Preliminary assessment of flutiorex, a new anorectic drug, in man.

1 The effects of +/--flutiorex, a new anorectic agent, on food intake, the sympathetic nervous system and the central nervous system were compared to those of fenfluramine and a placebo in a double-blind trial involving six healthy volunteers. 2. Flutiorex exerts a singificant anorectic effect and was shown to be approximately twice as potent as fenfluramine in this regard. 3 Flutiorex induces a definite alpha-adrenergic sympathomimetic stimulation as was shown by a rise in systolic blood pressure and the development of marked mydriasis. 4 Flutiorex is a central nervous system stimulant producing an increase in critical flicker frequency. It does not, however, influence psychomotor coordination as reflected in the pursuit rotor test. 5 Serial determinations of blood and urine levels of flutiorex and its deethylated metabolite, norflutiorex, showed that flutiorex is rapidly absorbed and deethylated, accumulates in large quantities in the tissues and, like its metabolite, is excreted in the urine in very small quantities. Blood levels of norflutiorex appear to remain elevated longer than those fo flutiorex

Pharmacokinetics and biological effects of captopril and hydrochlorothiazide after acute and chronic administration either alone or in combination in hypertensive patients

1 The pharmacokinetics of free unchanged captopril, total captopril and hydrochlorothiazide (HCTZ) were investigated in three groups of patients with moderate essential hypertension and normal renal function on the first and on the 45th days of an oral treatment with either captopril (50 mg once daily, n = 7) or HCTZ (25 mg once daily, n = 10) or their combination captopril 50 mg + HCTZ 25 mg once daily, n = 8. Simultaneously, the effects of the three treatments on plasma converting enzyme activity (PCEA) and plasma renin activity (PRA) were measured. 2 Elimination half-lives of total captopril after acute (7.8 ± 2.3 h) or chronic (7.0 ± 0.5 h) captopril dosing were similar to those of HCTZ after acute (6.5 ± 1.0 h) or chronic (8.0 ± 2.5 h) HCTZ dosing. Elimination half-life of free unchanged captopril was 0.81 ± 0.09 h after acute and 0.96 ± 0.03 h after chronic captopril dosing. 3 Addition of HCTZ to captopril induced no major change in free and total captopril pharmacokinetic parameters, in PCEA inhibition and in PRA increase (as they were determined after captopril alone) on acute as well as on chronic treatment. 4 Addition of captopril to HCTZ induced no major change in HCTZ pharmacokinetic parameters and in PRA increase compared with those determined after HCTZ alone. 5 Chronic treatment with captopril + HCTZ resulted, like chronic captopril treatment, in no accumulation of captopril, in no significant modification of free and total captopril pharmacokinetic parameters and of PCEA inhibition (as determined after acute administration) but led to a significant enhancement of the acutely induced increase in PRA. 6 Chronic treatment with captopril + HCTZ resulted, like chronic HCTZ treatment, in no accumulation of HCTZ, in no significant modification of HCTZ pharmacokinetic parameters (as determined after acute administration) but also led to a significant enhancement of the acutely induced increase in PRA. 7 Thus, the longer duration of the antihypertensive action of captopril + HCTZ as compared to that of captopril cannot be ascribed to a pharmacokinetic or biological interaction between captopril and HCTZ

Lack of involvement of bradykinin in the vascular sympathoinhibitory effects of angiotensin converting enzyme inhibitors in spontaneously hypertensive rats.

1. The aim of this study was to investigate the contribution of endogenous bradykinin to the vascular sympathoinhibitory effects exerted by angiotensin I converting enzyme inhibitors (ACEIs) in the spontaneously hypertensive rat (SHR). 2. Adult SHRs were treated daily for 8 days with either perindopril (3 mg kg-1), or a selective angiotensin II AT1 receptor antagonist, losartan (10 mg kg-1) both given orally--these two doses being equipotent in inhibiting angiotensin I (AI)-induced vascular responses--or distilled water (controls). After pithing, the animals were instrumented for determination of blood pressure, heart rate, cardiac output, regional (renal, mesenteric, hindlimb) blood flows (pulsed Doppler technique) and corresponding vascular resistances. Afterwards, half of the animals of each group were given the selective bradykinin B2 receptor antagonist, icatibant, used in a dose (10 micrograms kg-1, i.v.) that achieved B2 receptor blockade, the other half received saline (10 microliters kg-1, i.v.). Haemodynamic responses to increasing frequencies of spinal cord stimulation were then measured. 3. Pressor and vasoconstrictor responses to AI were significantly and similarly reduced in both perindopril- and losartan-treated groups. Perindopril and losartan both decreased to a similar extent the pressor and vasoconstrictor responses to electrical stimulation of the spinal cord. 4. In the dose used, icatibant did not affect any of the investigated haemodynamic parameters in any of the experimental groups. Furthermore, icatibant did not affect the stimulation frequency-response curves in the control animals and did not modify the vascular sympathoinhibitory effects exerted by perindopril and by losartan.(ABSTRACT TRUNCATED AT 250 WORDS

Clazepam: pharmacokinetics and effects on performance.

1. The effects of clazepam, a new benzodiazepine (30 mg orally) on performance tests and the cardiovascular system have been compared to those of chlordiazepoxide (30 mg orally) and a placebo in a double-blind trial involving six healthy volunteers. Simultaneously, the pharmacokinetics of clazepam were investigated. 2. While clazepam itself could be detected neither in plasma nor in urine, it gave rise to two plasma metabolites, the former, an alcoholic derivative with a short half-life, and the second, desmethyldiazepam, with a long half-life. These two metabolites and oxazepam were excreted in urine and, within the 24 h period following drug intake, accounted for 73% of the ingested dose. 3. Seven hours after its administration, clazepam slightly improved performance and reduced anxiety. The kinetics of these effects and the metabolic data suggest that clazepam acts mainly through the formation of desmethyldiazepam. However, owing to the low blood levels of this metabolite, the activity of clazepam was very moderate

Involvement of nitric oxide, but not prostaglandins, in the vascular sympathoinhibitory effects of losartan in the pithed spontaneously hypertensive rat.

1. The aim of this study was to investigate whether nitric oxide (NO) and/or vasodilator prostaglandins (PGs) are involved in the sympathoinhibitory effects exerted by losartan versus the vascular responses elicited by spinal cord electrical stimulation (SCS) in pithed spontaneously hypertensive rats (SHRs). 2. SHRs were given orally and for 8 days either losartan (10 mg kg-1 daily) or distilled water (controls). After pithing, blood pressure, heart rate, cardiac output, renal and muscular blood flows (pulsed Doppler technique) and the corresponding vascular resistance values were measured or calculated at baseline. Then, animals from both groups were given i.v. either saline, or NG-nitro-L-arginine methyl ester (L-NAME, 1 mg kg-1), or diclofenac (4 mg kg-1). Thereafter, haemodynamic parameters were determined in the six subgroups of animals in response (a) to SCS at increasing frequencies, and (b) to a noradrenaline bolus injection. 3. Losartan significantly decreased mean arterial pressure as well as renal and total peripheral resistances. In addition, losartan exhibited strong vascular sympathoinhibitory effects, significantly decreasing the systemic pressor and regional vasoconstrictor responses to SCS, but did not affect those to exogenous noradrenaline. In contrast, SCS-induced tachycardia was not modified by losartan. 4. L-NAME significantly increased total peripheral and regional vascular resistances but did not affect blood pressure and heart rate basal values. L-NAME potentiated the haemodynamic responses to SCS in control and, to a larger extent, in losartan-treated SHRs so that, with the exception of the renal vascular bed, the sympathoinhibitory effects of losartan were attenuated in all vascular beds studied. L-Arginine (300 mg kg-1) caused reversal of L-NAME effects in both control and losartan-treated SHRs. 5. Diclofenac did not affect the basal values of haemodynamic parameters in control and losartan-treated SHRs. Diclofenac potentiated the pressor and vasoconstrictor responses to SCS and to a similar extent, in both control and losartan-treated SHRs, so that the sympathoinhibitory effects of losartan were fully maintained. 6. These results demonstrate that in pithed SHRs: (a) NO but not PGs contribute to the basal vasomotor tone, (b) both NO and PGs attenuate the pressor and vasoconstrictor responses to SCS, (c) NO plays a major role in the vascular sympathoinhibitory effects of losartan, except at the renal level, and (d) endogenous PGs are not involved in these sympathoinhibitory effects

The effect of enalapril on baroreceptor mediated reflex function in normotensive subjects.

The effects of enalapril, 20 mg orally, on the responses to baroreflex activation and deactivation by respectively phenylephrine and nitroglycerin were investigated in normotensive subjects on a normal sodium diet, with simultaneous measurement of plasma renin activity (PRA), converting enzyme activity (PCEA), aldosterone and catecholamines. Enalapril, 4 h after administration, lowered artificial blood pressure without modifying heart rate and plasma catecholamines. PCEA was abolished, PRA increased and plasma aldosterone decreased. Enalapril (a) displaced to the left the baroreflex set-point, (b) did not affect baroreflex sensitivity since the slopes of the RR-interval/systolic blood pressure regression lines remained unchanged during both activation and deactivation and (c) did not modify baroreflex efficacy since the maximal RR-interval responses as well as the overall RR-interval-time products to identical blood pressure variations were not modified. Thus, enalapril induced a resetting of the baroreflex, which probably accounts for the lack of reflex tachycardia observed during the drug-induced fall in blood pressure

Influence of chronic renal failure on captopril pharmacokinetics and clinical and biological effects in hypertensive patients.

The pharmacokinetic parameters of unchanged plasma captopril and the kinetics of the drug effects on plasma converting enzyme activity (PCEA), plasma renin activity (PRA), plasma aldosterone (PA) and mean blood pressure (MBP) were studied over 24 h after oral administration in three groups of hypertensive patients: with normal renal function (group 1, plasma creatinine less than 110 mumol/l, n = 10), with moderate chronic renal failure (group 2, 135 less than plasma creatinine less than 450 mumol/l, n = 10) and with severe chronic renal failure (group 3, plasma creatinine greater than 500 mumol/l, n = 10). Renal impairment had no effect on plasma captopril Cmax, CLtot and relative bioavailability (AUC). In contrast, captopril kel decreased while T1/2 increased progressively from group 1 to group 3. PCEA blockade (T1/2 and AUC) was increased significantly and proportionally to the degree of renal impairment. However, there were no differences between the three groups regarding captopril-induced modifications of PRA and PA. Although the maximal reduction in MBP was identical in the three groups, the overall antihypertensive effect (AUC) of captopril increased significantly and progressively from group 1 to group 3, especially in duration. There was no correlation between basal plasma creatinine values and unchanged captopril relative bioavailability (AUC) and between unchanged captopril relative bioavailability (AUC) and the drug effects (AUC) on PCEA, PRA, PA and MBP. However there was a correlation between basal plasma creatinine values and plasma captopril T1/2, PCEA blockade (AUC) and overall antihypertensive effect (AUC). The apparent discrepancy between the lack of effects of chronic renal failure on plasma unchanged captopril bioavailability and its potentiating effects on PCEA blockade and MBP reduction may be accounted for by the renal impairment-induced accumulation of captopril metabolites

Lack of beneficial effects on the NO-donor, molsidomine, in the L-NAME-induced pre-eclamptic syndrome in pregnant rats.

1. In pregnant rats, chronic NO-synthase inhibition induces the development of a pre-eclamptic syndrome, characterized by an increase in maternal blood pressure, a loss of vascular refractoriness to pressor stimuli, a reduction in litter size and a decrease in pups (and maternal) weight. We investigated whether a NO-donor, molsidomine, administered during NO synthase inhibition, could restore a normal pregnancy. 2. Pregnant rats were given daily, starting from day 14 of gestation, saline (controls), or L-NAME (50 mg kg-1 d-1), or molsidomine (15 or 30 mg kg-1 d-1), or the L-NAME + molsidomine combinations. Maternal blood pressure and body weight, litter size, pups weight and vascular reactivity to pressor stimuli (angiotensin II, noradrenaline, electrical stimulation of the spinal cord) were investigated. 3. L-NAME alone, as compared to controls, increased maternal blood pressure, reduced litter size (-59%), increased foetal reabsorptions (+ 625%) and decreased foetal weight (-10%). Vascular reactivity to pressor stimuli was enhanced. 4. Molsidomine alone, as compared to controls, dose-dependently decreased maternal blood pressure but had no effect vascular reactivity and, whatever the dose, on foetal outcome. 5. The L-NAME-molsidomine combinations dose (of molsidomine)-dependently limited the rise in maternal blood pressure induced by L-NAME alone but unexpectedly, dose-dependently and significantly worsened pregnancy evolution, e.g., at 30 mg kg-1 d-1: litter size (-80%), foetal reabsorptions (+ 1025%), foetal weight (-24%). Vascular reactivity to pressor stimuli was paradoxically further enhanced. 6. Thus, in a chronic NO deprivation-induced model of pre-eclampsia in rats, molsidomine, possibly because of its hypotensive action, worsens the foetal outcome, which questions the usefulness of NO-donors in pre-eclamptic women