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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.

Lidocaine is a first line antiarrhythmic agent for treatment and prevention of severe acute ventricular arrhythmias in patients with myocardial infarction. Its efficacy and safety is limited, however, by a large unpredictable between-patient variability in the dose-concentration relationship. We have developed an adaptive microcomputer-based method that helps the physician to choose the optimum dose in an individual patient. The algorithm known in pharmacokinetics as Bayesian feedback uses the concept of nonlinear filtering theory. In this paper the performance of the method is evaluated on the basis of data obtained in 93 patients treated with lidocaine in three clinical studies. With respect to point prediction of future drug levels the performance was excellent. With only one individual feedback measurement of the lidocaine concentration, obtained early in the course of treatment, the serum drug level after 12 hours on continuous intravenous infusion could be predicted with high precision: root mean squared error (RMSE) = 25 %. The estimate of the prediction interval was found to be upwards biased. 86 % of the 93 drug levels lay within the 68 % prediction interval. This was significantly larger than the expected 68 %. On the basis of these results we conclude that, although somewhat inefficient, the method was under realistic routine clinical conditions precise and safe.

Trimethoprim (TMP), sulfamethoxazole (SMZ) and sulfadiazine (SDZ) are characterized by elimination half-lives of 9 to 15 h. Effective serum concentrations can therefore be maintained by twice daily administration, but without a loading dose steady state levels will be reached only after 3 days. Renal disease has little effect on the pharmacokinetics of unchanged SMZ, whereas TMP and SDZ elimination is prolonged in uremia. Dosage adaptation to creatinine clearance is difficult, since the ratio of the two components in serum and urine will be altered. Abnormal drug accumulation in liver disease during a treatment with TMP and SMZ has not been demonstrated.

The antiarrhythmic effect of slow-release disopyramide phosphate (DR) 300 mg twice daily and of long-acting propranolol (PR) 1 × 160 mg daily was compared in a randomized cross-over study in patients with premature ventricular beats (PVB). 12 patients with PVB (Lown Classes II–V) were given: placebo I for 3 days, DR or PR for 7 days, placebo II for 5 days and PR or DR for 7 days. During each study phase Holter-ECG recordings were taken over a period of 24h. With DR 6 patients showed a positive qualitative effect, improving by at least one Lown class, whereas only 2 patients did so with PR. With DR reduction of PVB>80% occurred in 7 patients, and with PR in 2 patients. In all patients with any reduction in PVB, the median decrease was 85% with DR and 59% with PR. The overall results suggest that the antiarrhythmic effect of disopyramide phosphate in the slow-release preparation is at least satisfactory and comparable to that of disopyramide phosphate in the standard capsule formulation given in the usual and more complicated regime of four divided doses. The antiarrhythmic effect of PR in the recommended dose as given was not convincing.

In 15 acutely ill asthmatics the steady-state serum theophylline concentration was predicted by the method of Chiou et al. using two serum concentration measurements obtained 1 and 5h after starting a continuous infusion of aminophylline. Two theophylline assays with different precision characteristics were compared. With a precise HPLC-assay the prediction was excellent: prediction error (predicted minus measured concentration)=-0.22±1.97 mg/l (mean ± SD); r=0.922. When the theophylline concentration was determined by a rapid enzyme immunoassay of lower precision, but convenient for clinical use, the prediction was less accurate (prediction error=0.58±3.88, r=0.852). However, it was still clearly superior to dosing recommendations based on the population average of theophylline clearance, even after taking into consideration the effect of smoking, congestive heart failure and cirrhosis (prediction error=3.62±13.36, r=0.560). As employed in this study, the method may be useful in helping the physician to choose the optimal dose in severely ill asthmatics.

Abstract: Objective: The electrophysiological effects of intravenously administered pure (S)- and (R)-propafenone hydrochloride has been determined for the first time in humans – 12 patients with supraventricular tachycardia. Methods:Measurements were performed before and during drug therapy. Results:(S)- and (R)-propafenone prolonged the AH interval from 82 to 107 ms and 75 to 84 ms, respectively, and significantly increased the AV nodal Wenckebach cycle length by 58 ms and 37 ms , respectively. The AV nodal effective refractory period in both groups was increased significantly to the same extent (45 vs 42 ms). Sinus node recovery times were not significantly influenced by either enantiomers. Both (S)- and (R)-propafenone significantly prolonged the HV interval to the same extent (from 41 to 51 ms, and 42 to 53 ms). Changes in the electrophysiological characteristics of the myocardium were more pronounced in the atria than in the ventricles. Only (S)-propafenone significantly increased the atrial effective refractory period from 204 to 230 ms, and the ventricular effective refractory period from 225 to 241 ms compared to (R)-propafenone (from 221 to 239 ms, and from 219 to 222 ms, respectively). There was a more pronounced electrophysiological effect on AV nodal conduction of (S)- than (R)-propafenone, probably as a result of its beta-blocking activity. Conclusion:The electrophysiological effects of (S)- compared to (R)-propafenone were not very pronounced, so it still remains questionable whether one of the enantiomers might be clinically superior to the other, or to the racemic mixture.

The pharmacological methods used to assess the intrinsic sympathomimetic activity (ISA) of ß-blockers are discussed. The clinical relevance of ISA to respiratory function, peripheral resistance and cardiac function is reviewed. It appears doubtful whether ISA is always of predominant clinical significance and an alternative explanation is offered for many clinical effects observed with certain ß-blockers, e.g. pindolol, oxprenolol, tolamolol, metoprolol, etc. Some effects of these ß-blockers resemble those of labetalol, a new drug with both a- and ß-blocking activity. Some clinical effects of certain ß-blockers are more likely to be due to a-blocking activity than to their ISA.

During once-daily dosing regimens of aminoglycosides, administration of large single doses results in high peak levels and low 24-h trough levels. However, commercial assays for monitoring aminoglycoside levels are designed to cover the smaller range of serum concentrations usually observed during multiple daily dosing regimens. The study assessed (a) the range of serum concentrations during once-daily dosing of amikacin and (b) the performance of a widely used assay system for measuring concentrations within this range. A total of 42 dosing intervals from eight patients receiving a once-daily regimen of amikacin (20 mg/kg) were monitored. Median (and range) of peak, 8− and 24-h trough levels were 61 (25–89), 5.9 (2.2–19), and 1.3 (<0.8–6.2) mg/L, respectively. The accuracy of a fluorescence polarization immunoassay for measuring concentrations of amikacin during once-daily dosing regimens was assessed in an international multicenter study. The performance of the assay was excellent for peak and 8-h concentrations; median deviations from the target concentrations were <5. The majority of the trough levels (26 of 42) measured in patients during once-daily treatment were within the range of 1–2 mg/L and could also be determined with an accuracy sufficient for clinical monitoring (median deviations 14).

Summary: In 6 healthy volunteers, intravenous infusions of nitroglycerin 4.8 and 10.6 µg/min yielded mean steady-state plasma concentrations of 0.5±0.02 and 0.82±0.04 ng/ml as determined by a gas chromatographic/mass spectrometric method. The plasma concentrations reached in the same subjects 17 h after application of Nitroderm TTS 5 and 10 with in vivo release rates of 3.7 and 5.7 µg/min were 0.28±0.01 and 0.37±0.01 ng/ml, respectively. Thus, 75% of the quantity of nitroglycerin released by the systems passed into the circulation. The inter-individual and intra-individual variations in plasma concentrations were similar for both modes of administration. The nitroglycerin-induced morphological changes in the fingerpulse wave were clearly dose-dependent, but it seems that this pharmacodynamic parameter is determined less by the plasma concentration than by the nitroglycerin content of the vascular wall.

Clinical and laboratory data on infectious complications in 100 consecutive heart transplant recipients were analyzed retrospectively. The mean length of follow-up was 651±466 days. All patients received a basic immunosuppressive regimen including cyclosporine (whole blood target trough level 400–600 µg/l), azathioprine (1 mg/kg/day) and prednisone (0.15 mg/kg/day). Early rejection prophylaxis consisted of polyclonal rabbit antithymocyte globulin (ATG) (4 mg/kg/day for 4 days) in the first 57 patients and monoclonal murine OKT-3 (5 mg/day for 14 days) in the remaining patients. The primary cause of death was infection in three patients and rejection in 16 (p<0.001). The incidence of infection was 0.96/patient/year (n=179); 95 infections were nosocomial (53 %), 47 community-acquired (26 %) and 37 opportunistic (21 %). The number of hospitalizations due to infections was fewer than that due to rejection (53 versus 246 respectively, p<0.0001), but the mean length of hospital stay was longer in the first group (13.85±10.92 days versus 3.48±2.28 days, p<0.001). Previous early rejection prophylaxis with OKT-3 was associated with a greater number of opportunistic and nosocomial infections compared to prophylaxis with ATG (p<0.05), as was treatment with ATG and steroid pulses compared to steroid pulses alone in cases of opportunistic infection (p<0.05).

A newly developed homogeneous enzyme immunoassay for the determination of netilmicin in serum was evaluated and compared with a radioenzymatic assay. A total of 102 serum samples from patients treated with netilmicin were measured by both methods. This comparison showed an excellent correlation (r = 0.993). The enzyme immunoassay has proved to be precise, accurate, and specific. Because of its rapidity and the ease of performance, this method is a useful alternative to current assays for monitoring serum netilmicin concentrations.

Ten critically ill patients presenting with nosocomial infection caused by Serratia marcescens (SM) not responding to prior chemotherapy were treated in an open study with MoxalactamOfficial generic name in the USA; trade mark (Eli Lilly & Co) in most of Europe (MOX) alone [6] or in combination with an aminoglycoside [4]. In initial disc diffusion tests, all isolates of SM were highly susceptible to MOX. Clinically, three patients were cured and four improved. Three patients died: one from SM pneumonia, one from gangrenous cholecystitis and another from ARDS. Bacteriologically, SM were eliminated from blood cultures in all seven patients with septicemia but were recovered post mortem from the lung of one patient. In three cases with localized infection, SM were eliminated once and persisted twice. Selection of resistant SM was observed in three patients but became clinically relevant in one case only. Resistant SM strains also showed reduced susceptibility to other cephalosporins and aminoglycosides. Emergence of enterococci occurred four times, in two cases with clinical consequences. MOX is a useful drug for the treatment of SM infections, but a definite risk of selecting multiresistant SM strains and of enterococcal overgrowth must be kept in mind.

The therapeutic efficacy and safety of ciprofloxacin was studied in 30 patients withPseudomonas aeruginosa infections. In 20 patients ciprofloxacin was given alone and in 10 patients (including 8 compromized hosts) in combination with an aminoglycoside (9) or azlocillin (1). Ciprofloxacin was given in doses of 500 mg orally or 200–300 mg i. v. every 12 h. In patients receiving only ciprofloxacin clinical cure with eradication of bacteria was obtained in 15 patients (75%) with infections of bone and joint (6), skin and soft tissue (4), lung (2), middle ear (2) and CSF (1). Two patients with lymphoma andPseudomonas aeruginosa pneumonia died. In patients receiving combination therapy a definite therapeutic success was achieved in four (40%). Three patients withPseudomonas aeruginosa septicemia died. In seven patients nine bacterial strains with decreasing susceptibility of ciprofloxacin (increase in MIC from ⩽0.5μg/ml to 2–16 μg/ml) were selected (6Pseudomonas aeruginosa, 1Enterobacter cloacae, 1Serratia marcescens, 1Staphylococcus aureus). Ciprofloxacin was well tolerated. This new quinolone seems to be suitable for single drug treatment ofPseudomonas aeruginosa infections in patients with normal host defense mechanisms, while its therapeutic potential in compromized hosts requires further evaluation.

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 haemaotological diseases were present. Resistant strains ofEnterobacter cloacae (14),Serratia marcescens (4),Klebsiella oxytoca (3),Pseudomonas aeruginosa (2) andCitrobacter 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.