Biomedical subjects

J Gras

Publications and source records attributed to J Gras.

At least 19 recordsLinked to original sources

PubMed1999

Effects of H1 antihistamines on animal models of QTc prolongation.

OBJECTIVE: The clinical use of some nonsedating H1 antihistamines (histamine H1 receptor antagonists) has been associated with a rare but life-threatening type of arrhythmia, torsade de pointes, especially when these drugs are coadministered with cytochrome P450 (CYP) 3A4 enzyme inhibitors. On the basis of the latter observation and the fact that most of these H1 antihistamines undergo extensive first-pass metabolism to active metabolites apparently devoid of cardiovascular adverse effects, this arrhythmogenicity has been attributed to the parent drug. The objective of this study was to find an animal model with the ability to predict the proclivity of drugs to produce torsade de pointes. DESIGN: Two experimental approaches were used: (i) blockade of CYP3A4 metabolism by coadministration of ketoconazole to increase the plasma concentrations of the parent compound in the conscious guinea-pig, and (ii) administration of the compound directly into the coronary circulation of the anaesthetised dog in order to circumvent first-pass metabolism. RESULTS: The first approach demonstrated that terfenadine administered in the presence of ketoconazole prolongs the corrected QT (QTc) interval of the electrocardiogram, whereas ebastine does not. Similarly, when terfenadine was administered through the coronary circulation, a statistically significant increase in the QTc interval was also seen, whereas ebastine and carebastine were without effect. Thus, it is clear that ebastine was much better tolerated than terfenadine from a cardiovascular standpoint, since ebastine and its metabolite are devoid of effects on cardiac repolarisation, as measured by the QTc interval in these animal models.

Animals↗

PubMed1998

Urge incontinence: the patient's perspective.

Urge incontinence has a profound effect on the day-to-day lives of women. The purpose of this study was to identify specific aspects of functioning and well-being affected by urge incontinence or mixed incontinence with a primary urge component. We conducted six focus groups of 65 racially and age diverse, community-dwelling women with urge incontinence. Transcripts of the focus groups were quantitatively analyzed for word use frequency with QSR NUD*IST software. Demographics, symptomatology, and the impact of incontinence on daily activities and feelings were assessed by questionnaire. Participants in the focus groups were on average 62 years of age; 52% were nonwhite, and 26% had a high school or less education. In the three identified broad domains, 52% of domain-related words were associated with feelings, 40% with activities, and 8% with relationships. Frequently identified references were bathroom availability (24%), loss of control (14%), anxiety (11%), and sleep disturbance (10%). Women under the age of 70 compared with older women more commonly identified feeling unattractive and low self-esteem (12% versus 2%, p < 0.007) and adverse effects on dating and sexual activity (45% versus 0%, p < 0.02). The effect of incontinence on quality of life correlated with frequency, nocturia, and pad use (Kendall's tau beta 0.02-0.32, p < 0.05). Urge incontinence affects many quality of life issues and contributes to limitation of activities, loss of control, and negative self-perception. Focus groups of diverse women with urge incontinence symptomatology are useful in understanding these effects.

Activities of Daily Living↗

PubMed1996

Inhibition of lipopolysaccharide-induced bowel erythrocyte extravasation in rats, and of mesenteric hypoperfusion in dogs, by phosphodiesterase inhibitors.

Sepsis is intricately associated with mesenteric ischemia. The remote complications of mesenteric ischemia are essentially those of sepsis, whether as a cause or as a consequence. Experimental endotoxic shock induces bowel hypoperfusion, erythrocyte extravasation and intestinal necrosis. The effects of pentoxifylline, rolipram and denbufylline, three phosphodiesterase inhibitors, were studied on endotoxin-induced bowel erythrocyte extravasation and intestinal and renal hypoperfusion, in conscious rats and anaesthetized dogs, respectively. Two hours after lipopolysaccharide i.v. injection in rats, erythrocyte extravasation was evident throughout the intestinal musculature and mucosa, apparently without affecting lungs, heart, kidneys, liver or pancreas. Pretreatment with the non-selective phosphodiesterase inhibitor, pentoxifylline, or selective phosphodiesterase IV inhibitors such as denbufylline or rolipram reduced intestinal haemoconcentration. In the anaesthetized dog, pentoxifylline and denbufylline both inhibited the E. coli lipopolysaccharide-induced mesenteric blood flow fall, without affecting renal blood flow or cardiac index. In conclusion, phosphodiesterase inhibitors protected from intestinal damage and bowel hypoperfusion after lipopolysaccharide challenge. This action may thus play a role in the protective effects against endotoxin-induced lethal toxicity previously described for phosphodiesterase inhibitors.

Animals↗

PubMed1996

The role of ketoconazole in the QTc interval prolonging effects of H1-antihistamines in a guinea-pig model of arrhythmogenicity.

We have carried out experiments to re-evaluate the influence of ketoconazole (400 mg kg-1,p.o.) on the effects of ebastine, terfenadine and loratadine on the QTc interval in conscious guinea-pigs. Following a previously described protocol of oral drug administration, but using telemetric recording of the ECG, we have found that the prolongation of the QTc interval attributed to ebastine and terfenadine is in fact entirely due to ketoconazole, and that neither terfenadine, ebastine nor loratadine produce any additional effects on subsequent administration.

Animals↗

PubMed1990

Potential histamine H2-receptor antagonists. Synthesis, conformational studies and activity of novel 3-oxo-1,2,5-thiadiazole 1,1-dioxide derivatives.

New histamine H2-receptor antagonists bearing a novel "urea equivalent", the 3-oxo-1,2,5-thiadiazole 1,1-dioxide ring, have been synthesized in a transamination reaction. Open chain derivatives have also been obtained. Theoretical conformational analysis of the compounds has been carried out using a molecular modelling program. Semiempirical CNDO/2 calculations have also been performed. The antisecretory and cytoprotective activities of the compounds have been evaluated.

Animals↗

PubMed1989

[Study of lipids (cholesterol, triglycerides and phospholipids), plasma lipoproteins (HDL-cholesterol) and apoproteins (apo A and apo B in patients with acute myocardial infarction].

Several lipid parameters were evaluated in 88 patients with acute myocardial infarction (AMI). A reduction in cholesterol and phospholipid level was observed, with minimal values between the days 10-20, followed by a subsequent increase. Triglycerides increased after 12-14 hours, with a maximal value after 20-30 days. Cholesterol bound to high-density lipoproteins (HDL-cholesterol) decreased after 24 hours, with a minimal value after 20-30 days. Apoprotein A decreased from the initial measurement until days 20-30. The initial lipid profile (indicating the risk of coronary artery disease) was constituted by high cholesterol (particularly in males below 60 years), high triglyceride and low HDL-cholesterol levels. The latter finding was more marked and characteristic in the overall group of evaluated patients. All values were compared with a control group of 24 healthy persons. Relevant data for prognosis included the following: males above 60 years had a greater reduction in cholesterol and apoprotein A during AMI; the males who died had lower apoprotein A levels than the survivors; females with higher haptoglobin levels also had higher apoprotein B levels. All these findings were statistically significant (p less than 0.01).

Aged↗

PubMed1988