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Biomedical subjects

W Kirch

Publications and source records attributed to W Kirch.

300 records · Page 17Linked to original sources
PubMedDate not supplied

Clinical pharmacokinetics of the nifedipine/co-dergocrine combination in impaired liver and renal function.

Following a single oral dose of 20 mg nifedipine combined with 2 mg co-dergocrine to 24 subjects, the pharmacokinetics of this drug were studied. 8 normotensive subjects had normal renal and hepatic function, 8 patients had chronic renal insufficiency (creatinine clearance less than 30 ml.min-1) and 8 patients had liver cirrhosis which was confirmed by liver biopsy. The area under the plasma level time curve (AUC infinity) of co-dergocrine increased from 0.59 +/- 0.41 ng.ml-1. (mean +/- SD) in the normals to 1.24 +/- 0.95 ng.ml-1.h in liver cirrhosis (P less than 0.05) and to 1.81 +/- 0.9 ng.ml-1.h in renal failure (P less than 0.05 compared with the control group). Corresponding values for the nifedipine AUC infinity were 564.5 +/- 268 ng.ml-1.h, 1547.5 +/- 1134 (P less than 0.05) and 929 +/- 533 ng.ml-1.h (P less than 0.05; gas chromatographic method). The incidence of adverse effects was lower in patients with renal failure than in subjects with normal renal and liver function as well as in those with liver cirrhosis.

Adult↗
PubMedDate not supplied

Pharmacokinetics and safety of propiverine in patients with fatty liver disease.

OBJECTIVE: The present study was designed to assess the pharmacokinetics of propiverine after single and multiple dosing in patients with and without fatty liver disease. METHODS: The serum concentration-time curves of propiverine and its main metabolite propiverine-N-oxide were investigated in 12 patients with mild to moderate impairment of liver function (mean antipyrine clearance 26.0 ml x min(-1)) and in 12 controls (antipyrine clearance 42.8 ml x min(-1)). Subjects were treated orally with propiverine hydrochloride (Mictonorm) for 5 days (15 mg t. i. d.) to reach steady state. RESULTS: No significant differences were observed for propiverine and its main metabolite with regard to peak serum concentration (Cmax), area under the serum concentration-time curve (AUC) and elimination half-life (t1/2). Adverse events were reported by 12 patients. Five patients with fatty liver disease and seven patients with normal liver function complained of dry mouth and/or blurred vision. All adverse events reported were transient and mild. CONCLUSION: No pharmacokinetic differences relevant for safety were observed, comparing patients with and without fatty liver disease following repeated oral administration of propiverine. Thus there seems to be no need to adjust the dose in patients with mild to moderate impairment of liver function.

Adult↗
PubMedDate not supplied

The effect of age on pharmacokinetics of the local anesthetic drug articaine.

BACKGROUND AND OBJECTIVES: With increasing age, there are physiologic changes that could affect pharmacokinetics of drugs. More elderly patients are undergoing routine dental procedures for which local anesthesia could be required. The goal of the present study was to evaluate the effect of age on pharmacokinetics of the local anesthetic agent articaine. METHODS: The submucosal infiltration anesthesia from two different dosages of 4% articaine without epinephrine was compared in healthy elderly and young volunteers. High performance liquid chromatography has been used to determine concentrations of articaine in serum. Basic pharmacokinetic parameters were calculated according to standard procedures using a two-exponent equation. RESULTS: The clearance and volume of distribution (Vdss) of articaine after infiltration anesthesia were significantly lower in elderly volunteers compared with young volunteers. The area under the serum concentration-time curve and maximum drug concentration (Cmax) values did not differ significantly with age; however, both parameters tended to be higher in elderly volunteers. No changes in terminal half-life and time to reach maximum serum concentration (t(max)) were observed. The Cmax and tmax values of the metabolite articainic acid were similar in young and elderly volunteers. CONCLUSIONS The results show that the metabolism of articaine is age-independent in healthy male volunteers. The smaller Vdss in the elderly results in a trend to higher serum levels after a given dose of articaine. No change of dosage of articaine in elderly patients should be necessary.

Adult↗
PubMedDate not supplied

Endralazine, a new peripheral vasodilator--a randomized cross-over trial against dihydralazine.

In a randomized cross-over trial in 23 patients with essential hypertension, a new peripheral vasodilator, endralazine, in a dose of 10-20 mg t.i.d. was compared with dihydralazine in a dose of 25-50 mg t.i.d. All patients also received pindolol (a beta-blocker) in a dose of 5-15 mg t.i.d. The lowest dose of both drugs was given to all patients for 2 weeks and was increased only if indicated. Endralazine was more effective than dihydralazine, but the side effects were about the same in frequency and severity, apart from flushing, which was more common with endralazine. Patients receiving endralazine in the second phase of the cross-over design continued to be treated with endralazine for a period of 10-12 months. Blood pressure control remained good during this time, and the dosage was slightly reduced. No side effects suggestive of drug-induced lupus were seen, and only borderline changes in immunological tests [antinuclear antibodies (ANA)] in one patient were seen. One patient was reported to have lupus erythematosus (LE) cells in the peripheral blood but the ANA test was negative. Endralazine appears to be a useful new drug for the treatment of hypertension.

Adolescent↗
PubMedDate not supplied

Pharmacokinetics and pharmacodynamics of the 5-HT2 receptor antagonist ketanserin in man.

We determined the pharmacokinetics of ketanserin and its effects on blood pressure and heart rate in eight healthy volunteers following single-dose intravenous (10 mg) and oral (20 mg) administration of ketanserin. Following intravenous injection, plasma concentration-time data could most adequately be described by an open, three-compartment model. Plasma concentration declined with a mean terminal half-life of 15.6 +/- 6.2 h (mean +/- SD). Total clearance and volume of distribution at steady state were 0.39 +/- 0.07 L/kg/h and 3.3 +/- 1.1L/kg, respectively. The free fraction in plasma determined by equilibrium dialysis was 9.36 +/- 0.56%. Following single oral doses, a bioavailability of 0.51 +/- 0.06 was estimated. The half-life of the elimination phase tended to be somewhat longer (18.5 +/- 5.1 h, p greater than 0.05) than after intravenous administration. In addition, pharmacokinetics and effects of ketanserin on blood pressure and heart rate were investigated in two healthy volunteers after continuous treatment with ketanserin (20 mg three times a day) over a period of 5 days. No evidence of time-dependent nonlinear changes in pharmacokinetics was observed. Following single-dose as well as continuous treatment with ketanserin, no significant changes either in systolic and diastolic blood pressure or in pulse rate could be detected.

Adult↗
PubMedDate not supplied

The influence of renal function on plasma concentration, urinary excretion and antihypertensive effect of guanfacine.

18 hypertensive patients with a glomerular filtration rate (GFR) between 3.8 and 113ml/min received guanfacine as single intravenous and multiple oral dose treatment. Mean plasma concentrations of guanfacine on the fifth day or oral treatment ranged from 6.5 to 8.6ng/ml in patients with normal renal function (GFR > 90ml/min), as well as in those with a moderate degree of renal impairment (GFR 30 to 10ml/min) and in uraemic patients (GFR < 10ml/min). During guanfacine treatment plasma concentrations and fall in blood pressure did not differ in a statistically significant fashion among patients with varying degrees of renal function. Independent of renal function, in all investigated patients the elimination rate constant obtained from serum and urine values were close to 0.05h-1. Mean half-life of guanfacine was calculated to be 14h. The cumulative urinary excretion up to 48h fell from 57% in patients with normal renal function to 7.5% in uraemic patients. Thus, non-renal excretion plays an importat role in patients with impaired renal function.

Adult↗
PubMedDate not supplied

Interactions and non-interactions with ranitidine.

At present, there are two H2-receptor antagonists available for the treatment of peptic ulcer disease - cimetidine and ranitidine. Cimetidine is well known to interact with a number of concurrently administered drugs. Like cimetidine, ranitidine binds to cytochrome P-450 in the liver where it appears to exert an inhibitory effect, but to a lesser extent than cimetidine. Both H2-receptor antagonists may also reduce hepatic blood flow. Several drugs which are known to interact with cimetidine have been found not to interact significantly with ranitidine, including propranolol, lignocaine, phenytoin and diazepam. However, significant pharmacokinetic interactions between ranitidine and several other drugs have been established. These interactions may be attributed variously to an effect of ranitidine on hepatic metabolism or to an effect on the absorption of concomitantly administered drugs. For example, the bioavailability of midazolam is significantly increased due to the influence of ranitidine on gastric pH and thus on absorption of midazolam, leading to an increased soporific effect of this benzodiazepine; an effect of ranitidine on oxidative liver metabolism also appears to be a contributory factor in this interaction. Conversely, ranitidine distinctly reduced protein-bound cobalamin absorption from a mean of 7.66% prior to ranitidine administration to 0.84% during treatment with ranitidine 300 mg daily. A significant pharmacokinetic interaction has also been demonstrated between ranitidine and procainamide: the AUC of procainamide increased and the renal clearance fell significantly from a mean of 378 to 309 ml/min with ranitidine co-administration. However, this interaction is due to a different mechanism. In this case, ranitidine appears to compete with procainamide for the common renal proximal tubular secretion site. The reported interactions of ranitidine with warfarin, metoprolol, nifedipine, theophylline and fentanyl appear to be due to inhibition of cytochrome P-450. In a clinical study, warfarin clearance was significantly reduced from 66.7 to 48.7 ml/min by ranitidine, and by cimetidine to 42.9 ml/min. Similarly, the elimination half-lives of metoprolol and nifedipine were distinctly prolonged and the AUCs significantly increased by ranitidine. However, the latter pharmacokinetic interactions appear unlikely to be of clinical significance since the clinical effects of metoprolol and nifedipine were unaffected by ranitidine treatment. In therapeutic concentrations, ranitidine inhibited the disappearance of fentanyl from an in vitro microsomal preparation, indicating that it inhibits microsomal drug metabolism.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholinesterase↗
PubMedDate not supplied

Saturable in vitro metabolism of articaine by serum esterases. Does it contribute to the persistence of the local anesthetic effect?

BACKGROUND AND OBJECTIVES: The amide-type local anesthetic articaine is unique in that hydrolysis to articainic acid by serum esterases is its main metabolic pathway. The purpose of the present investigation was to study the concentration dependence of this pathway in vitro. METHODS: To unbuffered (pH 8.2) as well as phosphate-buffered (pH 7.4) heated serum samples were added various amounts of articaine in the range 10-300 micrograms/mL. Concentrations of articaine and articainic acid were measured by high-performance liquid chromatography after incubating the samples at 37 degrees C for intervals ranging from 5 minutes to 6 hours after addition of articaine. RESULTS: The in vitro metabolism of articaine was shown to undergo pH-dependent Michaelis-Menten kinetics, indicating saturation at higher substrate concentrations. The Michaelis constant K(m) was determined as 175 micrograms/mL and 22.1 micrograms/mL and the maximum reaction rate Vmax as 2.1 micrograms/mL/min and 0.17 microgram/mL/min at pH 8.2 and pH 7.2, respectively. These results support previous in vivo observations that suggest saturable articaine metabolism, indicated by higher articaine/articainic acid metabolic ratio with higher articaine concentrations in alveolar blood after dental extraction. CONCLUSION: Local saturation of the serum esterases may contribute to the advantageous relationship between persistence of the local anesthetic effect and low systemic toxicity caused by the last systemic elimination of articaine (ie, its wide toxic therapeutic ratio).

Anesthetics, Local↗