[Comparison of the clinical effect between digoxin and a diuretic in chronic left heart failure and sinus rhythm]. / Klinischer Wirkungsvergleich zwischen Digoxin und einem Diuretikum bei chronischer Linksherzinsuffizienz und Sinusrhythmus.

Because of conflicting results from studies examining the initial treatment of patients with chronic left heart failure (CHF) and sinus rhythm, the clinical efficacy and safety of digoxin and a diuretic were compared in a multicenter, randomised, open twelve-week study. 47 patients with CHF (NYHA II and III) were treated either with digoxin or a combination of hydrochlorothiazide and triamterene. Three patients from the diuretic group and four from the digoxin group required premature termination of study periods because of increasing symptoms of CHF. Both regimens decreased significantly a heart failure score and increased distinctly the symptom-limited exercise tolerance, but results did not differ between the groups. Echocardiographic parameters, ejection fraction and radionuclide indices of diastolic function estimated by gated blood pool scan did not change with either treatment. It was concluded that digoxin or the diuretic therapy alone was effective in ameliorating the clinical signs of CHF. Due to missing differences in the clinical efficacy of both drugs an individual and not schematic treatment regimen of CHF is warranted.

Pharmacokinetic optimisation in the treatment of Pneumocystis carinii pneumonia.

Several drugs and drug combinations are currently used in the treatment of patients with Pneumocystis carinii pneumonia (PCP)--pentamidine and cotrimoxazole (trimethoprim plus sulphamethoxazole), which are indicated for this usage, dapsone/trimethoprim and clindamycin/primaquine, which are not licensed for PCP, and trimetrexate/calcium folinate (leucovorin), eflornithine and BW-566C (566 C80) as investigational drugs. For most of these agents, recommendations regarding the use of pharmacokinetic parameters to establish individualised therapy cannot be made. The pharmacokinetics of antipneumocystis drugs are not well documented and clinical trials evaluating the relationship between the individual plasma pharmacokinetic profiles and responses to treatment are sparse. In clinical trials, the reduction of the daily dose of pentamidine to 3 or 2 mg/kg/day and of cotrimoxazole to 15 mg/kg of the trimethoprim component resulted in a substantial reduction of frequency and severity of adverse drug effects without diminishing efficacy. For pentamidine, a long half-life of > or = 4 days implies the need for a loading dose. Plasma concentrations of the parent drug at steady-state varied between 30 and 100 micrograms/L. The elimination pharmacokinetics are characterised by several elimination slopes indicating the existence of a deep peripheral compartment. Due to its very low renal clearance, dosage adjustments are not necessary in patients with renal impairment. The pharmacokinetics of cotrimoxazole follow first-order kinetics in PCP and the particular parameters are similar to those reported in the treatment of bacterial infection. Steady-state plasma concentrations of both trimethoprim and sulphamethoxazole are attained within 2 to 3 days, but the range of 'therapeutic' plasma concentrations must be newly defined, since elevated trimethoprim concentrations could not be correlated with the frequency and severity of adverse drug reactions. The concentrations of sulphamethoxazole may be at least as important as those of trimethoprim in defining a toxic range. With dapsone/trimethoprim, clindamycin/primaquine and BW-566C (566 C 80) good clinical response rates were found in groups of patients with mild to moderate PCP. Comparative trials with standard drugs are still ongoing. Therapeutic to toxic concentration ratios have not been established in patients with PCP. Pharmacokinetic data pertaining to patients with PCP are either nonexistent or incomplete, or are complicated by a drug interaction between dapsone and trimethoprim suggesting an inhibition of metabolism of dapsone. Eflornithine and trimetrexate/calcium folinate have been used under specific research protocols, showing partial success as salvage agents for desperately ill patients with AIDS. Regarding all antipneumocystis drugs, additional clinical and pharmacokinetic data are needed to optimise and more fully individualise the treatment regimens for this severe infection.

Pentamidine aerosol for prophylaxis of Pneumocystis carinii pneumonia after BMT.

Following BMT there is a 5-15% risk of interstitial pneumonia caused by Pneumocystis carinii (PcP). Cotrimoxazole is therefore administered prophylactically, but may cause myelodepression, allergic reactions and nephrotoxicity. As PcP prophylaxis with pentamidine aerosol is effective in patients with AIDS, we conducted a prospective trial with regular inhalations of pentamidine. The aim of this study was to evaluate toxicity, safety, practicability and possible resorption of aerosolized pentamidine. We treated 31 allogeneic and 12 autologous BMT patients with 60 mg pentamidine 3 days before and 14 days after BMT. Starting 4 weeks after BMT, 300 mg pentamidine was given every 4 weeks for 6 months. There was no pneumonia caused by Pneumocystis carinii. The only noteworthy side-effects were cough (19.8%), salivation (9.6%), and sore throat (5.7%), of similar frequency after allogeneic or autologous BMT. Using high pressure liquid chromatography, pentamidine could only be detected in the serum of 33-54% of patients tested. In these patients the median serum levels were 7.5-9 ng/ml. We conclude that pentamidine aerosol has only minor side-effects, is well tolerated and safe, and is therefore an attractive alternative for PcP prophylaxis after BMT.

[Determinants of serum pentamidine concentration in the human]. / Determinanten der Pentamidin-Konzentration im Serum beim Menschen.

By means of serial measurements of pentamidine in plasma, urine and feces the significance of biologically available dose, volume of distribution, elimination and dose interval for serum concentration is investigated in patients with AIDS and bone marrow transplantation after inhaled and intravenous application. Aerosolisation of the drug yields to serum concentration mostly below the detection limit (HPLC). In urine only 0.15 to 0.8% of the substance biologically available in the lung are measured as unaltered pentamidine-base. After i.v. infusion the dose dependent low serum concentrations of 30 to 100 ng/ml indicate a fast distribution in peripheral compartments from which a very slow deliberation is seen. The half-life of the drug is also dose dependent and amounts under clinical conditions at minimum four days. The fecal excretion is found to be only one third of that measured in urine. A difference in the kinetic of elimination between bone marrow transplantated and AIDS-patients could not be evaluated. For clinical therapy the most important pharmacokinetic variable seems to be the terminal elimination constant which would implicate a prolongation of the common dose interval.

[Risk factors and prevention of pneumocystis carinii pneumonia after bone marrow transplantation]. / Risikofaktoren und Prophylaxe der Pneumocystis-carinii-Pneumonie nach Knochenmarktransplantation.

For six months after bone marrow transplantation (BMT) there is a risk of 5 to 15% to suffer from interstitial pneumonia due to pneumocystis carinii (PcP). Prophylaxis with trimethoprim/sulfamethoxazol is therefore routinely and successfully applied. However myelotoxicity, allergic reactions, augmentation of the risk of nephrotoxicity with cyclosporine A and noncompliance may be serious problems. Since the prophylaxis of PcP with pentamidine-aerosol proved to be effective in patients with AIDS, we conducted a prospective trial with regular inhalations of pentamidine. The aim of this study was to evaluate the toxicity, safety, practicability and possible resorption of pentamidine when applied as aerosol. The first of 43 patients were treated with 60 mg pentamidine on two days before, at the day of BMT and 14 days after BMT. Starting four weeks after BMT, 300 mg pentamidine were given every four weeks up to six months. After the study, the four 60 mg inhalations were replaced by two 300 mg inhalations before BMT, because this proved to be more convenient for the patients. There was no pneumonia due to pneumocystis carinii. The only noteworthy side effects observed were cough (19.8%), salivation (9.6%) and sore throat (5.7%). In general pentamidine was well tolerated and well accepted by the patients. Pentamidine could only be detected in the serum of 40 to 60% of all patients. In those patients the serum levels were 7.5 to 9 ng/ml and similar to concentrations found in comparable patients with AIDS. We conclude, that pentamidine-aerosol has only minor side effects, is well tolerated and safe and is therefore an attractive alternative for PcP-prophylaxis after BMT.

[Pharmacologic studies with pentamidine aerosol in HIV patients]. / Pharmakologische Untersuchungen mit Pentamidin-Aerosol bei HIV-Patienten.

1. After multiple intravenous and inhaled application of pentamidine a steady state of plasma concentrations and of urinary excretion amounts is suggested to occur between the sixth and eighth day of the treatment. An elimination half life of at mean four days and a great volume of distribution of greater than 100 l/kg body weight could be evaluated. However, a deep compartment with a delayed elimination and/or a biotransformation of the drug cannot be excluded. 2. The daily elimination of unchanged pentamidine via urine is small: 3 to 4% of the daily dose after intravenous infusion vs. 0.06 to 0.12% after inhaled application, respectively. The smaller excretion amounts after inhalation correspond to mostly non detectable plasma concentrations and to by far fewer side effects compared to intravenous treatment. 3. With a jet nebuliser system up to 40% of the dose are left in the nebuliser chamber and in the exhalation filter, whereby a dose related retention seems to exist.

[Initial experiences with pentamidine aerosol in prevention of Pneumocystis carinii pneumonia following bone marrow transplantation]. / Erste Erfahrungen mit Pentamidin-Aerosol zur Prophylaxe der Pneumocystis-carinii-Pneumonie nach Knochenmarktransplantation.

After bone marrow transplantation there is a risk of 10% to acquire a pneumonia caused by pneumocystis carinii, if no prophylaxis is used. So far cotrimoxazol is the treatment of choice from day -14 before to day +180 after bone marrow transplantation. This substance, however, may cause allergic reactions, may augment the risk of nephrotoxicity of other drugs, and may be myelosuppressive. The prophylaxis with pentamidine-inhalation was used in 26 patients after bone marrow transplantation so far. It could be shown, that after salbutamol-inhalation 60 to 300 mg of pentamidine can be given safely in 14 to 28 days intervals. The main side effects were cough and dyspnea in some patients. Only minimal amounts of the drug could be detected in serum and urine after application. No toxic side effects and no pneumocystis carinii pneumonia were observed.

Effect of plasma exchange on the steady-state kinetics of digoxin and digitoxin.

The pharmacokinetic effect of extracorporeal elimination can be evaluated from the extracorporeal elimination rate constant, from the amount of drug removed, and from extracorporeal clearance. To compare the validity of these approaches in clinical practice, the effect of multiple plasma exchanges on the steady-state kinetics of digoxin (5 patients) and digitoxin (9) was investigated. For digoxin, an unchanged elimination half-life (28 hours) and only slight increase in the total body clearance was found (from 203 to 204 ml/min). There was a more pronounced effect on the kinetics of digitoxin, where the elimination half-life decreased from 4.3 to 3.6 days, and the total body clearance increased from 4.4 to 4.7 ml/min. For digoxin there was no statistically significant difference between observed and predicted steady-state trough plasma concentrations. For digitoxin, the observed trough plasma concentrations at steady-state correlated well (p less than 0.05) with the predicted concentrations calculated from the amount removed or from extracorporeal clearance. The magnitude of the kinetic effect of plasma exchange is overestimated using the extracorporeal elimination rate constant; but the effect of extracorporeal elimination can be adequately evaluated from the amount of drug removed and from extracorporeal clearance. These later approaches can be considered model-independent. Thus, the influence of multiple plasma exchanges on the steady-state kinetics of digoxin and digitoxin will be limited and dosage adjustment is not required, if these drugs are given after - not before - the procedure and hypoalbuminaemia is corrected.