Search PubMed⌕ Search

Biomedical subjects

S R Hamann

Publications and source records attributed to S R Hamann.

32 records · Page 2Linked to original sources
PubMed1983

Nifedipine kinetics and bioavailability after single intravenous and oral doses in normal subjects.

Nifedipine kinetics have not been described in clinically relevant detail because of difficulties in formulating a stable preparation for intravenous use and lack of a specific and sensitive assay for plasma nifedipine. We recently developed a gas-chromatographic method and determined conditions in which nifedipine could be protected from photodegradation. Therefore, we evaluated the kinetics and bioavailability of nifedipine in 12 normal subjects after single intravenous (1 mg/5 min) and oral (10 mg) doses. After intravenous dosing, the drug was eliminated with a half-time of 1.77 +/- 0.25 hour, and total clearance was calculated at 0.62 +/- 0.09 liter/kg/hr. With oral drug administration, the elimination half-time was twice as long for the group; but within these subjects, marked variability in the rate of appearance of the drug in plasma was observed, giving profiles consistent with fast and slow absorption. In the latter group, peak plasma drug concentrations were only one third the level seen in those exhibiting a faster absorption profile, although the extent of drug absorption (as derived from areas under the plasma level-time curves) did not vary. Bioavailability was 0.45 +/- 0.08. Untoward effects resulting from the drug's pharmaco-subjects after intravenous administration (flushing).

Administration, Oral↗
PubMed1983

The pharmacology of verapamil. V. Tissue distribution of verapamil and norverapamil in rat and dog.

The relative distribution of verapamil and its demethylated metabolite, norverapamil, was studied in rats at intervals after intraperitoneal injection of the parent drug (30 mg/kg). This route of drug administration simulated oral drug dosing, and the highest concentrations of both unchanged drug and metabolite were found in the liver, with lung and kidney containing most of the remainder. The rates of disappearance of verapamil from various organs followed first-order kinetics, and the most rapid elimination occurred from brain and liver. In contrast, verapamil was given intravenously to 3 dogs by a bolus-infusion method to produce sustained steady state plasma concentrations (80, 140, 250 ng/ml) for 1, 2, and 3 h. After systemic administration, the lungs contained almost half the tissue verapamil and, 20% was found in kidney, with the liver accounting for only 17%. Norverapamil was not found in plasma or brain. These studies contrast the pattern of tissue distribution of verapamil after different routes of drug administration. The variable rates of drug elimination from specific tissues may explain the differing durations of the drug's observed effects.

Animals↗
PubMed1983

Reconstruction of the microscopic transmural edge of experimentally infarcted canine myocardium.

Experimental myocardial infarction of the posterolateral left ventricular wall in 2 dog hearts, the result of 1 h of occlusion of the left circumflex coronary artery followed by 4 days of reperfusion, was studied post mortem by serial histological sectioning. Microscopic examination in a transverse plane showed a zone of apparent necrotic muscle removal which formed a continuous boundary between necrotic and normal myocardium without outlying, detached "islands" of necrosis. Reconstruction of the histological transmural edge of infarction at its interface with viable subepicardial muscle demonstrated wide overlapping and angulated interdigitation of the separated tissues across the midzone of the ventricular wall. The observed 3-dimensional spatial complexity of the transmural infarct boundary may be a limiting factor in successful evaluation of this experimentally important region.

Animals↗
PubMed1983

Measurement of nifedipine in plasma by gas--liquid chromatography and electron-capture detection.

In this method for measuring nifedipine, a calcium-channel inhibitor now widely used in the treatment of cardiovascular disease, the drug is extracted from plasma under basic conditions into toluene, and an aliquot of the extract is injected directly into a gas chromatograph equipped with an OV-101 column and an electron-capture detector. The standard curve is linear between 1 and 100 micrograms/L; the assay measures not only nifedipine, but also a major metabolic product (found only after oral administration of the parent drug) and photodegradation products. The procedure is rapid and adequately sensitive for routine use in clinical monitoring of nifedipine in plasma.

Chromatography, Gas↗
PubMed1982

Hibernation "trigger": opioid-like inhibitory action on brain function of the monkey.

A hibernation "trigger" factor derived from the blood of the hibernating woodchuck acts to suppress vital physiological processes in the primate. When infused into the cerebral ventricle of the conscious monkey, the factor induced hypothermia, behavioral depression, bradycardia and aphagia. The opiate antagonists, naloxone and naltrexone, either reverse or retard these behavioral and physiological signs. We hypothesize that the "trigger" molecule is an endogenous opioid-like peptide which may be unique to the hibernator. Moreover, the non-hibernating primate apparently possesses receptor sites in the brain that are capable of responding to this potent molecule.

Animals↗
PubMed1982

Evaluation of gentamicin pharmacokinetics during peritoneal dialysis.

The pharmacokinetics of gentamicin were examined in two functionally anephric patients undergoing peritoneal dialysis (PD). Peritoneal dialysis effectively decreased the gentamicin half-life (t1/2 beta) by 73 and 78% while increasing total body clearance [QB(ml/min/kg] of gentamicin 4.3- and 3.4-fold. The appreciable variability in gentamicin pharmacokinetics among renal failure patients being peritoneally dialyzed may necessitate dosage adjustments based on rapid and accurate measurement of serum gentamicin concentrations.

Aged↗
PubMed1980

Comparison of gentamicin assays.

The reliability of the newly developed enzyme multiplied immunoassay technique (EMIT) for gentamicin with a radioimmunoassay (RIA) technique that utilizes a double antibody technique was compared. A split sample comparison was performed on 86 serum gentamicin levels from 35 patients. The Gilford System 4 and the Abbott Auto Log Gamma Counter were employed for the EMIT and RIA assays, respectively. Comparison of the two methods revealed good correlation (r = 0.954), slope (0.952), and an intercept of 0.017 over the range of the standard curve (1--16 microgram/ml). Within-run and between-run precision were comparable for both systems. Both assays have found widespread application for routine therapeutic monitoring of gentamicin. However, the EMIT gentamicin assay offers significant advantages in speed and simplicity while maintaining comparable accuracy and precision to that of the established RIA procedures.

Gentamicins↗
PubMedDate not supplied

Aspects of the clinical pharmacology of nifedipine, a dihydropyridine calcium-entry antagonist.

Although nifedipine has been characterized in terms of its general vasodilatory effects, this dihydropyridine must still be regarded as investigational with regard to available pharmacokinetic and pharmacodynamic data. Although limited studies are available, it is clear that the pharmacokinetic and pharmacodynamic data reported are quite variable among subjects. Further, it appears that single dose elimination kinetics may be of little predictive value with regard to the kinetic characteristics present during chronic drug administration. It is also possible that the plasma level-effect correlations for the drug may differ with single and sustained dosing regimens. At the present time the lack of definitive data to define the relationships between plasma levels of nifedipine and associated drug effects suggests that measurement of drug levels in plasma serves primarily as a research tool and to identify patient noncompliance or abnormal absorption of the drug. Finally, since the prototype of this class, nifedipine, has been shown to have the potential for non-linear kinetics during chronic dosing, dihydropyridine analogs should be subject to extensive pharmacokinetic and pharmacologic evaluation during both single and chronic dosing studies, prior to widespread clinical use.

Animals↗
PubMedDate not supplied

Thermally evoked tail avoidance reflex: input-output relationships and their modulation.

Latency to onset and magnitude (angular displacement) of thermally evoked tail avoidance reflexes (TETAR) to graded thermal stimuli were measured in pentobarbital-treated and untreated rats. The latency to onset was inversely and the magnitude was directly proportional to the thermal stimulus intensity. Pentobarbital prolonged the latency to onset of the TETAR to low by not high stimulus intensities. Activation of (-)-nicotine sensitive brainstem hyperalgesic processes shortened the latency and increased the magnitude of the TETAR. The hyperalgesic actions of (-)-nicotine were most demonstrable at lower thermal stimulus intensities. These studies suggest that the TETAR is graded in intensity as the stimulus intensity is increased and that the response evoked by different intensities of stimulus probably involve common neurophysiologic mechanisms.

Animals↗
PubMedDate not supplied

Plasma concentrations and hemodynamic effects of nifedipine: a study in anesthetized dogs.

The elimination kinetics of the calcium channel blocking agent nifedipine were studied in three male mongrel dogs after single intravenous bolus doses, and the drug's disposition followed first-order kinetics. After single intravenous doses, the elimination rate constant (mean +/- SE) was 0.693 +/- 0.069 h-1; the total body clearance, 0.736 +/- 0.226 L/h/kg; and the apparent volume of distribution, 1.15 +/- 0.12 L/kg. Based on these data, a model for the administration of nifedipine by an intravenous bolus-infusion regimen was developed to rapidly achieve and maintain stable plasma drug concentrations. Testing of this model in six anesthetized, open-chest dogs revealed pulmonary artery (mixed venous) drug concentrations that were consistently lower than those predicted, with stable plasma nifedipine levels achieved within 5 min and maintained over 60-min study periods. In these animals, a linear relationship was found between nifedipine concentrations in plasma and the total amount of drug administered (r = 0.92, p less than 0.001). Log-linear relationships were found between plasma nifedipine concentrations and mean arterial blood pressure (r = -0.93, p less than 0.001), cardiac output (r = 0.94, p less than 0.001), peripheral vascular resistance (r = -0.93, p less than 0.001), and pulmonary vascular resistance (r = -0.83, p less than 0.001). In addition, infusion of CaCl2 (3 mg/kg/min) resulted in increases in blood pressure despite the presence of stable plasma nifedipine concentrations. No electrocardiographic changes were seen at any plasma nifedipine level.

Anesthesia, General↗
PubMedDate not supplied

Pharmacodynamic comparison of verapamil and nifedipine in anesthetized dogs.

The relationships between steady-state plasma concentrations of verapamil or nifedipine and the resultant hemodynamic and electrophysiologic effects were evaluated in anesthetized, instrumented dogs. In different groups of animals, the drugs were given intravenously by loading-maintenance infusions designed to rapidly achieve and sustain stable plasma drug concentrations, over four different target ranges which span those found in clinical use of these agents. Plasma levels of nifedipine varied from 5 to 125 ng/ml, and those of verapamil, from 40 to 500 ng/ml. Nifedipine produced no apparent effects on the surface electrocardiogram. Verapamil dosing resulted in progressive prolongation of the PR interval as plasma drug levels increased from 40 to 250 ng/ml; at higher drug levels, complete atrioventricular block occurred. At the highest plasma concentrations used, the maximal vasodilation produced by both drugs was approximately equal, with mean aortic pressure levels falling to 50-60% of control values. The effects of the two agents on cardiac pump performance, however, differed: nifedipine administration produced dose-related increases in cardiac output at all plasma drug concentrations studied; the effects of verapamil were critically dependent upon drug levels in plasma, with cardiac output increased above control values at drug concentrations between 40 and 250 ng/ml, and progressively depressed at higher plasma levels of the drug. As a result, the calculated systemic vascular resistance declined progressively during nifedipine administration, while after verapamil doses, this parameter varied inversely with observed effects on cardiac output.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMedDate not supplied

Clinical pharmacokinetics of verapamil.

Verapamil is widely used in the treatment of supraventricular tachyarrhythmias as well as for hypertension and control of symptoms in angina pectoris. Unlike other calcium antagonists, detailed pharmacokinetic data are available for verapamil. Plasma concentrations of verapamil appear to correlate with both electrophysiological and haemodynamic activity after either intravenous or oral drug administration, although considerable intra- and intersubject variation has been found in the intensity of pharmacological effects resulting at specific plasma drug levels. Verapamil is widely distributed throughout body tissues; animal studies suggest that drug distribution to target organs and tissues is different with parenteral administration from that found after oral administration. The drug is eliminated by hepatic metabolism, with excretion of inactive products in the urine and/or faeces. An N-demethylated metabolite, norverapamil, has been shown to have a fraction of the vasodilator effect of the parent compound in in vitro studies. After intravenous administration, the systemic clearance of verapamil appears to approach liver blood flow. The high hepatic extraction results in low systemic bioavailability (20%) after oral drug administration. Multicompartmental kinetics are observed after single doses; accumulation occurs during multiple-dose oral administration with an associated decrease in apparent oral clearance. Norverapamil plasma concentrations approximate those of verapamil following single or multiple oral doses of the parent drug. Because of the complex pharmacokinetics associated with multiple-dose administration and the variation in individual patient responsiveness to the drug, 'standard' dosing recommendations are difficult to determine; use of verapamil must be titrated to a clinical end-point. Further, the potential for alteration in verapamil's disposition by the presence of hepatic dysfunction or cardiovascular disorders which result in altered hepatic blood flow is only now becoming apparent. A potentially toxic interaction has been reported between verapamil and digoxin, in which renal excretion of the glycoside is impaired, but the true clinical significance of this remains debatable. Combination therapy with verapamil and beta-adrenoceptor blocking compounds has been advocated by some investigators, but may be hazardous because of the additive negative inotropic and chronotropic effects inherent in both agents.

Adult↗