In the present study the effects of artificial magnetic fields on pineal serotonin-N-acetyltransferase (NAT) activity and melatonin content in male Sprague-Dawley rats were investigated to study the secretory activity of the pineal gland. Experimental inversion of the horizontal component of the natural magnetic field, performed at night-time, led to a significant decrease of both parameters investigated. During day-time, this effect was less conspicuous. During night-time, inversion of the horizontal component is followed by a reduced pineal secretory activity for about 2 h. After 24 h exposure to the inverted horizontal component, return to the natural condition was followed by a renewed clear depression of pineal NAT activity and melatonin content, indicating that the main stimulus is not the inverted magnetic field itself but rather its change. Changing the inclination of the local magnetic field from 63 degrees to 58 degrees, 68 degrees or 78 degrees, respectively also decreased the secretory activity of the rat pineal gland.

Mibefradil, a tetralol derivative, is a new long-acting calcium antagonist used for the treatment of patients with hypertension and chronic stable angina pectoris. The drug is virtually completely metabolised, with less than 3% of an oral dose excreted unchanged in urine. Its metabolism occurs via parallel pathways, which fall into 2 broad categories: esterase-catalysed hydrolysis (producing the major plasma metabolite) and cytochrome P450 (CYP) 3A4-mediated oxidation. Plasma protein binding is greater than 99.5%, predominantly to alpha 1-acid glycoprotein. Oral multiple dose administration of mibefradil 50 or 100 mg once daily is associated with inhibition of the CYP3A4 pathway of metabolism, increasing the half-life and bioavailability of the parent compound. The intensity of the inhibition of CYP similarly results in numerous clinically relevant drug interactions which ultimately motivated the voluntary withdrawal of mibefradil from the market. With multiple oral doses of 50 to 100 mg once daily, the time to maximum plasma concentration was approximately 2.4 hours, absolute bioavailability was around 80%, clearance was 5.7 to 7.5 L/h, oral terminal exponential volume of distribution was 180 L, and terminal exponential half-life was 22 hours (ranging between 17 and 25 hours). A NONMEM sparse data analysis indicated that apparent clearance is not affected by race, gender, age or bodyweight. Renal function does not affect the pharmacokinetics of mibefradil.

Key Words: Ro 40-5967--calcium antagonists-hypertension-coronary heart diseaseCalcium antagonists are now widely used for the treatment of angina pectoris and hypertension (for review, see ref. 25). Despite different chemical structures, they all inhibit the slow Ca2+ inward current (7,15). Three main classes of calcium antagonists have been described: dihydropyridines, represented by nifedipine; phenylalkylamines, represented by verapamil; and benzothiazepines, represented by diltiazem. Each of these compounds has its own advantages and disadvantages. Dihydropyridine-type calcium antagonists are very potent peripheral vasodilators and can therefore produce headache, ankle edema, and reflex tachycardia (24). Verapamil has a very potent negative inotropic effect (29) that makes this compound dangerous in patients with a compromised myocardium (8,27). Diltiazem is also negatively inotropic, can produce severe bradycardia, and has also been shown to increase the mortality of patients with prior myocardial infarction and clinical signs of heart failure (30).Finally, all existing calcium antagonists (except the novel dihydropyridine, amlodipine) have a poor bioavailability due to a large first-pass effect and a rather short half-life requiring slow-release formulation for once-a-day dosing. Therefore, the purpose of the calcium antagonist program at F. Hoffmann-La Roche Ltd, Basel was to find a compound with the following properties: (a) high bioavailability; (b) long half-life, allowing once-a-day dosing; (c) lack of biologically relevant negative inotropism; and (d) no strong peripheral vasodilation in normotensive subjects.Ro 40-5967, a novel calcium antagonist, which was selected in animal experiments, fulfilled these criteria. The first clinical studies confirmed the preclinical findings. CHEMISTRYThe chemical name of Ro 40-5967 (see Fig. 1) is (lS,2S)-2-(2-[[3-(2-benzimidazolyl)propyl]methylamino]ethyl)-6-fluoro-1,2,3 ,Ctetrahydro-1 -isopropy1-2-naphthylAddress conespondence and reprint requests to Dr.

The tolerability and hemodynamic and humoral effects of the structurally novel calcium antagonist Ro 40-5967 were investigated in 64 patients with hypertension. In a double-blind, placebo-controlled study, ascending oral doses of 50, 100, 150, or 200 mg were administered once daily for 8 days in a solution. Ro 40-5967 was well tolerated up to 150 mg, but treatment was stopped in one patient in the 200 mg group because of bradycardia. Blood pressure was dose-dependently reduced over the full 24-hour dosing period with more pronounced effects on day 8 than on day 1. The maximum blood pressure reduction was obtained after 150 mg (supine blood pressure, -34/-25 mm Hg, p less than 0.001). Despite a slight decrease in supine heart rate, cardiac output increased. PQ time was dose-dependently increased and concentration-effect analysis showed that relevant atrioventricular conduction disturbances occur only at concentrations much higher than those required to reduce blood pressure. Changes in catecholamines, plasma renin activity, and aldosterone were small and inconsistent. In conclusion, Ro 40-5967 has a long-lasting antihypertensive effect after once-daily administration.

Remikiren is a potent inhibitor of renin in humans with long-lasting effects after both intravenous and oral administration.

The pharmacokinetics of ganciclovir were similar between the two dosing groups (100 vs. 200 days), with the majority of patients achieving an area under the concentration time curve in the target therapeutic range (40-60 μg hr/mL). The fact that the majority of patients were within the target therapeutic range and the absence of a control arm (no treatment) precluded any attempt to validate a correlation with clinical parameters (i.e., CMV disease).

1. The metabolism of mibefradil has been examined in rat, marmoset, cynomolgus monkey and man after single and multiple oral administration. 2. Metabolites typically represent between 50 and 80% of the circulating drug-related material after single oral doses of mibefradil to man, rat and marmoset. They arise by a combination of enzymatic processes: cytochrome P450-mediated oxidation at saturated and unsaturated carbon atoms, cytochrome P450-catalysed dealkylation and hydrolysis of the ester side-chain. 3. Plasma levels of mibefradil in the cynomolgus monkey are extremely low as a result of very efficient first-pass hydrolysis of its side-chain to give the corresponding alcohol. Steady-state concentrations of this metabolite are comparable with those of the parent drug in man and marmoset, but are relatively low in rat plasma. 4. Hydroxylation at the benzylic carbon of the tetrahydronaphthyl ring leads to further important metabolites in primates, whereas the products of O- and N-demethylation are found in small amounts in all four species. 5. Estimates of the exposure of the various species to the principal metabolites indicate that the choice of the rat, marmoset and cynomolgus monkey for the toxicological assessment of mibefradil was appropriate.

Previous studies aimed at elucidating day/night changes of pineal gland size and pinealocyte nuclear volume have yielded contradictory results. The aim of the present investigation was to examine the above parameters over a period of 10 successive days, at 6-hour intervals under a lighting regimen of LD 12:12 (7 a.m. to 7 p.m.). It was found that changes in pineal gland volume could not be correlated with the light/dark phases; instead, a rhythm with a two-day period was encountered. Pinealocyte nuclear volume, by contrast, showed clear circadian changes, exhibiting troughs during photophase and peaks during scotophase. In this experimental series, the karyometric results conformed to the melatonin forming rhythm in the rat pineal gland as reported in the literature.