Comparative Effects of Phenytoin and/or Phenobarbital Treatment on Sister Chromatid Exchange

The potential of the widely prescribed antiepileptic drugs (AEDs) phenytoin (PHT) and phenobarbital (PB) to interact with genetic material was tested using sister chromatid exchange (SCE) assay. Thirty adult male patients with epilepsy receiving long-term AED therapy (16 with PHT, 6 with PB, and 8 with combined PHT and PB therapy) and 30 healthy controls were selected for the study of SCE frequencies in peripheral lymphocytes. The patients and controls were carefully screened and matched for sex, age, and smoking habits. All potential probands with exposure to factors known or suspected of affecting the SCE frequencies were excluded. Statistical analyses did not show any significant differences between the SCE rates of PHT- and/or PB-treated patients and controls, indicating a lack of mutagenicity of the tested drugs as expressed by induction of SCE on adult recipients. Smoking, however, affected the SCE levels considerably. The smokers had higher SCE frequencies than the nonsmokers, both among patients and controls. Caffeine consumption was also associated with SCE increases in patients but not in controls.     

Toxic effects of antiepileptic drugs on immunoglobulin gene expression.

Murine myeloma cells were exposed to toxic, growth-retarding levels of two antiepileptic drugs (AEDs2), phenytoin (PHT) and carbamazepine (CBZ). J558L cells were treated for 12 days, washed free of drug and, upon recovery of growth, cloned to determine the frequency of lambda light chain secreting lines. Our results indicate that short-term exposure to high, toxic levels (5-10 times the therapeutic dose) of PHT and CBZ reduces or eliminates lambda light chain secretion at a high frequency. Furthermore, although most cloned lines tested positive for cytoplasmic lambda light chain, some lines had no detectable cytoplasmic immunoglobulin (Ig). The data are consistent with the hypothesis that long-term changes in fully differentiated B cell function may occur after toxic level AED exposure.     

Empirical monotherapy with meropenem versus imipenem/cilastatin for febrile episodes in neutropenic patients

Summary In a nonblind, randomised, parallel-group study, initial empirical monotherapy with meropenem 1 g intravenously every 8 h was compared to an identical dosage of imipenem/cilastatin for the treatment of 66 febrile episodes in 61 adult neutropenic patients. 25/31 episodes treated with meropenem and 24/30 imipenem/cilastatin-treated episodes were still receiving unmodified therapy at 72 h (primary endpoint); this difference was not statistically significant. By the end of the treatment courses, 18/31 meropenem-treated episodes had responded clinically (cured or improved) compared with 18/30 episodes treated with imipenem/cilastatin. Another ten episodes initially treated with meropenem and six episodes treated with imipenem/cilastatin were cured after an additional antimicrobial agent had been administered (cured with modification). Satisfactory bacteriological responses (eradication plus presumed eradication) at the end of unmodified therapy was 9/11 in the meropenem group and 14/16 in the comparator group. Both regimes were well tolerated; however, there were more reports of nausea and/or vomiting in the imipenem/cilastatin group (7/33 vs. 2/33 in the meropenem group). The carbapenems meropenem and imipenem/cilastatin appear to be suitable agents for empirical monotherapy of febrile episodes in neutropenic patients. Meropenem may be better tolerated than imipenem/cilastatin, allowing optimal dosing in this patient population.

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Empirische Monotherapie mit Meropenem oder Imipenem/Cilastatin für Fieber bei neutropenischen Patienten

Zusammenfassung In einer offenen, randomisierten Vergleichsstudie wurde die initiale empirische Monotherapie mit Meropenem in einer Dosierung von 3 × 1g täglich verglichen mit Imipenem/Cilastatin in der gleichen Dosierung bei 66 Fieberepisoden von 61 erwachsenen neutropenischen Patienten. 72 Stunden nach Therapiebeginn erhielten noch 25/31 Patienten aus der Meropenem-Gruppe und 24/30 Patienten aus der Behandlungsgruppe mit Imipenem/Cilastatin die usprünglich zugewiesene Initialtherapie (Hauptzielkriterium). Bei Therapieende waren in der Meropenem-Gruppe 18/31 Episoden geheilt oder gebessert gegenüber 18/30 in der Gruppe mit Imipenem/Cilastatin. Weitere 10 Infektionsepisoden, die initial mit Meropenem behandelt wurden, und sechs Infektionsepisoden aus der Vergleichsgruppe konnten erfolgreich behandelt werden, nachdem eine zusätzliche antimikrobielle Substanz verabreicht worden war (Heilung nach Therapiemodifikation). Das zufriedenstellende bakteriologische Ansprechen (Keimelimination sowie vermutete Keimelimination) mit der Initialtherapie Meropenem betrug 9/11 und 14/16 mit Imipenem/Cilastatin. Beide Antibiotika wurden gut vertragen; es wurden jedoch unter Imipenem/Cilastatin mehr Fälle von Übelkeit und/oder Erbrechen registriert (7/33 vs 2/33 unter Meropenem). Die Carbapenem-Antibiotika Meropenem und Imipenem/Cilastatin scheinen geeignet für die empirische Monotherapie bei Fieberepisoden neutropenischer Patienten zu sein. Meropenem erlaubt durch seine offensichtlich bessere Verträglichkeit im Vergleich zu Impienem/Cilastatin auch eine optimale Dosierung bei diesem Patientengut.

     

Inducible Metronidazole Resistance in nim–Positive and nim–Negative Bacteroides fragilis Group Strains after Several Passages Metronidazole Containing Columbia Agar Plates

Abstract Background: Recent data show an emergence of resistance in the Bacteroides fragilis group against several antimicrobial agents and inducible resistance against metronidazole in nim–positive strains. The aim of the present study was to investigate inducible metronidazole resistance in nim–positive as well as in nim–negative B. fragilis group strains. Materials and Methods: Of 18 B. fragilis strains (including four nim–positive reference strains and one ATCC strain), two Bacteroides ovatus strains, and one Bacteroides thetaiotaomicron DSM strain minimum inhibitory concentration (MIC) values for metronidazole were determined by Etest^? and analyzed for nim genes (nimA to –G) by PCR. For this purpose bacterial suspensions were incubated on supplemented Columbia agar plates containing metronidazole at twice the MIC value of the specific strain and incubated under anaerobic conditions for 48 hours. After incubation, growing bacteria were harvested and thereafter incubated at four times the original MIC. This procedure was repeated with increasing antibiotic concentrations. The resulting MIC values were confirmed by Etest^?. Results: The MIC values for metronidazole of the four nim–positive reference strains ranged from 3 to 8 mg/l. The B. fragilis ATCC 25285 strain and the B. thetaiotaomicron DSM 2255 strain were nim negative with MIC values of 0.19 mg/l and 0.75 mg/l, respectively. Three clinical isolates of B. fragilis strains showed MIC values of > 256 mg/l. In all three strains, nim genes were detected by PCR. The other clinical isolates were nim negative. In these strains, MIC values ranged from 0.19 to 0.75 mg/l. After several passages on metronidazole containing agar, all B. fragilis group strains exhibited MIC values of > 256 mg/l determined by Etest^?. Conclusion: Metronidazole resistance can be selected not only in nim–positive strains but also in nim–negative strains, suggesting that mechanisms other than nim genes are involved. These findings and the emerging resistance of the B. fragilis group against several antimicrobial agents underscore the importance of susceptibility testing of anaerobes even in routine laboratories. This paper is dedicated to the founders of the Walter Marget Foundation, D. Adam and F. Daschner, in gratitude for their support of the training in infectious diseases.     

Kinetics of the fab fragments of digoxin antibodies and of bound digoxin in patients with severe digoxin intoxication

Summary 17 patients with severe digoxin intoxication were successfully treated with 320 to 480 mg Fab fragments of digoxin-specific IgG from sheep. The infusion period ranged between 0.5 and 7 h. Serum and urine concentrations of digoxin bound to Fab fragments, and in 11 cases unbound Fab fragments in serum, were determined during and after the infusion.The renal clearance of bound digoxin and therefore of the antibody was 13.6 ml/min. The median extrarenal clearance of the Fab fragments was 10.9 ml/min.The half-life of the serum concentrations starting at 12 h was 14.3 h, and the value was increased to 25.4 h when regression began at 24 h; the corresponding apparent distribution volumes were 25.9 and 541. These figures exceed the volume of the extracellular space and suggest intracellular penetration of the Fab fragments.The dosage of the antibody should be sufficiently high to bind digoxin in the most severe cases of poisoning. The maximum serum concentrations of bound antibody were 30 mg/l after 3 h and 20 mg/l after 5 h. A loading dose of 160 mg followed by an infusion of 0.5 mg/min was sufficient to absorb digoxin re-diffusing into the serum during the first 8 h. In some cases free digoxin reappeared in the serum 8–12 h after beginning the treatment. This might be prevented by infusing a further ampoule at a rate of 0.1 mg/min or less.     

Eine Methode zur gleichzeitigen Erfassung pharmakologischer Wirkungen auf das Atemzentrum und die neuromuskuläre Übertragung

Zusammenfassung In Versuchen an Ratten wurden die Aktivität des Atemzentrums und die Kontraktionen des Zwerchfells registriert und miteinander verglichen.Als Maß für die Aktivität des Atemzentrums dienten die Entladungen des linken N. phrenicus, die oszillographische registriert und elektronisch integriert wurden. Die Kontraktionen der rechten, innervierten Zwerchfellhälfte wurden mit einem mechano-elektrischen Transducer gemessen.Mit dieser Methode ist es möglich, pharmakologische Wirkungen auf das Atemzentrum und auf die neuromuskuläre Übertragung gleichzeitig zu erfassen.Mit 4 Textabbildungen     

Antagonistische Wirkung von Morphin und Cholinesterase-Hemmern auf das Atemzentrum

Ohne ZusammenfassungMit 6 TextabbildungenDurchgeführt mit Unterstützung der Deutschen Forschungsgemeinschaft.     

A family with amyotrophic lateral sclerosis and parkinsonism

Zusammenfassung Bericht über einen 45jährigen Mann mit der Kombination von myatrophischer Lateralsklerose und Parkinson-Syndrome, dessen Vater ebenfalls diese Krankheitskombination aufwies. Die epidemiologische Bedeutung derartiger Fälle wird diskutiert unter Bezugnahme auf das gehäufte Vorkommen auf den Marianen-Inseln und die Mitteilungen für das familiäre Vorkommen in Europa. Ein gemeinsamer genetischer Faktor wird für wahrscheinlich gehalten.