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Biomedical subjects

W H Ziegler

Publications and source records attributed to W H Ziegler.

At least 55 records · Page 3Linked to original sources
PubMed1982

Pharmacokinetics of ceftriaxone following intravenous administration of a 3 g dose.

The pharmacokinetic parameters of total (bound and unbound) and free (unbound) ceftriaxone in six healthy volunteers after intravenous injection of 39 were compared with low-dose data from a previous study. The dose-dependent behaviour of total drug was considerably more pronounced after the 3 gram dose. In contrast, total body clearance (C1FS = 258 ml/Min), renal clearance (C1FR = 170 ml/min) and volume of distribution (VFD (beta) = 168 1) of free (unbound) drug did not differ from the data reported earlier. There was no significant change in biological half-life (t1/2 (beta) = 7.8 h) or in the fraction excreted unchanged in urine (fu = 0.67).

Adult↗
PubMed1982

Acute effects of prizidilol on blood pressure, heart rate, catecholamines, renin and aldosterone in essential hypertension.

Prizidilol is a new antihypertensive agent reported to possess combined precapillary vasodilator and betareceptor-blocking properties. To clarify the profile of the acute effects of prizidilol in man, a variable dose study was performed in 8 patients with benign essential hypertension. Blood pressure, heart rate, plasma renin activity, aldosterone, plasma and urinary catecholamines and electrolytes were determined at short intervals before and up to 23 h after oral administration of placebo and prizidilol 150, 300 and 600 mg. The 4 studies were performed at weekly intervals according to a Latin square design. Prizidilol produced dose-dependent decreases in supine and upright blood pressure, with an initial change after about 2 h and maximal effects from 4 to 8 h after drug ingestion. Following a high dose of prizidilol, supine mean blood pressure (average 128 mmHg prior to treatment) was normalised (less than 107 mmHg) from 3 to 7 h and was still below predose level 23 h after ingestion. The only reported side effects were postural dizziness in 2 cases (corresponding to a fall in systolic upright blood pressure to less than 95 mmHg) and headache in one case. A biphasic variation in heart rate and plasma renin activity, with an early drop and a subsequent tendency to a slight rise, was observed after an intermediate or high dose of prizidilol. Plasma norepinephrine levels were increased by a high dose of prizidilol, while plasma epinephrine, aldosterone and plasma and urinary electrolytes were not consistently changed. Prizidilol in a a single oral dose appeared to be a potent antihypertensive agent. The profile of heart rate and plasma renin point to early dominance of beta-blockade followed by appearance of the concomitant vasodilator properties of prizidiol.

Adrenergic beta-Antagonists↗
PubMed1982

Catecholamines, sodium and renin in unilateral renal hypertension in man.

The relative roles of plasma or urinary norepinephrine (NE) and epinephrine (E), exchangeable sodium, blood volume, and plasma renin (PRA) or aldosterone in the pathogenesis of unilateral renal hypertension was evaluated. 99 normal subjects and 33 age-matched untreated hypertensive patients with unilateral renal parenchymal disease (RPD) (n = 18) or unilateral renal artery stenosis (RAS) (n = 15) were compared. Measurements were repeated following operative treatment in 23 patients. Plasma and urinary NE or E, exchangeable sodium and blood volume did not differ significantly between normal and untreated subjects with RPD or RAS. Both patient subgroups had increased blood pressure and supine PRA (p less than 0.001); these abnormalities were milder with RPD. Plasma aldosterone and upright PRA were significantly elevated (p less than 0.05) in RAS only. Operative treatment of RPD and RAS caused decreases in blood pressure (-18 and -28%) and PRA; they correlated in RPD (r = 0.56; p less than 0.05). In RPD and RAS, exchangeable sodium, blood volume, and NE or E values were not significantly changed following operation, except for mildly increased upright PNE in RAS. These observations suggest that the sympathetic system plays no major role in the maintenance of unilateral renal hypertension in man. However, the 'normal' body sodium-volume state in RPD or RAS may be inappropriate relative to coexisting hypertension. In addition to its established role in RAS, mild activation of the renin-angiotensin system may also be important for the pathogenesis of hypertension caused by unilateral RPD.

Adult↗
PubMed1981

Catecholamines, renin, aldosterone, and blood volume during chronic minoxidil therapy.

Several pressor factors were studied before and during chronic minoxidil therapy (median dose 27.5 mg/day) in 16 patients with hypertension that was refractory to conventional drugs. Following treatment with minoxidil and intensified diuretic therapy, blood pressure was decreased markedly; pulse rate, body weight, plasma volume, plasma aldosterone and epinephrine levels were not significantly altered, while plasma renin activity tended to be increased. Supine and upright plasma norepinephrine concentrations were increased by 140 (P less than 0.005) and 50% (P less than 0.05), respectively, but no significant change in urinary norepinephrine excretion was apparent. The latter parameter may not be a close index of sympathetic activity in patients with severe hypertension treated with minoxidil. While a search for underlying pheochromocytoma is always indicated in refractory hypertension, it appears mandatory to evaluate plasma catecholamines prior to or following discontinuation of treatment with minoxidil, to avoid a wrong diagnosis of pheochromocytoma.

Aldosterone↗
PubMed1981

Relationship between plasma catecholamines and urinary catecholamine excretion rates in normal subjects and certain diseased states.

Relationships between plasma norepinephrine (PNE) or epinephrine (PE) and urinary norepinephrine (UNE) or epinephrine (UE) excretion rates were studied in 37 normal subjects, 39 patients with benign essential hypertension, 23 with unilateral renal hypertension, and 20 with bilateral renal disease (serum creatinine 2.3 +/- 2.6 mg/100 ml). measurements were also performed after 6 weeks of diuretic treatment in 27 normal subjects and all patients with essential hypertension. In the untreated state, PNE and UNE values were generally normal in essential or unilateral renal hypertension; PNE tended to be decreased in diabetics and increased in bilateral renal disease. Diuretic treatment caused a tendency for slightly increased PNE and UNE. UNE correlated significantly with supine PNE or upright PNE or their mean value, and this relationship appeared to be comparable between untreated normal subjects and the various patients groups, except for a tendency for slightly higher PNE at given UNE values in bilateral renal disease. No significant correlations between UE and PE were apparent in the normal subjects or patient groups. These data demonstrate a dissociation of UE from PE levels. In contrast, UNE is an approximative index of PNE, and this relationship appeared to be generally unaltered in essential or unilateral renal hypertension. In patients with bilateral renal disease the slight shift of this relationship indicates that consideration of renal function is necessary for interpretation of NE levels.

Adult↗
PubMed1981

Chronic treatment with the new potent vasodilator Ro 12-4713 in moderate to severe hypertension: effects on blood pressure, endocrine function, sodium and plasma volume.

The antihypertensive efficacy and endocrine profile of the new antihypertensive agent, Ro 12-4713, were evaluated in 23 patients (17 men and 6 women) with moderate to severe arterial hypertension. Following addition of Ro 12-4713 to pre-existing therapy with diuretics and beta-blockers or sympatholytics, blood pressure in most of the patients was normalized within one month by a daily dose of 60 to 120 mg. Heart rate was only slightly increased. Orthostatic hypotension was not observed. Weight gain or oedema formation occurred in 14 patients within the first four weeks, but could be controlled satisfactorily by intensified diuretic therapy. Increased hair growth occurred in most of the patients. After a mean duration of treatment of 2.8 months, plasma volume and plasma and urine sodium were unaltered, and plasma potassium was slightly decreased. Plasma renin activity was doubled, whereas plasma aldosterone concentrations were unaltered. Plasma norepinephrine levels were high before and increased only slightly during chronic Ro 12-4713 treatment, whereas urinary norepinephrine excretion was unchanged. Plasma and urinary epinephrine were unaltered by Ro 12-4713. Ro 12-4713 appears to be a potent vasodilator for the combination treatment of hypertension in men.

Adult↗
PubMed1981

Effects of concentration-dependent plasma protein binding on ceftriaxone kinetics.

The kinetics of ceftriaxone, a cephalosporin, was studied in six healthy subjects who received bolus injections of 150, 500, and 1,500 mg intravenously in a random crossover fashion. Although total drug concentration time profiles after all doses could be described by biexponential equation, simple compartment analysis was inappropriate because a disproportional increase in the area under the total drug concentration time curves occurred with dose. This resulted in a dose-dependent increase in total systemic clearance (ClTS) from 9.7 ml/min at the 150-mg dose to 13 ml/min at the 1500-mg dose. The dose-dependent changes in ClTS could be explained in terms of the concentration-dependent plasma protein binding of ceftriaxone (fplasma ranging from 0.04 to 0.167), because the area under the free drug concentration time curves (AUCFO-infinity) increased proportionately to dose. Mean total clearance with reference to free (unbound) ceftriaxone (ClFS) was constant at 255 ml/min. Calculated mean renal clearance with reference to free ceftriaxone (ClFR) was 173 ml/min, or slightly more than the average glomerular filtration rate in humans. Mean plasma ceftriaxone t1/2 was not influenced by dose and averaged 8 hr. This biological t1/2 is by far the longest ever for a cephalosporin in healthy subjects.

Adult↗
PubMed1981

Insulin hypoglycaemia in normal and adrenalectomized subjects: comparison of metabolic parameters and endocrine counter regulation.

Insulin tolerance tests were carried out in normal subjects and in adrenalectomized (ADX) patients in order to better understand the importance of counter regulatory hormones for the recovery from hypoglycaemia. Compared to normal subjects recovery of plasma glucose and of free fatty acid levels in adrenalectomized patients is retarded. The levels of glucagon are significantly higher in ADX patients during rest than in normal subjects. As expected, epinephrine and norepinephrine levels did not increase in ADX patients and, accordingly, blood pressure did not change. Growth hormone levels were the same in both groups of subjects. Interestingly, there was no clear-cut difference with regard to subjective symptoms of hypoglycaemia. It would appear that epinephrine is important for the rapid initial recovery from hypoglycaemia, whereas other hormones play a more important role later on.

Adrenalectomy↗
PubMed1981

[Relationship between clinical effects and pharmacokinetics of midazolam on i.m. and i.v. application to volunteers/1st comm.: Clinical aspects (author's transl)].

The onset of action of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine (midazolam, Ro 21-3981, Dormicum), after i.v. injection of 12.5 mg, occurs towards the end of the injection and reaches its maximum level in about 3 min. After i.m. injection, the first effects are generally seen about 5 min later. The maximum effect is reached in about 20 min. Psychometric tests tend to return to normal within 2 h after the injection and are completely normalized within 4 h. Although no objective effect was measurable, the subjects sometimes reported subjective effects lasting up to 6 h. These were mainly signs of mild residual fatigue. The objective and subjective symptoms disappeared after 6 h. General and local tolerance was excellent. A transient sensation (lasting a few minutes) of slight burning was mentioned by some subjects after i.m. injection. Midazolam is therefore a sleep-inducing agent distinguished by rapid and regular onset of action, relatively short duration of action and a low incidence of side effects.

Adult↗
PubMed1981

[Relation between the clinical effect and the pharmacokinetics of midazolam following i.m. and i.v. administration/2nd comm.: Pharmacokinetical aspects (author's transl)].

In a cross-over study 6 subjects were administered 12.5 mg 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a] [1,4]benzodiazepine (midazolam, Ro 21-3981, Dormicum) i.v. and i.m., with an interval of one week between the two applications. Midazolam, in the hydrochloride form, was administered by both the i.v. and i.m. route, and the lactate form only by the i.m. route. Determination of the concentration of midazolam in plasma was carried out by a gas chromatography method (Method ECD-GLC). After administration by i.m. route both salts were rapidly absorbed. The maximum concentrations were generally reached within 30 min after the injection. The mean absolute bioavailability is 91% for the hydrochloride and 82% for the lactate. The nature of the salts has no influence on bioavailability. On the basis of performance tests we obtained a good relation between the plasma concentration and the psychometric findings. 2--4 h after i.v. or i.m. administration the clinical effects are no longer measurable and the findings are approaching the initial values determined before the injection. The plasma concentration, on the other hand, is still measurable after the same lapse of time, at around 100 ng/ml.

Anti-Anxiety Agents↗
PubMed1981

Excretion and metabolism of 14C-midazolam in humans following oral dosing.

After oral dosing of 10 mg 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4] benzodiazepine (midazolam, Ro 21-3981, Dormicum) labelled with 14C (25 microCi) to 4 human volunteers, the total radioactivity is mainly excreted via the kidneys. Nearly 90% are excreted within 24 h. Main urinary metabolite is the conjugated 1-hydroxymethyl derivative, which amounts to 60-70% of the administered dose within 24 h. Compared to total radioactivity, levels of unchanged drug in plasma are rather low and differ from one subject to the next. Most of the plasma radioactivity consists of the 1-hydroxymethyl compound, most of it in conjugated form. Levels of free metabolite are lower than those of unchanged drug. Radioactivity is rapidly eliminated from plasma. The results of the present oral study seem to indicate significant first-pass metabolism.

Administration, Oral↗
PubMed1980

Effects of chronic alpha and beta adrenoceptor blockade with labetalol on plasma catecholamines and renal function in hypertension.

Plasma catecholamines and renal function were evaluated in 18 patients with essential hypertension treated with the alpha and beta adrenoceptor blocking agent, labetalol. Following 6 weeks of labetalol therapy, blood levels of epinephrine and norepinephrine remained unaltered. Glomerular filtration rate and renal plasma flow were decreased similarly by about 20% (P less than 0.025). Tubular rejection fraction of sodium was increased by 36% (P less than 0.001) while sodium excretion was comparable to control conditions. Labetalol's potential to cause a mild reduction in kidney function should be considered, but may have no clinical consequences in most hypertensive patients receiving such treatment. The lack of increased plasma catecholamine levels during therapy supports the concept that labetalol's alpha-blocking potential is limited to post-junctional receptors, leaving the prejunctional feedback control of catecholamine release intact. Moreover, labetalol's blood pressure-lowering mechanism may be largely independent of changes in sympathetic nervous activity.

Adult↗
PubMed1979

Evaluation of autonomic neuropathy in diabetes mellitus. Comparison of clinical, functional and biochemical parameters.

Quantitative assessment of signs or symptoms of neuropathy, and the beat-to-beat variation, valsalva, orthostasis, handgrip and cold pressor tests, and measurements of plasma renin and catecholamine excretion rate were performed in 23 diabetic patients and 10 age-matched normal subjects. Significant inverse correlations were found between the clinical score and the beat-to-beat variation (a test of efferent vagus function) (r=-0.55, -0.72, P less than 0.0005) or the pressor response to handgrip (possible test of efferent sympathetic integrity (r=p less than 0.005) or the values of both tests combined (r=-0.79, P less than 0.0005); but not with the other measured parameters. Beat-to-beat variation was abnormal in all 9 diabetics with increased and in 9 of 14 with normal clinical score, whereas only seven and one patient from these subgroups, respectively, had an abnormal Valsalva ratio. The pressor response to handgrip was only slightly reduced in the diabetic patients, with greater tendency in those with abnormal clinical score. Additional possible indices of adrenergic dysfunction such as the pressor response to cold stimulus, plasma renin levels and noradrenaline or adrenaline excretion rates did not differ significantly between normal subjects and diabetics. These finding demonstrate a greater prevalence of parasympathetic as compared to sympathetic impairment in diabetic autonomic neuropathy; the beat-to-beat variation was the most sensitive among the tests used. An assessment of clinical evidence combined with non-invasive functional procedures such as the beat-to-beat variation and handgrip tests provide a valuable and easy to perform tool in the evaluation of diabetic neuropathy.

Adult↗