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Biomedical subjects

F Follath

Publications and source records attributed to F Follath.

At least 127 records · Page 7Linked to original sources
PubMed1990

Shifts in auditory brainstem response latencies following plasma-level-controlled aminoglycoside therapy.

The ototoxic effect of plasma-level-controlled netilmicin and tobramycin was monitored in 20 intensive care patients, using auditory brainstem responses (ABRs). ABRs were recorded at the onset and after 6 days of treatment. Significant shifts in the ABR wave V latency were observed independent of the type of medication received or whether the patients were intubated or not. Shifts were also observed in wave I latencies. These latter changes were only significant for the complete population, probably because this potential is more difficult to elicit and measure than is wave V. The I-V interlatency time was greater for netilmicin than for tobramycin. These results indicate that the cumulative effects of aminoglycoside ototoxicity may be different for the central and peripheral nervous systems, and therefore ABR measurements may be the most accurate way of controlling ototoxicity in intensive care patients.

Adult↗
PubMed1990

Predictability and intraindividual variability of serum theophylline concentrations in patients with obstructive lung disease: 12-h versus 24-h dosing.

The predictability and intraindividual variability of serum theophylline concentrations (STC) after different dosing schedules were investigated in 24 patients with chronic obstructive lung disease (COLD). Three oral regimens were compared in 3 groups of 8 randomly assigned patients. Group I:Drug A once daily in the evening; Group II: Drug A b.d.; Group III: Drug B b.d. The doses for each patient were estimated by Bayesian forecasting aiming at an STC of 10-15 mg/l. STC and FEV1 were measured on two consecutive days at steady-state. The day-to-day variability of STC was less than 20% in all three groups. The within-day fluctuation in Group I amounted to 259% (median) compared to 57% and 38% in Groups II and III, respectively. Dose adjustment by Bayesian forecasting resulted in a therapeutic STC in most patients with a b.d. regimen, whereas for the once daily dose the prediction was not satisfactory. No difference in lung function was found between the 24-h and 12-h dosing, probably because of the large intersubject variability in FEV1. Therefore, the question whether the differences in STC profile are of clinical importance in COLD can only be investigated in a larger group of patients.

Adult↗
PubMed1990

Nonlinear kinetics of propafenone metabolites in healthy man.

The pharmacokinetics of oral and i.v. propafenone and its major metabolites have been investigated in 8 healthy subjects. The total body clearance of propafenone was 963 ml/min, the terminal half-life 198 min and its absolute bioavailability was 15.5%. The two active metabolites (5-hydroxypropafenone and N-depropylpropafenone) showed non-linear kinetics in that both the dose-corrected area under the serum concentration-time curve and the amount excreted in the urine were larger after oral dosing. This resulted in considerably higher serum concentrations of the metabolites despite comparable serum concentrations of the parent compound. Thus, the concentration-effect relationship in the same patient may differ after oral and intravenous doses if concentrations of the active metabolite(s) are not taken into consideration. Although the mechanism of the nonlinearity is not clear, the data indicate that it may be due to saturable biliary excretion of the metabolites.

Biotransformation↗
PubMed1990

Effect of antiarrhythmic therapy on mortality in survivors of myocardial infarction with asymptomatic complex ventricular arrhythmias: Basel Antiarrhythmic Study of Infarct Survival (BASIS)

In view of the high risk of sudden cardiac death and the prognostic importance of complex ventricular ectopic activity, the effects of prophylactic antiarrhythmic treatment were investigated prospectively in patients with persisting asymptomatic complex arrhythmias after myocardial infarction. End points were total mortality and arrhythmic events (sudden death, sustained ventricular tachycardia and ventricular fibrillation). Of 1,220 consecutively screened survivors of myocardial infarction, 312 had Lown class 3 or 4b arrhythmia on 24 h electrocardiographic recordings before hospital discharge and consented to the study. They were randomized to individualized antiarrhythmic treatment (Group 1, n = 100), treatment with low dose amiodarone, 200 mg/day (Group 2, n = 98) or no antiarrhythmic therapy (Group 3 [control group], n = 114). During the 1 year follow-up period, 10 patients in Group 1 died, as did 5 in Group 2 and 15 in Group 3. On the basis of an intention to treat analysis, the probability of survival of patients given amiodarone was significantly greater than that of control patients (p less than 0.05). In addition, arrhythmic events were significantly reduced by amiodarone (p less than 0.01). These effects were less marked and not significant for individually treated patients (Group 1). These findings suggest that low dose amiodarone decreases mortality in the 1st year after myocardial infarction in patients at high risk of sudden death.

Amiodarone↗
PubMed1990

Comparison of the pharmacodynamic effects of intravenous and oral propafenone.

The effect of propafenone and its major metabolite 5-hydroxy-propafenone on ECG intervals was investigated in eight healthy extensive metabolizers after single oral (300 to 450 mg) and intravenous (35 to 50 mg) doses of propafenone in a single-blind randomized trial. Peak serum concentrations were 278 +/- 233 ng/ml (oral) and 295 +/- 131 ng/ml (intravenous). After oral administration peak 5-hydroxy-propafenone levels were 194 +/- 65 ng/ml, whereas after intravenous dosing no metabolite was detected, except in one subject. Serum concentrations were related to effects by linear regression including a hypothetical effect-site compartment in a pharmacokinetic-pharmacodynamic model. Significant prolongations of ECG intervals were found in both sequences. Comparison of the two concentration-effect data sets (intravenous, oral) revealed an additive effect of 5-hydroxy-propafenone in four of eight subjects for PQ interval and seven of eight subjects for QRS duration. We conclude that 5-hydroxy-propafenone exerts pharmacologic activity and could thus contribute to the antiarrhythmic effect of propafenone.

Administration, Oral↗
PubMed1990

The relative potency of major metabolites and enantiomers of propafenone in an experimental reperfusion arrhythmia model.

We used isolated rat hearts subjected to coronary artery ligation and reperfusion to study the antiarrhythmic activity of 5-hydroxypropafenone (5OHP) and N-depropylpropafenone (NDPP), major metabolites of propafenone (P) in humans, and of the two enantiomers (R)- and (S)-propafenone. 5OHP suppressed reperfusion arrhythmias similar to the parent drug in a concentration-dependent manner. The concentration of 5OHP needed to prevent ventricular fibrillation in 50% of experiments (EC50) was significantly higher than that of P (0.186 +/- 0.05 vs. 0.153 +/- 0.005 mg/L, mean +/- SEM, p less than 0.05). 5OHP had a relative potency of 80% compared to P. When 5OHP and P were administered together, their antiarrhythmic effect appeared to be supra-additive. The NDPP metabolite showed very little antiarrhythmic potency and was about four times less active than P. The two enantiomers (R) and (S) were equipotent and showed antiarrhythmic activities similar to racemic P.

Animals↗
PubMed1990

Potent inhibition of cytochrome P450IID6 (debrisoquin 4-hydroxylase) by flecainide in vitro and in vivo.

Flecainide acetate, a class Ic antiarrhythmic agent, is eliminated to a larger extent by renal excretion and to a minor extent by the liver. In patients with impaired renal function or with elevated urinary pH, however, its elimination is dominated by hepatic metabolism. Recent evidence suggests that the in vivo metabolism of flecainide is controlled by the genetic polymorphism of the debrisoquin/sparteine type; i.e., it is a substrate of cytochrome P450IID6. We investigated the inhibitory effect of flecainide on bufuralol 1'-hydroxylation in human liver microsomes in vitro and on the metabolic dextromethorphan urinary ratio in eight healthy male volunteers. Both bufuralol and dextromethorphan are well-known substrates of cytochrome P450IID6. Microsomal bufuralol 1-hydroxylation was competitively inhibited by flecainide with an apparent Ki of 0.954 mumol/L. Moreover, a statistically significant increase in the urinary metabolic ratio (MR) of dextromethorphan/dextrorphan after 1 week of administration of oral flecainide was observed (p = 0.013) in all subjects. One individual increased the urinary MR to a value consistent with the poor metabolizer phenotype. We conclude that flecainide is a potent inhibitor of cytochrome P450IID6 in vitro and in vivo and that careful drug monitoring is required with respect to renal function, debrisoquine phenotype, and concomitant drug administration.

Adult↗
PubMed1989

[Blood pressure lowering action and tolerance of ketanserin in mono- or combination therapy].

The antihypertensive efficacy and tolerability of the 5HT2-receptor antagonist ketanserin was investigated in 188 patients aged 41 to 82 years with mild to moderate essential hypertension. Ketanserin was given as monotherapy (n = 107) as well as in combination with either the diuretic hydrochlorothiazide/amiloride (n = 42) or the betablocker atenolol (n = 39) for 12 weeks. Compared to placebo, ketanserin lowered systolic blood pressure by 11 +/- 16 (SD), 9 +/- 13 and 9 +/- 11 mm Hg (p less than 0.01 for all) and diastolic blood pressure by 9 +/- 10, 10 +/- 9 and 7 +/- 9 mm Hg (p less than 0.001 for all), in the three treatment groups; body weight, serum sodium, potassium, uric acid, cholesterol and triglycerides remained unchanged. The incidence of withdrawals due to unwanted effects was 4% on ketanserin monotherapy, and 12% and 10% on the diuretic/ketanserin and the betablocker/ketanserin combination respectively. Well-being during ketanserin therapy was improved in the older patients in particular; sleep disturbances, daytime fatigue and overall weakness decreased. Ketanserin was well tolerated in combination with the diuretic, whereas in combination with the betablocker the occurrence of dry mouth and stuffy nose was slightly higher. - Ketanserin proved to be an effective antihypertensive drug comparable to other blood pressure lowering agents. It can be combined advantageously with a potassium sparing diuretic or a betablocker. The greater efficacy and tolerability in patients greater than or equal to 60 years qualify ketanserin primarily as an antihypertensive agent for older patients.

Adult↗
PubMed1989

[Antibiotic therapy and long-term course in spondylodiscitis].

Long-term outcome and therapy are reported in 29 patients with vertebral osteomyelitis. Antibiotics were administered for a mean period of 21 (6-102) weeks. In 13 patients surgery was additionally necessary. After a mean follow-up of 53 (10-136) months only one relapse had occurred. Radiographs and erythrocyte sedimentation rate were the best indicators of successful treatment.

Adult↗
PubMed1989

The role of calcium antagonists in the treatment of myocardial ischemia.

Calcium antagonists are often prescribed for treatment of ischemic heart disease. Therapeutic activity is achieved by reducing myocardial oxygen requirements and by increasing blood supply in ischemic heart disease associated with coronary artery spasms. The efficacy of calcium antagonists depends on the type and clinical presentation of ischemic heart disease: (1) in vasospastic angina (variant angina, short episodes of angina at rest), first-line therapy with calcium antagonists will reduce the number of ischemic episodes and improve long-term prognosis. (2) In effort angina the efficacy of calcium antagonists is comparable with that of beta blockers. (3) In unstable angina the use of calcium antagonists is controversial. Large-scale studies with nifedipine showed no benefit when it was given alone but an additive effect in patients pretreated with beta blockers. In contrast, diltiazem and verapamil appear to have comparable efficacy to beta blockers in patients with unstable angina. (4) After myocardial infarction the results of treatment with calcium antagonists have been disappointing. Nifedipine and verapamil did not reduce mortality or the incidence of reinfarction. In one study diltiazem significantly reduced the rate of reinfarction in patients who had had a non-Q wave infarction, but in a recent large-scale multicenter trial it had no effect on mortality and cardiac events in patients with evidence of both Q- and non-Q wave infarctions. Other secondary preventative measures against reinfarction, such as the use of beta-blockers and aspirin, appear to be more effective than calcium antagonists. The most frequently prescribed calcium antagonists, verapamil, diltiazem, and nifedipine, each of which represents a different chemical class, have in general similar efficacy in vasospastic and effort angina. Their different pharmacologic profile, such as the slowing of heart rate with verapamil or diltiazem and a more marked vasodilatation with nifedipine and other dihydropyridines, may become clinically relevant in individual patients. The new dihydropyridine derivatives have a pharmacologic profile comparable to that of nifedipine but some of these compounds, especially amlodipine, have more favorable pharmacokinetics, such as a prolonged elimination half-life. These agents may offer the advantage of a more practical dosage regimen for long-term treatment in patients with ischemic heart disease.

Angina Pectoris↗
PubMed1989

Antihypertensive efficacy and well-being during monotherapy and combination therapy with ketanserin.

The effects of ketanserin on blood pressure and well-being were investigated in 188 patients, aged 41-82 years, with mild to moderate essential hypertension. At entry, 107 were untreated, 42 were taking the diuretic combination hydrochlorothiazide (50 mg/day) plus amiloride (5 mg/day) and another 39 were taking the beta-blocker atenolol (100 mg/day). A single-blind, 4-week placebo run-in period was followed by 12 weeks' oral ketanserin treatment at 20 or 40 mg twice a day. This regimen significantly reduced systolic and diastolic blood pressures in each group. Response rates were greater in patients aged over 60 years. Compared with placebo, sleep disturbances, daytime fatigue and overall weakness decreased during ketanserin treatment (P less than 0.05 for all), but the incidence of dry mouth and stuffy nose increased. In patients older than 60 years there was a greater reduction of complaints than in younger patients. Ketanserin proved effective and well tolerated, improving peripheral circulatory symptomatology, particularly in older patients and those with a good blood pressure response.

Adult↗
PubMed1989

Population pharmacokinetics of tobramycin.

1. Population pharmacokinetic parameters of tobramycin were determined in a heterogenous group of 97 patients using serum samples drawn for the routine monitoring of tobramycin concentrations, following multiple dosing regimens. 2. To describe the accumulation kinetics of tobramycin a two-compartment pharmacokinetic model was required. The best fit to the data was obtained when drug clearance (1 h-1) was related linearly to creatinine clearance (proportionality constant: 0.059 +/- 0.002 x CLcr (ml min-1)) and initial volume of distribution (1) was related linearly to body weight (proportionality constant: 0.327 +/- 0.014 x body weight (kg)). The intersubject variability in these two parameters was 32% and 3%, respectively, whilst the residual or intrasubject variability amounted to 21% of the tobramycin concentration. The terminal half-life of tobramycin, 26.6 +/- 9.4 h, was appreciably shorter than previously reported. 3. The population pharmacokinetic model was validated against data obtained from 34 independent patients and the predicted and observed concentrations were found to be in good agreement. The population pharmacokinetic model was used to design a priori dosing recommendations for tobramycin.

Adolescent↗
PubMed1988

[Drug treatment of heart insufficiency].

Patients with congestive heart failure (CHF) can be treated by diuretics, inotropic agents and vasodilators. Increased diuresis lowers left and right ventricular filling pressures but may further reduce cardiac output. Nevertheless, diuretics produce symptomatic improvement in most patients. Digoxin also has beneficial hemodynamic effects in patients with advanced CHF and sinus rhythm, but the frequency and degree of therapeutic response is inferior to that of vasodilators. Among the latter, ACE inhibitors are the most appropriate for long-term administration since they do not lead to development of tolerance and seem to improve long-term prognosis in patients with severe CHF. Newer inotropic agents have marked hemodynamic effects in the short term, but their utility for chronic treatment remains questionable. The optimum choice of drugs in various forms and stages of CHF is discussed.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1988

Clinical pharmacology of calcium antagonists.

The pharmacokinetics of the different calcium antagonists has many similarities and is characterized by incomplete bioavailability due to first-pass metabolism, predominant hepatic biotransformation with negligible amounts of unchanged renal excretion, and a high protein binding. Several of the newer dihydropyridine derivatives have prolonged half-lives allowing once-daily administration. Pharmacological effects usually depend on serum drug concentrations, but the presence of stereoisomers and active metabolites may influence the concentration-effect relationships. In patients with liver disease, the clearance of some calcium antagonists is markedly decreased, whereas in renal failure the elimination rate is not reduced. Calcium antagonists also participate in various drug interactions, in particular with digoxin.

Calcium Channel Blockers↗