Hemodynamic Effects of Dilevalol Following Acute and Long-Term Administration in Normal and Hypertensive Subjects.

Forearm hemodynamics using pulsed Doppler flowmetry were studied in 12 healthy volunteers and 20 patients with mild to moderate hypertension before and after acute and long-term oral administration of the beta-blocking agent dilevalol. The study was performed using a double-blind design versus placebo. Both 200-mg and 400-mg dosages produced a significant acute blood pressure reduction in normotensive and hypertensive subjects. In hypertensive subjects, forearm vascular resistance was poorly modified, brachial artery diameter decreased significantly but only with long-term administration of the 400-mg dosage. A significant reduction in brachial artery tangential tension was consequently observed. The study provides evidence that Dilevalol produced a significant decrease in blood pressure in normotensive and hypertensive subjects in association with a decrease in brachial artery tangential tension.

Influence of renal function on the pharmacokinetics of diacerein after a single oral dose.

The pharmacokinetics of diacetylrhein following a single oral dose of 50 mg was studied in 12 healthy volunteers and two groups of 8 patients with mild or severe renal insufficiency. Statistical analysis using a Kruskal-Wallis rank sum test showed a significant difference between the three groups for the following parameters. In severely uraemic patients, median AUC0-infinity was multiplied by a factor of about 2: 40.5 mg.h/l versus 21.3 mg.h/l in healthy subjects, P = 0.04; and t1/2 was prolonged by the same factor: 9.6 h versus 4.3 h in the control group, P = 0.003. Apparent drug availability and renal clearance assessed through urinary data decreased with renal failure, respectively: 14.5% and 0.045 l/h versus 35.4% (P = 0.01) and 0.13 l/h (P = 0.008) in healthy subjects. Amounts of glucuro- and sulpho-conjugates in urine were lower in severely uraemic patients. Intermediate values were observed for mildly uraemic patients. Other parameters: lag time, Cmax, tmax, Vss/F, urinary glucuro- to sulpho-conjugate ratios did not change significantly. Apparent total clearance of rhein was poorly correlated with creatinine clearance and this was related to a decrease of non-renal clearance of rhein in renal insufficiency. It was concluded that, from a pharmacokinetic point of view, a reduction (50%) in the initial dosage of diacerein should be considered in severe renal failure.

[Antiovulatory action of chlormadinone acetate]. / Action anti-ovulatoire de l'acétate de chlormadinone.

Antiovulatory action of chlormadinone acetate (5 mg twice daily from day 7 to day 25) has been assessed in 6 healthy volunteers by daily determination of plasma FSH, LH, estradiol and progesterone. Hormonal profiles during the second treated cycle show that preovulatory gonadotropin surge is blunted and that no significant progesterone secretion occurs. Estradiol production is variable up to the middle of the cycle, and then homogeneously low normal. Menstrual cyclicity is respected and ovarian function is restored during the first cycle after treatment disruption.

[Antiovulatory action of chlormadinone acetate]. / Action anti-ovulatoire de l'acetate de chlormadinone.

PIP: The antiovulatory action of chlormadinone acetate was studied in six healthy volunteers who were given two daily doses of 5 mg each from the seventh to the twenty-fifth cycle day. Chlormadinone acetate is of potential interest as a contraceptive method for the small group of women with contraindications to synthetic estrogens and norsteroid progestins for whom no other methods are acceptable. The observation period included four cycles: a control cycle before treatment during which ovulation was confirmed, two treatment cycles, and an observation cycle after treatment. Antiovulatory action was assessed by daily determination of plasma FSH, LH, estradiol, and progesterone levels. The results confirmed the antiovulatory action of chlormadinone acetate and revealed no clinical signs of functional ovarian cysts or premenstrual syndrome. In all cases, the LH surge observed in the control cycle was blunted by chlormadinone acetate, while the base gonadotropin levels were not modified. Hormonal profiles in the second treatment cycle showed no preovulatory gonadotropin surge and no significant progesterone secretion. Estradiol production was variable through midcycle and then low normal in all subjects. In the last cycle week, the estradiol level was below 50 pg/ml in two cases and between 50 and 100 pg/ml in the others. In five cases out of six, the level of progesterone was 1 ng/ml or lower. In the sixth case, the data were incompatible with ovulation. Cycle tolerance was good and ovarian function returned during the first posttreatment cycle. No significant variation in weight or blood pressure was observed at the end of the second treatment cycle.^ieng

Single and multiple dose pharmacokinetics of lansoprazole in elderly subjects.

Plasma concentrations of lansoprazole and of its sulphone, sulphide and 5-hydroxylated metabolites were determined after oral administration of a single 30 mg dose and after 7 days of treatment with a daily 30 mg dose in 12 elderly subjects (mean age 83 years). Results after a single dose were compared with those from a historical control group of 18 young subjects (mean age 23 years). Mean values of AUC after single dose were 2668 ng ml(-1) h in the young subjects and 5216 ng ml(-1) h in the elderly (P < 0.05). Mean t 1/2z values in young and elderly subjects were 1.4 h and 2.9 h, respectively (P < 0.001). Plasma concentrations of the metabolites were similar in both groups. However, the hydroxylated metabolite of the sulphone was detected only in elderly subjects. Steady state plasma concentrations of lansoprazole were reached after 3 days of dosing with lansoprazole. The accumulation ratio was 1.31 in the elderly subjects.

LH pulsatile secretion and testosterone blood levels are influenced by sexual arousal in human males.

To determine whether changes in LH and testosterone (T) blood levels and pulse signals were induced by sexual arousal, nine healthy young males were presented on two different days with a sexually arousing (S) and a sexually neutral control (C) film. On both sessions, blood was sampled every 10 min for 12 hr. The Cluster and the Detect pulse identification algorithms were used to characterize the peaks in LH and T series. The second plasma LH peak following the beginning of the film was higher in the S than in the C condition (percent increases above preceding nadir: 322.1 +/- 183.9% vs. 202.6 +/- 108.7%). The area of the second pituitary peak of LH instantaneous secretion rate, which corresponded to the second plasma LH peak, was also greater in the S condition (6.2 +/- 3.3 vs. 3.4 +/- 2.3 UI/l). Compared with the C condition, T blood levels were increased within the first 10 min of sexual arousal (25.2 +/- 6.3 vs. 22.2 +/- 5.6 nmol/l). These results, consistent with the findings of animal studies, indicate that LH pulsatile secretion and T blood levels are influenced by changes in the state of sexual arousal in human males.

Fluvoxamine does not interact with alcohol or potentiate alcohol-related impairment of cognitive function.

OBJECTIVE: To assess whether fluvoxamine alters the pharmacokinetics of alcohol or potentiates alcohol-related impairment of cognitive function. METHODS: The study design required partially "blinded" balanced crossover studies, each involving 12 healthy male volunteers who each received a 40 gm dose of intravenous or oral alcohol after single and multiple doses of 50 mg fluvoxamine. Main outcome measures for pharmacokinetics were venous blood alcohol and plasma fluvoxamine. Main outcome measures for pharmacodynamics were word recall, simple and choice reaction time, number vigilance, memory scanning, and word recognition. RESULTS: The pharmacokinetics of intravenous alcohol were not affected by concomitant administration of fluvoxamine. Compared with placebo-alcohol, alcohol slightly increased the rate of fluvoxamine absorption, but the area under the plasma concentration-time curve from 0 to 12 hours at steady state was unchanged. As expected, alcohol significantly impaired cognitive function in volunteers. However, fluvoxamine did not potentiate the effects of alcohol and in some instances appeared to reverse the effects or reduce their duration. Fluvoxamine was well tolerated: only mild adverse effects were reported, and none of those required intervention. CONCLUSION: Fluvoxamine does not interact significantly with alcohol or potentiate alcohol-related impairment of cognitive function.

Hemodynamic effects of carvedilol after acute oral administration in hypertensive and normal subjects.

Forearm hemodynamics using pulsed Doppler flowmetry were studied in nine healthy volunteers and 12 patients with mild-to-moderate hypertension before and after acute oral administration of the beta-blocking and vasodilating agent carvedilol. Both the 25- and the 50-mg dose produced a significant blood pressure reduction by comparison with placebo in normotensive and hypertensive subjects. Only the 50-mg dose caused a decrease in forearm vascular resistance in hypertensive subjects. The decrease disappeared after wrist occlusion. Although brachial artery diameter did not change, a significant decrease in tangential tension was observed. This study provides evidence that carvedilol produced arteriolar dilation within the forearm of hypertensive subjects in association with a decrease in brachial artery tangential tension.

Dose ranging study of lansoprazole, a new proton pump inhibitor, in patients with high gastric acid secretion.

The effects of single doses and of 7 days of lansoprazole 10, 20 and 30 mg PO versus placebo on gastric acid secretion have been evaluated in 8 patients with high gastric acid secretion. The double blind crossover period was followed by a simple blind 7 days on placebo to detect any rebound phenomenon. After the first dose lansoprazole did not modify basal acid output (BAO) but it significantly and dose dependently inhibited peak acid output (PAO) and increased the time during which nocturnal intragastric pH was greater than 3. After 7 days of treatment the same significant, dose-dependent suppression of gastric acid was found, but BAO was also blocked. One week after cessation of lansoprazole administration no rebound increase in gastric acid-secretion was observed. The plasma gastrin concentration remained unchanged throughout the study.

The alpha 2-adrenergic receptor antagonist yohimbine inhibits epinephrine-induced platelet aggregation in healthy subjects.

Onset of sudden death, myocardial infarction, and stroke occurs more likely in the morning hours. Similarly, a morning increase in epinephrine-induced platelet aggregation was observed accompanied by an increase in plasma catecholamines. Inhibition of the morning increase in platelet aggregation would be of therapeutic benefit. In this study the effect of the selective alpha 2-adrenergic receptor antagonist yohimbine on platelet aggregation was evaluated in healthy subjects. Yohimbine administered orally selectively antagonized epinephrine but not collagen, arachidonic acid, or adenosine diphosphate-induced ex vivo platelet aggregation. The lowest dose of yohimbine that significantly inhibited epinephrine-induced platelet aggregation was 8 mg. The inhibitory effect of yohimbine on platelet aggregation lasted 10 hours with the 12 mg dose. At the doses studied (4, 8, and 12 mg), yohimbine did not modify blood pressure, standing heart rate, or plasma catecholamine or glucose concentrations. Twelve milligrams of yohimbine moderately but significantly accelerated supine heart rate (mean maximal increase, 7 +/- 3 beats/min). Further clinical studies are needed to evaluate whether bedtime administration of 12 mg yohimbine may block the morning increase in epinephrine-induced platelet aggregation.

Urinary elimination of molybdenum by healthy subjects as determined by inductively coupled plasma mass spectrometry.

The concentration of molybdenum was measured by inductively coupled plasma mass spectrometry (ICPMS) in the urines of two groups of healthy people living in two areas of France, Brest and Paris, about 500 km away. The concentration of Mo in the 24-hour urines of 10 healthy subjects from the Brest region was 25 +/- 10 micrograms/l, 38 +/- 20 micrograms/24 h and 21 +/- 9 micrograms/g creatinine. The concentration of Mo in the morning urines of 23 healthy men of the Paris region was 41 +/- 34 micrograms/l and 21 +/- 15 micrograms/g creatinine. Thus the mean elimination of Mo per gram of creatinine was the same in the two groups (21 +/- 9 and 21 +/- 15). Since the three main isotopes of Mo m/z = 95, 96 and 98, corresponding to an abundance percentage of 16, 17 and 24.5, respectively, were simultaneously analyzed in each sample and led to similar results, the ICPMS method seems reliable.

The effect of food and antacids on lansoprazole absorption and disposition.

Bioavailability of lansoprazole, a new gastric proton pump inhibitor, was investigated in 12 healthy subjects. Each subject received in random order, lansoprazole (30 mg) alone or associated with standard meal or with antacids (aluminium and magnesium hydroxides) or one hour later than antacids. Lansoprazole and metabolite (sulfone (AG 1813), sulfide (AG 1777) and hydroxylated (AG 1908) metabolites) plasma concentrations were determined using a specific high pressure liquid chromatographic assay procedure, with a limit of detection of 2 ng/ml. The time to peak was significantly later with food (p less than 0.001) and its magnitude was significantly decreased (600 +/- 330 ng/ml vs 1151 +/- 344 ng/ml, p less than 0.001). The bioavailability of lansoprazole was significantly decreased by food, about 27%, (p less than 0.05) and slightly decreased by concomitant administration of antacids (NS), the effect was more pronounced in male subjects (p less than 0.05). Lansoprazole is presented as an enteric-coated granules, the concomitant administration of antacids, increasing the gastric pH, increased the absorption rate of lansoprazole. When antacids were administered one hour before lansoprazole, no effect was observed on lansoprazole bioavailability. This study showed that lansoprazole must be administered in fasting state and not simultaneously with antacids.

Pharmacokinetics of eltoprazine in healthy male subjects after single dose oral and intravenous administration.

The kinetics, safety and tolerability of eltoprazine hydrochloride were studied in an open, cross-over, partially randomised design after single oral (8 mg) and intravenous (3 and 8 mg) doses to 12 healthy male subjects. After intravenous administration, the mean t1/2 ranged from 7 to 9 h, the MRT was 11 h, CL was 487 +/- 148 (3 mg dose) and 471 +/- 56 (8 mg dose) ml kg-1 h-1, while CLR was 226 +/- 124 (3 mg dose) and 189 +/- 38 (8 mg dose) ml kg-1 h-1. The Vss was 3.3 +/- 0.7 (3 mg dose) and 3.8 +/- 0.5 (8 mg dose) 1 kg-1. Cumulative renal excretion was 40%. The AUC and the cumulative urinary excretion were directly proportional to dose within the range of 3-8 mg. Values of tmax varied from 1 to 4 h after oral administration. The mean Cmax value was 24 ng ml-1 after an oral dose of 8 mg. The plasma elimination half-life after oral administration was 9.8 +/- 3.9 h. Absolute oral bioavailability was 110 +/- 32%. Dose-dependent somnolence was observed.

Plasma and urine aluminium concentrations in healthy subjects after administration of sucralfate.

1. Sucralfate (basic sucrose aluminium sulphate), a topical intestinal agent, was administered in suspension or granule form to 25 healthy subjects at a total dose of 4 g day-1 for 21 days. Aluminium in plasma and 24 h urine samples was assayed before, during and after administration of sucralfate by inductively coupled plasma optical emission spectrometry. 2. Sucralfate produced significant increases in plasma and urine aluminium concentrations. On average, plasma aluminium increased from about 2 micrograms 1-1 to more than 5 micrograms 1-1 and 24 h urine aluminium increased from less than 5 micrograms to more than 30 micrograms. Both plasma and urine aluminium concentrations decreased rapidly after sucralfate was stopped. However, urinary aluminium concentrations remained higher than normal 5 and 10 days after discontinuation of sucralfate administration. Moreover subjects receiving sucralfate granules had significantly higher average urinary excretion of aluminium than subjects receiving the suspension. 3. The small but significant increase in plasma and urine aluminium following sucralfate administration in therapeutic doses may reflect intestinal absorption of aluminium. Although such absorption would appear to be moderate in healthy subjects, it is suggested that aluminium-based treatments should be used only intermittently, especially in patients with renal disorders.

Stereoselective protection of exogenous and endogenous atrial natriuretic factor by enkephalinase inhibitors in mice and humans.

We compared the relative potencies of sinorphan and retorphan, the S- and R-enantiomers of acetorphan a potent inhibitor of enkephalinase (EC 3.4.34.11), to inhibit membrane metalloendopeptidase in vivo and to protect exogenous and endogenous ANF after oral administration. In mice, sinorphan was 2-3 fold as potent as retorphan in inhibiting the specific in vivo binding of [3H]acetorphan to kidney enkephalinase. The same potency ratio was found for the enhancement of trichloroacetic acid-precipitated radioactivity in kidneys of mice that had received 125I-ANF, which is used as a test for the protection of the hormone against inactivation in vivo. In nine healthy human volunteers who had received a low oral dosage of sinorphan or retorphan in a double-blind, placebo-controlled, randomized trial, sinorphan was also 2-3 fold more potent than retorphan in inhibiting plasma enkephalinase activity. These effects were accompanied by a related rise in plasma ANF immunoreactivity, which also reflected the difference in the effectiveness of the two compounds. Sinorphan was also more potent than retorphan in enhancing urinary cyclic GMP excretion and sodium excretion in five of these subjects. These data indicate that, in humans as in rodents, enkephalinase plays a crucial role in the inactivation of ANF, its partial inhibition in vivo being accompanied by a significant protection of the exogenous or endogenous hormone as well as by typical ANF-like responses. Thus orally administered sinorphan appears to be a promising compound for therapeutic use in cardiovascular and renal diseases in which ANF has been postulated to exert beneficial effects.

Evaluation and comparison of the interaction between alcohol and moclobemide or clomipramine in healthy subjects.

The interaction of clomipramine and moclobemide with alcohol was compared in a double blind parallel groups study in 24 healthy volunteers. Moclobemide was given at the highest recommended therapeutic dose (200 mg t.i.d.) and clomipramine in a subtherapeutic dose (25 mg b.i.d.) because of its poor tolerance in healthy subjects. Psychometric evaluations were performed during a placebo run-in phase; after a 5-day treatment period; assessments were made before, and again 1 h and 4 h after alcohol ingestion. Alcohol doses were pre-determined for each subject in order to produce a blood alcohol concentration of 0.6 g/l 1 h after alcohol intake and this individual alcohol dose was given on test days. The day before alcohol intake tests for autonomic functions were made to assess the anticholinergic effects of the drugs. Alcohol significantly increased body sway, decreased critical flicker fusion frequency, prolonged choice reaction time, impaired copying skills, impaired memory and increased the subjective feelings of satisfaction and tension. Drugs increased the effect of alcohol on body sway and this was essentially due to clomipramine. Clomipramine both without and with alcohol increased body sway, prolonged choice reaction time more than did moclobemide. Clomipramine seemed to diminish alcohol-induced memory impairment in one of the memory tests used. Subjects taking clomipramine had significantly more adverse effects after alcohol ingestion than did subjects of the moclobemide group. In contrast to moclobemide, clomipramine produced a moderate but significant drop in standing systolic blood pressure and a clear inhibition of salivary excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Peripheral haemodynamic effects of smoking in habitual smokers. A methodological study.

The effect of smoking on forearm haemodynamics was studied in four groups of healthy subjects, who had all smoked cigarettes (10-15 cigarettes/day) on average for 10 years. Changes in heart rate, blood pressure, forearm blood flow, forearm vascular resistance and pulse wave velocity were determined before and every 15 min for 75 min after smoking two cigarettes within 10 min. The inhaled nicotine was about 2.2 mg. There was no significant difference between the four groups in any haemodynamic variable before or after smoking, which indicated adequate reproducibility of the parameters studied and so made it possible to pool the results from all 30 subjects. Smoking significantly increased blood pressure, heart rate and pulse wave velocity and decreased forearm blood flow. Forearm vascular resistance remained unchanged. The rises in systolic blood pressure and pulse wave velocity were transient and both peaked (7% and 28%, respectively) 15 min after smoking. In contrast, heart rate and diastolic blood pressure remained significantly elevated and forearm blood flow was significantly decreased throughout the 75 min follow-up. The maximal changes were: heart rate +34%, diastolic blood pressure +17%, and forearm blood flow -24%. It is concluded that smoking produces statistically significant changes in forearm haemodynamics affecting both small and large arteries. The reproducibility of the study design means that it can be used to evaluate substances which may antagonize the haemodynamic effects of tobacco smoking.

Development and pharmacokinetics of a new sustained-release formulation of diltiazem.

Among the antihypertensive agents, calcium antagonists and in particular diltiazem play a leading role. To improve the conditions of diltiazem administration in the treatment of hypertensive patients a galenic formulation allowing administration of a single daily dose has been developed. The studies discussed in the following are concerned with the pharmacotechnical and pharmacokinetic development of sustained-release microgranules (sustained-release diltiazem). Bioavailability studies were performed after single-dose administration and after repeated-dose administration which were compared to the conventional formulation of diltiazem, Tildiem. After single-dose administration the following results were achieved: a relative bioavailability of 1.06 +/- 0.35; a prolongation of tmax of 7.16 +/- 2.66 vs. 2.46 +/- 0.80 h; and a longer final half-life of 11.8 +/- 5.3 vs. 5.6 +/- 1.1. After repeated administration of sustained-release diltiazem at a single daily dose of 240 mg compared to repeated administration of the conventional formulation of diltiazem at doses of 120 mg every 12 h over a period of 6 days, the following results were obtained: a relative bioavailability of 0.90 +/- 0.17; a lowering effect on Cmax of 191 +/- 65 vs. 230 +/- 95 ng/ml; statistically equivalent minimum concentrations of 62 +/- 21 ng/ml vs. 74 +/- 33 ng/ml. In an additional study, the effect of concurrent food intake on the bioavailability of diltiazem was confirmed. An increase in bioavailability of 28% in combination with an increase in interindividual variability was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Protection of atrial natriuretic factor against degradation: diuretic and natriuretic responses after in vivo inhibition of enkephalinase (EC 3.4.24.11) by acetorphan.

Atrial natriuretic factor (ANF) might be beneficial in several cardiovascular disorders, but its poor oral absorption and rapid inactivation in vivo have so far prevented its use in therapeutics. We have assessed the role of enkephalinase (membrane metallo-endopeptidase, EC 3.4.24.11) in the in vivo inactivation of ANF in mice and healthy human volunteers by evaluating the effects of acetorphan, a potent inhibitor. In mice, the degradation of 125I-labeled ANF was markedly delayed, as shown by the levels of the intact peptide in the plasma and the kidney, a major target organ. The effect of acetorphan was due to the inhibition of enkephalinase activity, since it occurred at an ED50 very close to this drug's ID50 for the inhibition of the specific binding of radioactive material to the kidney or lung peptidase that was measured after administration of [3H]acetorphan. The effects of acetorphan were also studied in eight healthy human volunteers by using a randomized double-blind, placebo-controlled design. Oral administration of acetorphan elicited a lasting elevation of plasma ANF-like immunoreactivity, with a time course parallel to that of the inhibition of plasma enkephalinase activity. These effects were accompanied by significant increases in urinary volume and sodium excretion, two well-established renal responses to ANF peptides. These results indicate that enkephalinase plays a critical role in ANF degradation in vivo and that its inhibition enhances the levels of circulating endogenous ANF, which, in turn, results in diuresis and natriuresis. Enkephalinase inhibition may constitute another therapeutic approach to the treatment of cardiovascular diseases, such as congestive heart failure or essential hypertension, on which ANF is postulated to have a beneficial effect.

Determination and comparison of the pressor effect of tyramine during long-term moclobemide and tranylcypromine treatment in healthy volunteers.

Monoamine oxidase inhibitors can elicit increases in systolic blood pressure after tyramine ingestion (cheese effect). Moclobemide is a new, reversible, preferential monoamine oxidase A inhibitor with antidepressant properties. Its potentiation of the tyramine pressor effect during 200 mg t.i.d. chronic treatment was compared with tranylcypromine, 10 mg b.i.d., in a double-blind, parallel-group, placebo-controlled study (n = 16). Tyramine was mixed with food and ingested in increasing daily doses, during a normal meal, until a systolic blood pressure increase of at least 30 mm Hg was achieved (tyramine 30). When compared with the usual fasting oral tyramine tests performed in the same subjects, the mean tyramine 30 dose with a meal was 2.8 times higher. The mean tyramine 30 dose with a meal decreased from 1450 mg (range, 800 to 2000 mg) during placebo to 306 mg (range, 150 to 500 mg) during moclobemide (factor, 5.0) and from 1200 mg (range, 1000 to 1600 mg) during placebo to 35 mg (range, 20 to 50 mg) during tranylcypromine (factor, 38.2). The duration of the systolic blood pressure increase was longer with tranylcypromine (126 minutes) than with moclobemide (69 minutes) (p less than 0.01).