[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.

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.

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.

[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.

[Trial for digitalis withdrawal in hemodialysis patients]. / Digitalis-Auslassversuch bein Hämodialyse-Patienten.

The indication for digitalis treatment was investigated in a controlled and prospective study lasting 12 months in 110 patients on long-term haemodialysis. In ten patients, digitalis was needed because of tachyarrhythmia due to atrial fibrillation and in five because of recurrent pulmonary edema. In 57 patients receiving digitoxin, therapy was discontinued for 4 to 6 weeks, whereas 13 patients not yet treated with digitalis, received digitoxin for 4 weeks. Without digitoxin, trial fibrillation occurred in 4 patients, while no patient experienced atrial fibrillation with digitoxin (P = 0.002). In 13 patients, radiological findings (heart enlargement, pulmonary congestion) were better with digitoxin than without. Thus digitoxin appeared to be clearly indicated in 29% of the haemodialysed patients. Additionally, digitalis was indicated in 31 patients because of heart enlargement, pulmonary congestion and (or) previous pulmonary edema. Initially, 76% of the patients were receiving digitoxin, whereas, after the investigation, the rate was only 57% (P less than 0.001). The prospective frequency of clinically apparent digitoxin intoxication was low (3%) and so were the overall toxic plasma digitoxin levels (5%). Digitalis should be given deliberately but not restrictively to haemodialysis patients, since atrial fibrillation (13%) and heart failure (50%) are frequent and often concealed.

Intravenous short-term infusion of streptokinase in acute myocardial infarction.

Short-term i.v. infusion of streptokinase was performed in 93 patients within 6 hours after the onset of acute myocardial infarction. Twenty-six patients underwent angiography in the acute phase (group A) and 52 underwent angiography in the fourth week only (group B); 15 patients had no angiography. Seven patients died during the hospital stay and six suffered nonfatal reinfarctions. There were no bleeding complications. In 11 of 21 group A patients, occluded coronary arteries were opened within 1 hour after the streptokinase infusion was started. In 84% of groups A and B, the infarct-related coronary artery was patent in the fourth week. In 75% of the patent arteries, the residual luminal diameter stenosis was less than 70%. According to serial serum CK-MB curves, recanalization was achieved mostly within 1-2 hours. Myocardial salvage was indicated by improvement in local contraction disorders in the recanalized group A patients and by the significant relationship between infarct size and time from symptom onset to treatment in group B. These data suggest that a high-dose, short-term, i.v. infusion of streptokinase is a safe and efficient method of restoring coronary blood flow. Expeditious initiation of i.v. streptokinase infusion is a critical determinant for early recanalization and salvage of myocardium. Patients with thrombotically subtotal occlusion probably receive the most benefit. Evaluation of the true impact on survival and myocardial function will require controlled clinical trials.

[Systemic thrombolysis with short-term streptokinase infusion in acute myocardial infarct]. / Systemische Thrombolyse mit Streptokinase-Kurzzeitinfusion bei akutem Myokardinfarkt.

Within 6 hours after the onset of acute myocardial infarction, 93 patients received a brief high-dose intravenous infusion of streptokinase, 49 patients received 500,000 IU within 30 min and 44 patients received 1,500,000 IU within 60 min. 26 patients had angiography in the acute phase, after 24 hours, and in the 4th week; 52 patients had angiography in the 4th week only; and 15 had no angiography. 7 patients died in hospital and 6 suffered a nonfatal reinfarction. There were no complications with bleeding. In 52% of cases, reopening of an occluded infarct vessel was achieved within 1 hour of the beginning of treatment. During the 4th week after infarction a patent infarct vessel was found in 84%, and 58% had a residual stenosis less than 70%. In contrast, in a control group that received no streptokinase treatment, 25% had a patent infarct vessel and 4% had a residual stenosis less than 70%. Indicative for salvage of ischemic myocardium are a significant improvement in local contraction disorders between the acute phase and the 4th week and a significant correlation between infarct size in the 4th week and beginning of treatment after onset of symptoms. 1. It may be concluded that: brief intravenous infusion of streptokinase results in restoration of blood flow in an infarcted coronary artery in a high percentage of cases; the shorter thrombus-lysis time with intracoronary streptokinase infusion could be made up for by the earlier initiation of intravenous streptokinase treatment; and a conclusive randomized trial is needed to ascertain the true impact of a brief high-dose intravenous infusion of streptokinase on mortality and morbidity following acute myocardial infarction.

Digitalis therapy in renal failure with special regard to digitoxin.

When prescribing cardiac glycosides for patients with renal failure, one should consider the different pharmacokinetics of the two most important glycosides, digoxin and digitoxin. Whereas steady state plasma concentrations of digoxin are altered proportionally to renal clearance of creatinine, those of digitoxin remain the same throughout a wide range of renal impairment. The steady state level of both glycosides is partly determined by several clinical factors such as dose, body weight, height, age and serum potassium. However, it is thought that bioavailability, volume of distribution, biotransformation, and total body clearance have the greatest importance for the variability of the plasma glycoside concentrations in patients with normal and with impaired renal function. The bioavailability and biotransformation of digoxin do not vary between healthy subjects and patients with renal insufficiency. As the volume of distribution is smaller in patients with severe renal failure that in normal subjects, the loading dose has to be altered. With decreasing creatinine clearance the total body clearance as well as the renal clearance of digoxin is reduced. On the basis of this assumption maintenance dosage regiments must be adjusted. For digitoxin, the four above-mentioned pharmacokinetic parameters are not altered in patients with renal failure compared to healthy subjects. Moreover, investigations dealing with this problem have suggested an altered protein binding of digitoxin and its metabolites as a possible factor in avoiding accumulation of the drug. However, it is one of the aims of this article to show that a decreased urinary excretion of digitoxin and metabolites is compensated by an increased excretion via the feces. Loading dose and maintenance dose of digitoxin do not have to be adjusted in patients with renal failure.

Verapamil disposition in liver disease and intensive-care patients: kinetics, clearance, and apparent blood flow relationships.

Verapamil kinetics have been determined in liver disease (mainly in cirrhotic patients), in intensive-care patients, and in healthy control subjects. Areas under the concentration-time curves (AUCs) after intravenous 5-mg and oral 80-mg doses were used to calculate systemic blood clearance, intrinsic blood clearance, and bioavailability of verapamil in patients and to calculate apparent hepatic blood flow. Intravenous data showed that verapamil clearance was reduced in all patients with liver disease (mean = -66%), but intensive-care patients were a more heterogenous group in which some patients had increases (five patients; mean = +72%) and others had decreases (two patients; mean = 6-57%) in verapamil clearance. The changes in clearance corresponded to changes in the half-time for the beta-phase (t1/2 beta). Verapamil bioavailability is low, and the intensive-care patients and healthy subjects examined it ranged from 13% to 21%. There was considerable variation in liver disease subjects, in whom verapamil bioavailability ranged from 3.8% to 64%. THe systemic clearance of verapamil correlated linearly with calculated apparent hepatic blood flow (r = 0.99; regression coefficient = 0.87). In the case of one liver patient the kinetic results could be used to confirm the clinical diagnosis of hepatic shunts. It is concluded that there are clinically significant changes in verapamil elimination in liver disease and in intensive-care patients. For patients with normal hepatic vascular anatomy, these changes can be explained in terms of differences in hepatic blood flow.

[The biological availability of digitoxin]. / Die biologische Verfügbarkeit von Digitoxin.

The bioavailability of digitoxin after a single dose of 0.5 mg was studied in 6 healthy volunteers by estimation of tmax, cmax, AUC und urinary excretion rate. After tablets, absorption was rapid, after dragées delayed. The mean t1/2 of digitoxin for i.v. administration was 9.5 +/- 0.9 days, for oral administration of tablets 7.4 +/- 0.5 days and for dragées 9.7 +/- 2.0 days. The cumulative recovery of glycosides in urine during the first 48 hours was higher after tablets than after i.v. administration. The shorter t1/2 of digitoxin after tablets compared with the longer t1/2 after gastric juice resistent dragées demonstrated the presence of a substantial extrahepatic "first pass"-effect by degradation of digitoxin before absorption. Such mechanism would partly explain the shorter t1/2 after digitoxin-tablets due to an increased elimination of splitting products. By extrapolation to t-infinite AUC and urinary excretion rates were not significantly different between various formulations. The mean absolute bioavailability of digitoxin-dragées amounted to 82-88 percent and the relative bioavailability of digitoxin-tablets to 84-93 percent.

[Isomerisation and bioavailability of beta- and alpha-acetyldigoxin (author's transl)]. / Isomerisierung und biologische Verfügbarkeit von beta- und alpha-acetyldigoxin.

Bioavailability of acetylated derivatives of digoxin tablets have been studied in healthy subjects after a single oral and intravenous dose as well as during maintenance therapy. alpha-acetyldigoxin shows a lower bioavailability than beta-acetyldigoxin even if the alpha-acetylated derivative is incorporated in a matrix of aerosil (SiO2). Moreover, beta-acetyldigoxin can be transferred to alpha-acetyldigoxin in alkaline solutions. This isomerisation leads to a decrease of the bioavailability of such fixed preparations which contain beta-acetyldigoxin and the hygroscopic salts of potassium-magnesium-aspartate. A prevention of the isomerisation is attained by isolating beta-acetyldigoxin from potassium-magnesium-aspartate. The bioavailability of a such new formulation is comparable to that of beta-acetyldigoxin alone. The experiments show the bioavailability of acetylated derivatives of digoxin to be influenced by the physico-chemical properties of a drug and its preparation.

Influence of canrenoate-K and cardiac glycosides on their tissue distribution and elimination.

The combination of cardiac glycosides and canrenoate-potassium (CR-K) produces synergistic effects on hemodynamics. On the other hand, CR-K antagonizes digitalis-induced cardiac arrhythmias. Therefore, it was the purpose of this study to determine interactions between these substances, particularly of their myocardial uptake. The additional administration of CR-K leads to significantly higher concentrations of digoxin and ouabain in heart, liver, adrenal gland and spleen. Contrary to this, additional digoxin reduces the concentration of CR-K in the tissue. Particularly obvious is the reduced concentration in the kidney, adrenal gland, pancreas, brain and spleen. The renal excretion of digoxin and ouabain is reduced by the additional administration of CR-K, while digoxin accelerates the CR-K excretion within the first 60 min after application. Metabolic interference was not detected in the combination of cardiac glycosides and CR-K. The mechanisms for the interactions between cardiac glycosides and CR-K during the distribution phase are discussed. The inhomogenous interference of their myocardial uptake makes a common cardiac receptor for the synergistic effect of cardiac glycosides and CR-K rather unlikely. CR-K does not have a suppressant effect on digitalis-induced arrhythmias due to any diminution of the glycoside uptake by myocardial tissue.

[Pharmacokinetics of cardiac glycosides and clinical consequences]. / Pharmakokinetik von Herzglykosiden und klinische Konsequenzen

The purpose of pharmacokinetics of cardiac glycosides is to study the time courses of glycosides in biological fluids, tissues and excreta. The extent of accumulation of a given dose at uniform time intervals depends only from the overall elimination rate constant. By knowing the elimination rate constant the extent to which a cardiac glycoside would accumulate in the body following a fixed dosing regimen can be calculated. The higher accumulation in the central nervous system requires a much longer time. Therefore it may be assumed that the brain is a deep compartment for cardiac glycosides and this compartment cannot be detected by analysis of plasma glycoside concentrations. Central side effects of cardiac glycosides may occur at therapeutic plasma levels. In renal disease a lower maintenance dose of digoxin and methyldigoxin should be administered or the same dose less frequently. Digitoxin does not accumulate in patients with renal failure or in anuria since the extrarenal elimination of digitoxin is much higher compared to digoxin and methyldigoxin.