Biomedical subjects

W H Ziegler

Publications and source records attributed to W H Ziegler.

At least 37 records · Page 2Linked to original sources

PubMed1988

Mechanism of action of ketanserin: studies on cardiovascular reactivity in essential and diabetes-associated hypertension.

Ketanserin is a selective serotonin-S2 receptor antagonist with alpha 1-adrenoceptor inhibiting activity. The relative contribution of the latter mechanism to antihypertensive efficacy was studied in a group comprising eight normal subjects, 10 patients with essential hypertension and eight diabetics with arterial hypertension. Ketanserin treatment administered over a period of 8 weeks, decreased arterial pressure in patients with essential hypertension and, to a lesser extent, in diabetics, but not in normal subjects. In all three groups, exchangeable sodium, blood volume, the activity of the adrenergic and renin-angiotensin-aldosterone systems and the pressor responsiveness to norepinephrine (NE) or angiotensin II (Ang II) were unaltered, while the pressor reactivity to phenylephrine showed a significant decrease in normal subjects only. This suggests that the antihypertensive mechanism of ketanserin does not involve a modification of the physiological relationship between endogenous noradrenergic and pressor reactivity to NE. Moreover, ketanserin does not interfere with Ang II-dependent mechanisms.

Adult↗

PubMed1988

Blood pressure response to tyramine-enriched meal before and during MAO-inhibition in man: influence of dosage regimen.

In an open study oral tyramine in variable doses was administered to six healthy volunteers under three different conditions: 1) without moclobemide, 2) under moclobemide steady-state conditions (3 X 200 mg moclobemide daily) one hour after moclobemide intake and 3) under moclobemide steady-state conditions simultaneously with moclobemide. It was shown that the amount of tyramine effecting 30-50 mmHg systolic blood pressure increase was roughly doubled when moclobemide was administered together with tyramine instead of one hour before tyramine intake. The time interval between tyramine ingestion and maximal blood pressure increase did not differ significantly between conditions 2) and 3). The conclusion of this study is that moclobemide should always be taken at the end of a meal, which is anyway the usual time for drug intake.

Administration, Oral↗

PubMed1988

Effect of long-term physical exercise on lymphocyte reactivity: similarity to spaceflight reactions.

The response of critical immunological parameters in seven athletes to the sustained physical stress of marathon running was assessed. Variables analysed were the responsiveness of lymphocytes (measured as mitogenic response to concanavalin A), the numbers of lymphocytes, their subsets, and leukocyte numbers. In addition, blood levels of cortisol, epinephrine, and norepinephrine were determined. After the run, lymphocyte responsiveness was severely depressed to 1-70% of the resting values, even though the lymphocyte counts did not change. Leukocyte counts were elevated 2.8-fold. No dramatic changes were found within the lymphocyte subsets, although an increase in pan T-cells and the helper/inducer subset 2 d after the run was significant. In addition, the numbers of B-cells decreased significantly. No change was observed within the suppressor/cytotoxic subset. Cortisol increased 2.1-fold, epinephrine 3.2-fold and norepinephrine 2.7-fold. All these parameters returned to baseline values within 2 d. These data were compared with data obtained during and after spaceflight. We conclude that prolonged physical stress of marathon running induces changes in immunological responsiveness that are strikingly similar to those arising from the stress of spaceflight.

Epinephrine↗

PubMed1987

Insulin-like growth factor II in human adrenal pheochromocytomas and Wilms tumors: expression at the mRNA and protein level.

Two forms of insulin-like growth factor (IGF) II with molecular masses of 10 and 7.5 kDa, respectively, were found in tumor tissue from human adrenal pheochromocytomas. The tumors contained 5.3-7.1 micrograms of immunoreactive IGF-II per g of tissue, which is about 20 times more than in adrenal medulla. The total bioactive IGF in the pheochromocytomas exceeded that in normal liver or kidney, which contained only the 7.5-kDa IGF-II species, by a factor of approximately equal to 100. By contrast, the amount of IGF-I was just measurable and did not vary significantly between tumor and normal tissue. The high amounts of IGF-II in the pheochromocytomas were not reflected, however, by a corresponding increase of mRNA. The opposite situation was found in Wilms tumors, where IGF-II content was in the same range as in nontumor tissues despite increased expression of IGF-II mRNA.

Adrenal Gland Neoplasms↗

PubMed1986

Pharmacokinetics of the new benzodiazepine antagonist Ro 15-1788 in man following intravenous and oral administration.

During clinical pharmacology studies with the benzodiazepine antagonist Ro 15-1788 the pharmacokinetic characteristics of high intravenous doses (20 and 40 mg) and of an oral dose (200 mg) were examined in six healthy male volunteers. Ro 15-1788 was rapidly and extensively distributed in the body with an apparent volume of distribution Vss of 1.06 l kg-1. Elimination occurred rapidly by hepatic metabolism and the high plasma clearance of 1.14 l min-1 resulted in a short elimination half-life of less than 1 h. No difference in the disposition parameters calculated from the data after the 20 and 40 mg doses was observed reflecting a dose-proportionality in the areas under plasma concentration-time curves and unchanged distribution characteristics. Because the blood/plasma distribution coefficient is close to unity the disposition parameters obtained from plasma concentrations are similar to the corresponding parameters with reference to blood. Following oral administration of 200 mg the drug is rapidly absorbed. Peak levels were reached after 20-90 min and were close to or even higher than the values after the 40 mg intravenous dose at the same time point. Due to the high hepatic extraction ratio the fraction reaching the systemic circulation unchanged was reduced to approximately 16% during the absorption step.

Absorption↗

PubMed1986

Adrenergic activity and aldosterone regulation: no evidence for an alpha-1 adrenoceptor-mediated influence in normal subjects.

In normal man the sympathetic nervous system could exert an inhibitory influence on aldosterone responsiveness to angiotensin II. The possible role of alpha-1 adrenoceptors in the modulation of aldosterone response was assessed by studying the changes of plasma aldosterone during infusion of angiotensin II at the doses of 1, 2, 5 and 10 ng/kg.min or after corticotrophin injection, 0.25 mg, in 9 normal subjects before and after treatment with the selective alpha-1 adrenoceptor antagonist, prazosin. Prazosin, given during 3 weeks, did not modify supine arterial pressure, heart rate and the plasma levels of angiotensin II, renin, aldosterone or adrenaline but caused a significant (P less than 0.05) increase of plasma noradrenaline. The correlation relating plasma aldosterone to plasma angiotensin II levels before and during angiotensin II infusion and the response of plasma aldosterone to corticotrophin was not modified by prazosin. These findings suggest that in normal man there is no inhibitory influence of the noradrenergic system on aldosterone responsiveness to angiotensin II mediated by an alpha-1 dependent mechanism.

Adrenocorticotropic Hormone↗

PubMed1985

Effects of the dopaminergic agonist cianergoline on blood pressure, the renin-angiotensin-aldosterone axis and the sympathetic nervous system in patients with essential hypertension.

Cianergoline is a new dopaminergic agonist with a predominant cardiovascular action. Its effects on blood pressure, the renin-angiotensin-aldosterone axis, the sympathetic nervous system and lipid metabolism were assessed in 20 patients with benign essential hypertension. Cianergoline given in increasing doses for 4 weeks (maximum daily dose 12 +/- 2 mg (SD)) and placebo both caused a slight decrease in arterial pressure, (from 159/104 to 152/98 mm Hg and from 154/104 to 149/103 mm, respectively; difference not significant). Supine and upright plasma renin activity, plasma aldosterone, norepinephrine, epinephrine and dopamine levels, urinary catecholamine excretion rates as well as serum prolactin, low and high density cholesterol and triglyceride concentrations were not changed after cianergoline or placebo. Total serum cholesterol and triglyceride levels decreased significantly after placebo, but were unchanged after cianergoline. 3 out of 10 patients in the cianergoline group complained of nausea. The findings indicate that the new dopaminergic agonist cianergoline exerts only a mild blood pressure lowering effect in patients with essential hypertension and does not modify the release of prolactin, lipid metabolism or the basal activity or postural responsiveness of the renin-angiotensin-aldosterone axis and of the sympathetic nervous system.

Adult↗

PubMed1984

[Relation between the clinical effect and plasma concentration of midazolam in volunteers].

In 12 healthy volunteers, the pharmacological effects of midazolam were investigated following intravenous (0.15 mg X kg-1 and 12.5 mg in 6 subjects each), intramuscular (12.5 mg in 6 subjects) and oral administration (20 mg in 6 subjects and 10 mg in 4 subjects). The findings were correlated with the plasma concentrations of midazolam and its alpha-hydroxy metabolite. The effects were assessed using objective and subjective methods (reaction time, memory test and subjects' self-assessment with an analog scale covering the degree of sedation). Plasma samples were assayed for midazolam and its alpha-hydroxy metabolite by gas chromatography. The results of the memory test showed that mnemonic retention and recall of a number remained intact for the period preceding intravenous or intramuscular administration. The maximum impairment occurred at 30 min after injection for recall of a number presented at the 15th min. The impairment was no longer detectable 4 h after injection. The plasma concentration time course was similar to that of the reaction time after administration of an identical intravenous or intramuscular dose. The maximum effect was attained within 15 min and 30 min after intravenous and intramuscular administration respectively. Within 2 to 4 h after parenteral administration, the reaction time had returned to normal. At identical plasma concentrations of midazolam, the reaction time was slightly longer in the period immediately following oral administration than after parenteral administration. This result suggested that the alpha-hydroxy metabolite contributed actively to the effect of midazolam. After its intravenous injection, this metabolite's sedative effects attained their maximum with 15 min, having disappeared 4 h later.

Adult↗

PubMed1984

Single-dose pharmacokinetics of Ro 17-2301 (AMA-1080), a monocyclic beta-lactam, in humans.

Ro 17-2301 (AMA-1080) is a new N-sulfonated monocyclic beta-lactam that is highly active against gram-negative bacteria, especially against Enterobacteriaceae and Haemophilus, Neisseria, and Pseudomonas spp. (Kondo et al., Proc. Int. Congr. Chemother. 13th, Vienna, Austria, p. 56/1-56/5, 1983). The single-dose pharmacokinetics of this compound were studied in six healthy male volunteers who received intravenous infusions of 500, 1,000, and 2,000 mg. A good linear correlation (r2 = 0.99) was found between the dose infused and the resulting area under the plasma concentration-time curve. Maximal plasma concentrations of 36, 78, and 150 micrograms/ml appeared after doses of 500, 1,000, and 2,000 mg, respectively. The mean terminal elimination half-life was 1.8 h (range, 1.4 to 2.3 h), the apparent volume of distribution at steady state was 17 liters, and the total systemic clearance was 150 ml/min. Within 72 h 78 to 89% of the dose was recovered intact from urine. After administration of 14C-labeled Ro 17-2301, 96% of the radioactivity was found in the urine and 3% was found in the feces. The concomitant administration of probenecid did not affect the renal clearance or urinary excretion of this beta-lactam, an indication that the renal elimination of this substance is only by glomerular filtration. Ro 17-2301 was 18% bound to human plasma protein, and this binding was independent of concentration between 25 and 400 micrograms/ml. Based on these data, the pharmacokinetics of this monocyclic beta-lactam should be predictable in the foreseen dose ranges.

Adult↗

PubMed1983

[Effect of catecholamines and propranolol on the acute acclimatization to high altitude in man].

The venous concentrations of epinephrine and norepinephrine and changes in ventilation, respiratory gases, circulation and ECG were determined in 20 young healthy male medical students during standardized stepwise ascent to 6000 m in a low pressure chamber, once without (control) and once with beta-receptor blockade (propranolol). The results show that the plasma concentration of norepinephrine increased significantly as a result of hypoxic hypoxia. The moderate increase in epinephrine was, besides the minor but significant hypoxic influence, mainly due to psychic tension. Since beta-receptor blockade does not prevent the respiratory and circulatory adjustment, beta-adrenergic stimulation is not thought to be necessary at altitude. Propranolol, on the contrary, lowers the hypoxia-induced increase in cardiac output and diminishes the ECG changes, in particular the S-T depression, significantly. By antagonizing the effects of epinephrine and by its central effects, propranolol improves subjective tolerance to altitude, and, on the other hand, by economizing the cardiac work load, the objective ability to withstand oxygen want.

Acclimatization↗

PubMed1983

Antihypertensive mechanism of diuretic treatment with chlorthalidone. Complementary roles of sympathetic axis and sodium.

Twenty-three patients with untreated mild to moderate essential hypertension had on the average an abnormally increased cardiovascular pressor responsiveness to exogenous norepinephrine (NE), while plasma and urinary NE, exchangeable body sodium and blood volume were normal. An increased pressor responsiveness to angiotensin II in these patients was associated with a tendency for low plasma renin activity (PRA). Compared to placebo conditions, treatment with chlorthalidone, 100 mg/day, for 6 weeks significantly decreased blood pressure and exchangeable sodium in these hypertensive patients but not in ten normal subjects; blood volume and heart rate were unchanged in both groups. Chlorthalidone induced a marked increase in PRA, but only a mild increase in angiotensin II pressor dose. In contrast, the diuretic caused a greater increase in NE pressor dose than in plasma NE in the hypertensive group, thus improving the disturbed relationship between plasma NE and NE responsiveness in these patients. No significant modification of plasma NE and NE responsiveness occurred in diuretic-treated normal subjects. In addition to sodium and the renin-angiotensin system, the sympathetic regulatory axis seems to be involved in the antihypertensive mechanism of chlorthalidone. Thiazide-like diuretics may decrease blood pressure in essential hypertension in part by lowering an abnormally high cardiovascular NE responsiveness without causing an equivalent increase in circulating NE.

Adult↗

PubMed1983

Pharmacokinetics and bioavailability of midazolam in man.

The pharmacokinetic behaviour and the bioavailability of midazolam were investigated in six volunteers after intravenous (0.15 mg/kg) and oral administration (10, 20 and 40 mg). Following rapid intravenous injection of midazolam, the plasma concentration of the substance decreased to approximately 10% within 2 h owing to a rapid rate of distribution. A two compartment model adequately described the kinetics of midazolam in plasma. The following average values were found: elimination half-life, 2.3 h; total clearance, 323 ml/min, and apparent volume of distribution at steady-state (VSS), 50.21. After oral administration, the drug is rapidly absorbed. Maximum plasma levels are reached within 30 min and the drug is rapidly eliminated from plasma with practically the same half-life as determined after i.v. administration. The bioavailability after the ingestion of 10, 20 and 40 mg midazolam in the form of tablets ranged from 31 to 72%, due to the high liver extraction quota of midazolam.

Administration, Oral↗

PubMed1983

Relationship between plasma concentration and effect of midazolam after oral and intravenous administration.

In a double-blind, cross-over study in six healthy volunteers, the effects of different oral doses of midazolam (10, 20 and 40 mg), or 0.15 mg kg-1 midazolam administered intravenously and of placebo were investigated. Plasma concentrations of midazolam and of its active alpha-hydroxy metabolite were measured at the same time. The effect was assessed using objective and subjective methods (reaction time, tracing test, subjects' self-assessment and investigator's subjective assessment). The respective time courses of the plasma concentration and of the effect (reaction time, number of errors in the tracing test) were almost identical. Peak plasma levels and maximum effects were attained within 30 min. In general, the effect after intravenous injection of 0.15 mg kg-1 and after an oral dose of 10 mg midazolam lasted for 2 h following administration and its duration was doubled (i.e. to 4 h) after the 20 mg oral dose. Between the logarithm of the plasma concentration and the effect, there is a sigmoidal relationship that is virtually time independent. Particularly in the first few hours after oral administration the effect is intensified by the alpha-hydroxy metabolite of midazolam which is formed by first-pass metabolism. At identical plasma concentrations of midazolam, the oral dose produced more marked effects than did the intravenous administration. Correlation of the measured effects with the total (midazolam + alpha-hydroxy midazolam) plasma concentration reveals a closer sigmoidal relationship.

Administration, Oral↗

PubMed1983

Comparison of the effects of intravenously administered midazolam, triazolam and their hydroxy metabolites.

The aim of the study was to compare the pharmacological activity and clinical effect after i.v. administration of midazolam, triazolam and their hydroxy metabolites, and, secondly, to compare the clinical effects of midazolam and triazolam in doses yielding the same duration of action (15 mg and 0.25 mg, respectively). In a randomized, cross-over procedure, six healthy volunteers received one of the following in the morning at approximately weekly intervals: 15 mg midazolam; 9 mg alpha-hydroxy midazolam; 1 mg triazolam; 1 mg alpha-hydroxy triazolam; 1 mg 4-hydroxy triazolam. Tests of drug effect (investigator's assessment, psychometric testing, and self-rating by subjects) were carried out at different times in the 24-h period following administration. Triazolam 0.25 mg was also studied in four of these six subjects to supplement the findings in the cross-over study. Triazolam 1 mg was shown to have the strongest, most long-lasting effect. Midazolam 15 mg had almost the same intensity of effect but this was shorter lasting, i.e. 5 h as against 10 h for 1 mg triazolam. The alpha-hydroxy metabolites had a duration of action about half that of the parent compounds and a less potent effect, and 4-hydroxy triazolam was virtually devoid of effect. The lower 0.25-mg dose of triazolam had about the same duration of action as 15 mg midazolam but did not achieve the same degree of maximum effect as measured by psychometric tests and self-assessment by subjects. The findings of this study indicate that midazolam would be suitable for use in situations in which a brief but intense hypnotic sedative effect is desired.

Adult↗

PubMed1982

[Familial studies in medullary thyroid carcinoma and multiple endocrine adenomatosis].

Medullary thyroid carcinoma secreting calcitonin frequently occurs familially and in association with pheochromocytomas and hyperplastic parathyroid glands (multiple endocrine adenomatosis type II). Thyroid tumors develop from a hyperplasia of the C-cells and can be diagnosed at an early stage in the light of raised plasma levels of calcitonin and with provocation tests using i.v. calcium. Observation of two index patients with pheochromocytomas and one patient with medullary thyroid carcinoma led to endocrinological study of three families. A one min i.v. calcium injection test has been shown to be a reliable and well tolerated screening procedure for the medullary carcinoma. Endocrine adenomatosis type II was diagnosed in two of the three kindreds. While pheochromocytomas were usually found in only 30-50% of the affected family members, an elevated plasma adrenalin level after histamine provocation was measured in all our patients with pathological calcitonin tests. The third family did not present evidence of adrenal hyperplasia. Plasma levels of calcitonin were only marginally stimulated after the i.v. administration of calcium, and the stimulation remained constant for over seven years; therefore, either familial medullary thyroid carcinoma could not be diagnosed with certainty or the condition remained clinically stable.

Adrenal Gland Neoplasms↗

PubMed1982

Responses of catecholamines and blood pressure to beta-blockade in diuretic-treated patients with essential hypertension.

Twenty patients (mean age 49 +/- 4 (SEM) yr) with mild to moderate essential hypertension were studied during placebo conditions, following 6 weeks of chlorthalidone monotherapy and 6 to 28 weeks of combined beta-blocker-chlorthalidone treatment, or vice versa. Compared to chlorthalidone therapy alone, addition of a beta-blocker to this diuretic caused a further blood pressure reduction in 11 patients (Responders); in 9 patients addition of a beta-blocking agent failed to further reduce blood pressure (Non-responders). Supine and upright plasma renin, aldosterone, norepinephrine and epinephrine levels and catecholamine excretion rates were always comparable between Responders and Non-responders. In both groups plasma and urinary norepinephrine or epinephrine values were not significantly altered following addition of a beta-blocker; heart rate and plasma renin activity were decreased in both groups to a similar extent. It is concluded that the antihypertensive mechanism of beta-blockers given to diuretic treated patients with essential hypertension is independant of renin and not associated with changes in plasma or urinary catecholamines.

Adrenergic beta-Antagonists↗

PubMed1982

Insulin absorption from the abdomen and the thigh in healthy subjects during rest and exercise: blood glucose, plasma insulin, growth hormone, adrenaline and noradrenaline levels.

Insulin was absorbed faster from the abdomen than from the thigh under resting conditions and during exercise. Exercise enhanced the rate of insulin absorption marginally. The fall of blood glucose during rest and exercise was not significantly different after insulin injection into either site. The faster absorption of insulin from the abdomen during rest and exercise was reflected in a sharper rise of serum growth hormone levels and urinary adrenaline excretion. Therefore exercise should not be taken immediately after injection of a large dose of soluble insulin, particularly into the abdomen.

Abdomen↗

PubMed1982

Antihypertensive mechanism of the diuretic muzolimine in mild renal failure. Roles of sodium and cardiovascular norepinephrine responsiveness.

Eighteen patients with mild impairment of renal function (glomerular filtration rate 65 +/- 5 ml/min:m +/- SEM) and hypertension (168/105 +/- 6/3 mmHg) were shown on average to have abnormally increased cardiovascular pressor responsiveness to infused norepinephrine (NE; p less than 0.05), whereas plasma and urinary NE, exchangeable body sodium and blood-volume did not differ significantly from normal. A slightly increased pressor responsiveness to angiotensin II was associated with a tendency to low plasma renin activity (PRA). Compared to placebo conditions, treatment with the loop-diuretic muzolimine in a mean dose of 35 +/- 2 mg/day for six weeks decreased blood-pressure and exchangeable sodium (p less than 0.05), and NE pressor responsiveness was restored to normal values, whilst plasma and urinary NE were not significantly changed. This was consistent with improvement of the initially abnormal relationship between NE levels and NE responsiveness factors. In contrast, the pressor dose of angiotensin II and PRA were increased to an approximatively similar extent during muzolimine treatment. These observations suggest that removal of body sodium and a decrease in NE reactivity without an equivalent increase in sympathetic nervous activity may be important complementary factors in the antihypertensive mechanisms of diuretic treatment in patients with mild renal functional impairment.

Adult↗