Jose A. Ortiz

Comparative in vitro and in vivo inhibition of cytochrome P450 CYP1A2, CYP2D6, and CYP3A by H2‐receptor antagonists

The isozymes CYP1A2, CYP2D6, and CYP3A4/5 are involved in the majority of all cytochrome P450– mediated drug biotransformations. In this study we investigated the inhibition profiles of CYP1A2 (substrate: caffeine) CYP2D6 (substrate: dextromethorphan), and CYP3A4/5 (substrate: dextrorphan) by cimetidine, ranitidine, and the novel H2‐receptor antagonist ebrotidine in human liver microsomes. The inhibitory effect of the drugs on the enzymes activities were as follows: CYP1A2: cimetidine >> ranitidine = ebrotidine; CYP2D6: cimetidine >>> ranitidine = ebrotidine; CYP3A4/5: ebrotidine > cimetidine >>> ranitidine. The inhibition of CYP3A4/5 enzyme activity by ebrotidine was competitive. To test whether the inhibitory effect of ebrotidine in CYP3A activity was also found in vivo, we analyzed the biodisposition of midazolam in 8 healthy volunteers. Midazolam biodisposition was significantly reduced when administered together with cimetidine (P < .05), whereas no significant inhibition was observed with ebrotidine or ranitidine compared with placebo. Psychomotor performance analysis revealed no significant effect of the observed reduction on midazolam biodisposition. We concluded that patients who are receiving treatment with drugs metabolized through CYP3A may experience enhanced drug effects as a result of pharmacokinetic interaction when treated concomitantly with cimetidine. In contrast, the effect of ranitidine or ebrotidine on CYP3A activity in vivo seems to have little clinical significance.

Cytidine (5′) Diphosphocholine Modulates Dopamine K+‐evoked Release in Striatum Measured by Microdialysis

Abstract: Experiments were performed to determine whether exogenous cytidine (5′) diphosphocholine (CDP‐choline) could modify the release of dopamine (DA) in the striatum. Rats were divided into two groups, receiving either a standard diet (UAR 004) or the same diet supplemented with CDP‐choline (250 mg/kg day) for 28 days. On the last day the dialysis probes were inserted in the striatum, and DA, homovanillic acid (HVA), and 3,4‐dihydroxyphenylacetic acid (DOPAC) efflux were measured in the dialysis stream basally and during K+depolarization (80 mM K+). Basal DA, HVA, and DOPAC did not show any difference between treated and untreated groups. Depolarization with K+ increased DA levels by up to 3,000% in the control group and by up to 4,770% in the CDP‐choline‐treated group (p<0.05), and reduced extracellular HVA and DOPAC concentration by up to 45 and 35%, respectively, both in the untreated and CDP‐choline‐treated groups. These results show that long‐term treatment with CDP‐choline increases the K+ induced release of DA and suggest, in accordance with previous research, that by providing exogenous choline and cytidine, CDP‐choline modulates dopaminergic transmission.

Effects of Dotarizine on Peripheral and Pulmonary Circulation and Cardiac Dynamics in Dogs

The cardiovascular effects of dotarizine in 10-min intravenous infusions were studied in thiopental-anesthetized dogs. The effects of dotarizine 0.024 mg/kg/min almost paralleled those of saline controls; 0.079 mg/kg/min dotarizine significantly raised the stroke index and ejection fraction, and, at a rate of 0.25 mg/kg/min, further effects appeared and were dose-dependent. Dotarizine produced arterial dilation in both systemic and pulmonary circulation: the total peripheral resistance dropped, and femoral artery flow rose; aortic and pulmonary artery mean and diastolic pressures declined, and systolic pressures remained almost stable. A trend of bradycardia and pulmonary artery pressure reduction persisted for 30 min. As compared with the reduced total peripheral resistance, aortic pressure fell only moderately because of rising cardiac output due to a higher ejection fraction and stroke volume. Cardiac preload tended to decline; contractility tended to increase. Cardiac performance remained stable while myocardial oxygen consumption tended to fall, as did the pressure-rate product and the tension time index. Dotarizine exerted direct cardiovascular effects similar to those of the 5-HT2-receptor antagonist ketanserin and, more generally, to calcium channel blockers rather than to alpha-adrenoceptor blockers.

Asymmetric synthesis of pyrrolo[2,1-b][1,3,4]thiadiazepine derivatives

Abstract The asymmetric synthesis of compound 2 , with potential ACE inhibitory activity, is reported. The key intermediaet 3 contains the novel heterocyclic nucleus pyrrolo[2,1- b ][1,3,4]thiadiazepine. This compound has been prepared through a sequence involving pyrrole thiocyanation, followed by reductive cleavage of the thiocyanate group, and cyclization of the resulting halo-thiol in the key synthetic steps.

Pharmacokinetics of Camonagrel in experimental animal: rat, rabbit and dog

Camonagrel is a novel selective thromboxane synthetase inhibitor. The aim of this study was to determine its main pharmacokinetic parameters in rats, rabbits and dogs after intravenous and oral administration at doses of 10 mg kg−1. Plasma and urine concentrations of camonagrel were analyzed by HPLC with UV detection.Pharmacokinetics of camonagrel was generally fitted to a two-compartmental model and the values which defined the absorption process were: Cmax≃15.96 μg.ml−1, Tmax≃0.33 h, AUC0-∞ (oral) ≃12.45 μg·h·ml−1 (rat, n=3 per pont); Cmax≃2.04 mg·ml−1 Tmax ≃ 1.50 h, AUC0-∞ (oral) ≃ 4.85 μg·h·ml−1 (rabbit, n=3); Cmax ≃ 18.60 μg·ml−1, Tmax ≃ 0.44 h, AUC0-∞ (oral) ≃ 13.40 μg·h·ml−1 (dog, n=4). The more representative values in the distribution and elimination phase were: protein binding rate ≃ 80% in the three species (“in vitro” experiment); t1/2β≃ 0.22 h (rat, i.v.), =0.28 h (rabbit i.v.) and ≃ 0.45 h (dog i.v.); CI ≃ 635.73 ml·h−1 (rat i.v.), ≃ 448.26 ml·h−1 (rabbit i.v.) and ≃ 463.8 ml·h−1 (dog i.v.).The absolute bioavailability of camonagrel was ≃ 79.1% in rat, ≃ 21.7% in rabbit and ≃ 59.3% in dog.Available elimination data in rat indicated that Camonagrel was mainly excreted in urine (≃80%) as unchanged drug. An unknown minor metabolite (≃10%) was observed only after oral dosing.Finally, the main pharmacokinetic parameters of camonagrel in rats, rabbits and dogs are presented, which allow to define its absorption, distribution and elimination processes in these species.

Age-dependent changes in essential elements and oxidative stress biomarkers in blood of red deer and vulnerability to nutritional deficiencies

Changes in the concentration of circulating essential elements in animals over life may be indicative of periods of vulnerability to deficiencies and associated diseases. Here we studied age-related variations in essential elements (Se, Cu, Zn and Mn) and some selected oxidative stress biomarkers (GPx, SOD, vitamin A and vitamin E) in blood of an Iberian red deer (Cervus elaphus hispanicus) population living in semicaptive conditions. Animals during their first year of life showed to be especially vulnerable to suffer Se- and Cu-related diseases and disorders. Older female deer had lower blood levels of Zn and Mn, which was accompanied by a lower blood SOD activity. On the contrary, GPx blood activity was elevated in older deer, which may help to compensate the reduction of other antioxidants with during aging. Age-related changes in GPx and SOD and their positive relationships with the essential elements suggest that the observed nutritional deficiencies at certain age stages may have a detrimental effect on the antioxidant system, increasing the risk of oxidative stress. Thus, the biomarkers used in the present study may be important tools for the subclinical diagnosis of nutritional disorders and diseases related to the generation of oxidative stress in both domestic and wild ungulates.