis of either dermatophytosis. They were distributed at random in two treatment groups, one treated with ajoene at 0.6% and the other with terbinafine at 1%. All patients were evaluated clinically and mycologically 30 and 60 days after completion of the treatment, which was considered effective when clinical signs and symptoms had disappeared and the mycological cultures were negative. Thirty days after treatment, the percent healing rate was 77 and 75 for the groups treated with ajoene and terbinafine, respectively. Sixty days after treatment, the healing rate 73% and 71% for the groups treated with ajoene and terbinafine, respectively. These results and those obtained in previous studies confirm that ajoene is a new agent for the topic treatment of superficial mycoses, and for the first time show the therapeutic usefulness of an inhibitor of phospholipids biosynthesis in eukaryotes.     

Patterns of practice for acute myocardial infarction in a population from ten countries

Background: There is conclusive evidence from large scale randomized clinical trials (RCTs) that several treatments administered in the acute phase of a myocardial infarction (AMI) reduce mortality. However, only a minority of patients admitted with AMI receives at the appropriate treatments. Objectives: This study aims at (1) describe the utilization patterns for AMI; (2) determine the appropriateness of prescribing, measured as adherence to the ACC/AHA guidelines; and (3) determine which factors are associated with the administration of thrombolytic agents. Methods: The study was a multi-center survey carried out in ten countries (nine European and one Canadian province) over a 3-month period. Data were prospectively collected by clinical pharmacists. All consecutive patients admitted to the participating hospitals during the study period with a diagnosis of suspected AMI were included in the study. Rates of use were calculated as “overall utilization” and “adjusted utilization” (e.g., accounting for eligibility). Results: Data were available on 1976 patients from 56 participating centers. The mean age of the patients was 65 years (range 25–95, SD = 12.6) and 29.7% were women. Adjusted utilization rates were 63.7% for thrombolysis, 88% for aspirin, and 65.9% for β-adrenergic blocking agents. The most utilized thrombolytic agent was streptokinase (65.9%). The main reasons given by physicians for not administering thrombolysis was the delay from chest pain onset to admission. Patients admitted to teaching hospitals were less likely to receive aspirin than patients admitted to general hospitals (adjusted rate 90.1% vs 86%, P = 0.007), but they were more likely to undergo a primary invasive procedure (11.0% vs 2.5% P = 0.001). Multivariate analysis showed that age greater than 74 years, delay, prior myocardial infarction, and Killip scale were correlated with the non-utilization of thrombolysis. Conclusion: Recommended treatments are still underutilized in patients with AMI. Increased utilization is required, particularly for elderly people. There is a wide variability among hospitals with different affiliations (teaching vs non teaching), demonstrating the different patterns of practice in various settings. Received: 2 February 1998 / Accepted in revised form: 8 August 1998