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Biomedical subjects

F Follath

Publications and source records attributed to F Follath.

At least 145 records · Page 8Linked to original sources
PubMed1988

Pharmacokinetics of cyclosporine G in patients with renal failure.

The pharmacokinetics of the cyclosporine A (CsA, Sandimmune) analogue Nva2-cyclosporine, or cyclosporine G (CsG) was investigated in 6 patients with terminal renal failure after a 4-hr intravenous infusion (3.5 mg/kg) and after oral administration (600 mg) of the drug. Blood samples were collected up to 38 hr and CsG concentrations were measured by radioimmunoassay and high-performance liquid chromatography. The resulting pharmacokinetic parameters of CsG were similar to those described for CsA in the same patient population. Based on HPLC determinations, a mean terminal elimination half-life of 18.9 hr was calculated. The total body clearance was 0.55 L/hr/kg, the volume of the central compartment was 0.32 L/kg, and the steady-state volume of distribution was 5.97 L/kg. After oral administration maximum CsG concentrations in blood were reached between 2.5 and 3 hr, and the bioavailability was in the range of 24-55% (mean 36%). The ratios between the polyvalent RIA and HPLC determinations were considerably larger after oral dosing than after i.v. infusion. The blood-to-plasma ratio was 1.23, which is smaller than that observed for CsA. These results suggest that in patients undergoing renal transplantation the same dosing strategies can be applied for CsG as have been established for CsA.

Adult↗
PubMed1988

Prospective controlled randomized trial of prophylactic antiarrhythmic therapy in postmyocardial infarction patients with asymptomatic ventricular arrhythmias--study design and initial results.

In order to assess the effect of prophylactic antiarrhythmic therapy in asymptomatic patients with persistent complex ventricular ectopic activity after myocardial infarction, a prospective controlled trial was started in 1981 and is still ongoing. Until August 1986, 965 consecutive patients less than or equal to 70 hospitalized for acute myocardial infarction were screened without antiarrhythmic drugs by 24-h ECG before discharge from the hospital. In this group, 238 patients (28%) had ventricular arrhythmias Lown class III-IVb during at least 2 of 24 hours; they were randomly assigned to three treatment groups: (1) individualized antiarrhythmic therapy based on efficacy in multiple 24-h ECGs and drug level determinations (starting with mexiletine or quinidine; n = 79), (2) treatment with low-dose amiodarone (200-400 mg/day after a loading phase; n = 73), and (3) no antiarrhythmic therapy (n = 86). The three groups were comparable regarding age, gender, previous infarction, Q-wave infarction, ejection fraction, as well as incidence and severity of ventricular ectopic activity. Follow-up, including 24-h ECGs, was performed after 3, 6, and 12 months. Based on the results of this study which will be completed by the end of June 1988, it should be possible to estimate the benefit--or harm--of antiarrhythmic drug therapy as well as its cost in postmyocardial infarction patients with asymptomatic ventricular ectopic activity and to decide whether such treatment may improve survival.

Aged↗
PubMed1988

Midazolam in plasma from hospitalized patients as measured by gas-liquid chromatography with electron-capture detection.

The present assay was developed for quantifying midazolam in plasma of patients hospitalized in intensive-care units or undergoing anesthesia and receiving many other drugs as well. Plasma samples are alkalinized with NaOH and midazolam is extracted into n-hexane. The organic phase is evaporated and reconstituted in n-butyl acetate, and the midazolam is quantified by gas-liquid chromatography with electron-capture detection. The calibration graph for midazolam was linear in the ranges 5-200 and 200-800 micrograms/L. The CVs for precision and reproducibility of the assay were less than 8%. The method was very specific for midazolam; most of the drugs commonly used in anesthesia and in the intensive-care unit did not interfere with the assay. The lowest detectable concentration was 1 microgram/L. The method is adaptable for use with an automated chromatographic system.

Aged↗
PubMed1987

Pharmacodynamics of 3-hydroxyquinidine alone and in combination with quinidine in healthy persons.

The relation between serum concentration of 3-hydroxyquinidine (3-OHQ), a major metabolite of quinidine in humans, and the pharmacologic effect alone and in combination with the parent drug was studied. The heart rate-corrected, computer-averaged QT interval (QTc) was used as the pharmacologic endpoint. In a randomized, double-blind study, 5 healthy subjects received, on 3 separate days 1 week apart, either (1) 300 to 400 mg 3-OHQ orally or (2) 150 mg quinidine base intravenously or (3) a combination in the same doses. Blood samples and electrocardiographic recordings were obtained over the following 10 hours. Serum concentrations of 3-OHQ and quinidine were determined by high-pressure liquid chromatography and the free fraction by ultrafiltration. Peak concentrations of 3-OHQ varied between 1,362 and 3,480 ng/ml after oral 3-OHQ ingestion, but were negligible after intravenous quinidine infusion. The free fraction was 49% +/- 4.8 (mean +/- standard deviation) for 3-OHQ and 20% +/- 4.3 for quinidine. In all 5 subjects a statistically significant correlation was found between serum concentration and QTc prolongation for both quinidine and 3-OHQ (largest p value less than 0.025). The mean slope of the regression line was 0.0184 +/- 0.0128 for 3-OHQ and 0.0297 +/- 0.0111 for quinidine. Multiple linear regression revealed in each subject a significant additive effect of 3-OHQ when administered together with quinidine (largest p value less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Clinical consequences of development of resistance to third generation cephalosporins.

Eighteen patients are described in whom initially sensitive microorganisms were replaced by resistant isolates during administration of ceftriaxone (n = 8), cefoperazone (n = 5), moxalactam (n = 4), cefotaxime (n = 2) or ceftazidime (n = 1), despite combination with aminoglycosides. All patients had documented gram-negative infections; in 12 patients underlying haematological diseases were present. Resistant strains of Enterobacter cloacae (14), Serratia marcescens (4), Klebsiella oxytoca (3), Pseudomonas aeruginosa (2) and Citrobacter freundii (2) emerged within 2 to 19 (mean 9) days after the beginning of treatment. In 12 patients relapse or secondary infections occurred. Seven of the patients with haematological disorders died. Resistance development was seen in 8 of 29 patients on ceftriaxone and 4 of 10 patients on moxalactam during prospective evaluations; the other drugs were used sporadically. Thus, selection of resistant bacteria is relatively frequent and may have serious clinical consequences in patients with impaired host-defense mechanisms.

Adolescent↗
PubMed1987

Computer-assisted individualized lidocaine dosage: clinical evaluation and comparison with physician performance.

The performance of a computerized dosing aid in achieving a target serum concentration of lidocaine in the middle of the recommended therapeutic range (3.5 mg/L) was evaluated in 63 patients treated for acute ventricular arrhythmias. In all patients a serum concentration measurement was obtained shortly after starting lidocaine infusion. In 22 patients a microcomputer program based on a Bayesian forecasting technique was used for dosing recommendations, whereas in 41 the serum concentration was interpreted and the dose was adjusted by the unaided physician. Both groups were similar with respect to the average concentration achieved (control: 3.8 +/- 1.13 [SD] mg/L, computer-aided: 3.5 +/- 0.59 mg/L). However, the interindividual variability was significantly larger in the control group (95% confidence interval: 1.5 to 6.1 mg/L vs 2.3 to 4.7 mg/L [p less than 0.01]). Nine of the 41 patients in the control group had a lidocaine concentration outside the recommended therapeutic range of 2 to 5 mg/L compared to only 1 of 22 in the computer-aided group. Lidocaine concentrations greater than 2 mg/L were associated with significantly more effective suppression of ventricular arrhythmias (p less than 0.05). The results show that Bayesian forecasting outperforms the physician in early adjustment of lidocaine dosage based on serum concentration measurements.

Aged↗
PubMed1987

Method for stable measurement of the electrocardiogram in isolated guinea pig heart. Evaluation of the RR-QT relationship and the effect of quinidine.

A method for stable measurement of ECG in an excised guinea pig heart was presented. The effects of quinidine and its major metabolite, 3-OH quinidine, on QT interval were compared using excised guinea pig hearts with A-V nodal rhythm paced at a constant frequency (190 beats/min). The relative potency of 3-OH quinidine to its parent drug was about one-fourth. Taking into account the fact that the free fraction of 3-OH quinidine in blood is larger than quinidine, this metabolite may contribute to the effects of quinidine in man. Changing the frequency of electrical pacing in excised hearts with A-V nodal rhythm, the RR-QT relation was determined to be rather linear, and this relation became more curvilinear after addition of quinidine (2 mg/liter), suggesting that the Bazett's formula for correcting QT interval with the heart rate is not applicable to guinea pig heart and/or after an addition of drug.

Animals↗
PubMed1987

Kinetics and dynamics of quinidine-N-oxide in healthy subjects.

The pharmacokinetics of a major metabolite of quinidine in humans, quinidine-N-oxide, were investigated after single oral doses (3 to 15 mg) in four healthy subjects. The concentration in serum and urine was determined by an HPLC assay. Because of a small volume of distribution, the elimination half-life of quinidine-N-oxide was only 2.5 +/- 0.28 hours (mean +/- SD), considerably shorter than that of quinidine. The renal clearance was 1.3 +/- 0.3 L/hr. Only 13.9% +/- 3.7% of the dose was recovered in urine as unchanged compound for up to 12 hours. Two unidentified compounds with the same retention time as quinidine and 3-hydroxyquinidine were found in the urine samples of two subjects. The free fraction in serum was 3.3% +/- 0.83%. No systematic changes in heart rate-corrected QT interval were observed up to concentrations of 500 ng/ml. The results indicate that quinidine-N-oxide, in contrast to 3-hydroxyquinidine, does not possess quinidine-like pharmacologic activity.

Administration, Oral↗
PubMed1987

Acute hemodynamic effects of MDL 19205 in mild congestive heart failure.

MDL 19205 4-ethyl-1-,3-dihydro-5-(4-pyridinylcarbonyl)-2H-imidazol-2-one, a new cardioactive agent, has been shown to increase myocardial contractile force in animals. It is effective by both oral and intravenous routes. We studied 11 patients with congestive heart failure--in 10 cases owing to coronary artery disease, and in one to cardiomyopathy. All patients had symptoms of NYHA class II or III, left ventricular ejection fractions (LVEF) less than 55%, and left ventricular end-diastolic pressures (LVEDP) greater than 15 mm Hg. Following routine coronary angiography and ventriculography, 0.5 mg/kg MDL 19205 was administered intravenously over 5 min to six patients. Thirty minutes after injection, hemodynamic measurements and ventriculography were repeated. Mean LVEF increased from 42 to 49% (p less than 0.05 for baseline vs. 30 min). In five patients ventriculography was repeated 60 min after placebo administration: LVEF decreased from 45 to 40%. LVEDP decreased from 29 +/- 8 to 16 +/- 8 mm Hg after MDL 19205 administration (p less than 0.05) and remained constant at 24 mm Hg in the placebo group. The small although nonsignificant increase of LVdP/dt after MDL 19205 administration (10 +/- 33%), together with a considerable decrease in LVEDP, was consistent with a positive inotropic effect. LVdP/dt/total pressure developed (VPM), a measure of contractility relatively independent of changes in pre- and afterload, increased from 1.0 +/- 0.3 to 1.3 +/- 0.3 s-1 (p less than 0.05). Neither parameter of contractility (LVdP/dt and VPM) changed significantly in the placebo group.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiotonic Agents↗
PubMed1987

Antihypertensive efficacy of ketanserin alone or in combination with a beta-blocker or a diuretic: the Swiss Ketanserin Study.

In the Swiss Ketanserin Study the antihypertensive efficacy and tolerability of ketanserin (given in 20 or 40 mg doses twice daily) was investigated, after a placebo run-in phase, as monotherapy (n = 68) as well as in combination with either atenolol (100 mg/day) (n = 30) or the potassium-sparing diuretic hydrochlorothiazide (50 mg/day) and amiloride (5 mg/day) (n = 26) in 124 patients with essential hypertension, aged 41 to 82 years. With the addition of ketanserin, diastolic blood pressure fell by 8 +/- 8, 8 +/- 8, and 7 +/- 9 (+/- SD) mm Hg, respectively (p less than 0.05 for all) in the three treatment groups; heart rate remained unchanged or fell slightly. Ketanserin had no effect on body weight, or biochemical variables, including total serum cholesterol and triglycerides, with the exception of a minor increase in apolipoprotein B. Using a patient self-assessment questionnaire (30 items), the addition of ketanserin was associated with a reduction of most of the symptoms encountered in the placebo phase, including sleep disturbances, general feeling of weakness, headaches, nervousness, and fatigue, but there was a tendency toward increases in stuffy nose and dry mouth. In patients older than 60 years, the antihypertensive efficacy of ketanserin was greater, with 59% achieving a diastolic pressure less than or equal to 95 mm Hg versus 45% in the younger patients. This age trend also emerged when ketanserin was combined with either atenolol or the diuretic.

Adrenergic beta-Antagonists↗
PubMed1987

Antiarrhythmic activity of two quinidine metabolites in experimental reperfusion arrhythmia: relative potency and pharmacodynamic interaction with the parent drug.

We investigated the antiarrhythmic activity of two major metabolites of quinidine in human, 3-hydroxyquinidine and quinidine-N-oxide, alone and in combination with the parent drug in an experimental model using reperfusion arrhythmias in an isolated rat heart preparation. No definite pharmacological activity could be shown for quinidine-N-oxide up to concentrations of 16 mg/l. Quinidine and 3-hydroxyquinidine prevented ventricular fibrillation and ventricular tachycardia after coronary reperfusion in a concentration-dependent manner. The relationship between the drug concentration in the perfusate and the fractional suppression of arrhythmia could be described adequately for both compounds by the Hill equation. Whereas no difference was found for the Hill coefficient, the estimates of the concentration associated with 50% arrhythmia suppression was significantly higher for 3-hydroxyquinidine (10.7 +/- 0.3 mg/l vs. 2.2 +/- 0.25 mg/l), indicating that the relative potency of the metabolite was only about 20% compared to the parent compound. To investigate the pharmacodynamic interaction of the two compounds the concentration-response curve was determined for quinidine also in the presence of 3-hydroxyquinidine at a constant concentration of 4 mg/l. A method has been derived that allows quantitative assessment of the pharmacodynamic interaction of two compounds for which the concentration-effect relationship can be described by the Hill equation. The results indicate that the antiarrhythmic effects of 3-hydroxyquinidine and quinidine are additive.

Animals↗
PubMed1986

[Acute myocardial infarct after prophylactic administration of low doses of heparin-ergotamine: coronary artery spasm the cause?].

There have been several recent publications reporting vasospastic complications under heparin-dihydroergotamine prophylaxis. We report on 2 patients without significant coronary artery stenosis who died of acute myocardial infarction. Both patients had been operated on for a lumbar disc protrusion and were treated with 2500 IU heparin + 0.5 mg dihydroergotamine s.c. twice daily. The possibility of coronary arterial spasm as the cause of the myocardial infarctions is discussed. Publications reporting cases with myocardial infarctions, presumably caused by coronary arterial spasm, and other vasospastic complications under ergotamine therapy are briefly reviewed.

Adult↗
PubMed1986

Effects of the enantiomers of the dihydropyridine derivative 202-791 on contractility, coronary flow and ischemia-related arrhythmias in rat heart.

The (+)-enantiomer of the dihydropyridine 202-791 produced coronary constrictor and positive inotropic effects in Langendorff-perfused rat hearts whereas (--)-202-791 showed coronary dilator and negative inotropic effects. Both enantiomers showed the vascular effects at lower concentrations than the myocardial effects. Furthermore, the (+)-enantiomer significantly increased whilst the (--)-enantiomer reduced the number of ventricular ectopic beats occurring during coronary ligation. Arrhythmia-enhancing effects must therefore be considered when the potential therapeutic uses of calcium channel activators are discussed.

Animals↗
PubMed1986

[Drug therapy in liver diseases: problems in intensive care].

Most analgesics, antiarrhythmics, antiepileptics, theophylline and sedatives are inactivated by hepatic biotransformation. The use of these drugs in intensive care patients with abnormal liver function may be difficult because no reliable laboratory tests are available to predict the pharmacokinetic changes. Measurement of serum drug levels is the best method for individualized dosage adaptation, but the possibilities of routine drug monitoring are limited. To avoid toxic drug accumulation, agents with predominantly renal elimination should be selected. If no such alternatives exist, treatment should be initiated in a reduced dose and then modified according to the pharmacological effects observed.

Analgesics↗