Fexinidazole for human African trypanosomiasis, the fruit of a successful public-private partnership

After 100 years of chemotherapy with impractical and toxic drugs, an oral cure for human African trypanosomiasis (HAT) is available: Fexinidazole. In this case, we review the history of drug discovery for HAT with special emphasis on the discovery, pre-clinical development, and operational challenges of the clinical trials of fexinidazole. The screening of the Drugs for Neglected Diseases initiative (DNDi) HAT-library by the Swiss TPH had singled out fexinidazole, originally developed by Hoechst (now Sanofi), as the most promising of a series of over 800 nitroimidazoles and related molecules. In cell culture, fexinidazole has an IC50 of around 1 microM against Trypanosoma brucei and is more than 100-fold less toxic to mammalian cells. In the mouse model, fexinidazole cures both the first, haemolymphatic, and the second, meningoencephalitic stage of the infection, the latter at 100 mg/kg twice daily for 5 days. In patients, the clinical trials managed by DNDi and supported by Swiss TPH mainly conducted in the Democratic Republic of the Congo demonstrated that oral fexinidazole is safe and effective for use against first- and early second-stage sleeping sickness. Based on the positive opinion issued by the European Medicines Agency in 2018, the WHO has released new interim guidelines for the treatment of HAT including fexinidazole as the new therapy for first-stage and non-severe second-stage sleeping sickness caused by Trypanosoma brucei gambiense (gHAT). This greatly facilitates the diagnosis and treatment algorithm for gHAT, increasing the attainable coverage and paving the way towards the envisaged goal of zero transmission by 2030

Effectiveness of a 10-day melarsoprol schedule for the treatment of late-stage human African trypanosomiasis: confirmation from a multinational study (IMPAMEL II).

BACKGROUND: Treatment of late-stage human African trypanosomiasis (HAT) with melarsoprol can be improved by shortening the regimen. A previous trial demonstrated the safety and efficacy of a 10-day treatment schedule. We demonstrate the effectiveness of this schedule in a noncontrolled, multinational drug-utilization study. METHODS: A total of 2020 patients with late-stage HAT were treated with the 10-day melarsoprol schedule in 16 centers in 7 African countries. We assessed outcome on the basis of major adverse events and the cure rate after treatment and during 2 years of follow-up. RESULTS: The cure rate 24 h after treatment was 93.9%; 2 years later, it was 86.2%. However, 49.3% of patients were lost to follow-up. The overall fatality rate was 5.9%. Of treated patients, 8.7% had an encephalopathic syndrome that was fatal 45.5% of the time. The rate of severe bullous and maculopapular eruptions was 0.8% and 6.8%, respectively. CONCLUSIONS: The 10-day treatment schedule was well implemented in the field and was effective. It reduces treatment duration, drug amount, and hospitalization costs per patient, and it increases treatment-center capacity. The shorter protocol has been recommended by the International Scientific Council for Trypanosomiasis Research and Control for the treatment of late-stage HAT caused by Trypanosoma brucei gambiense

Mycobacterium-avium -Pneumonie bei HIV-negativem Patienten

Zusammenfassung: Ein 79-jähriger Patient mit kurativ behandeltem Lungenkarzinom wurde wegen Fieber, Atemnot und Husten zugewiesen. Eine Antibiotikatherapie zur Pneumoniebehandlung brachte keine Besserung, und radiologisch war die Pneumonie progredient. Ein Erreger konnte nicht gefunden werden. Erst unter einer Steroidtherapie bei vermuteter kryptogener Pneumonitis normalisierten sich die Entzündungszeichen und die Symptomatik war rückläufig. Nach 3-wöchiger Kultivierung konnten im Eintrittssputum Mycobacterium avium Complex (MAC) gefunden und eine MAC-Pneumonie diagnostiziert werde

Trypanosoma brucei brucei: differences in the nuclear chromatin of bloodstream forms and procyclic culture forms

Nucleosome filaments of two stages of the life-cycle of Trypanosoma brucei brucei, namely bloodstream forms and procyclic culture forms, were investigated by electron microscopy. Chromatin of bloodstream forms showed a salt-dependent condensation. The level of condensation was higher than that shown by chromatin from procyclic culture forms, but 30 nm fibres as formed in rat liver chromatin preparations were not found. Analysis of histones provided new evidence for the existence of H1-like proteins, which comigrated in the region of the core histones in SDS-PAGE and in front of the core histones in Triton acid urea gels. Differences were found between the H1-like proteins of the two trypanosome stages as well as between the core histones in their amount, number of bands and banding pattern. It can be concluded that T. b. brucei contains a full set of histones, including H1-like proteins, and that the poor condensation of its chromatin is not due to the absence of H1, but most probably due to histone-DNA interaction being weak. It is obvious that structural and functional differences of the chromatin exist not only between T. b. brucei and higher eukaryotes, but also between various stages of the life-cycle of the parasite. It is therefore not adequate to investigate the chromatin only of the procyclic culture forms as a model for all stages of the life-cycle of T. b. bruce

28-jähriger Patient mit erfolgreich behandelter dilatativer Kardiomyopathie

Zusammenfassung: Ein 28-jähriger Patient wurde mit dekompensierter Herzinsuffizienz notfallmäßig zugewiesen. In der Vorgeschichte bestand ein hypogonadotroper Hypogonadismus. Echokardiographisch fand sich eine dilatative Kardiomyopathie. Ein erhöhtes Serumferritin und eine Eisenüberladung in der Leberbiopsie ließen eine hereditäre Hämochromatose vermuten. Die kardiale Beteiligung konnte mittels Magnetresonanztomographie nachgewiesen werden. Genetische Abklärungen ergaben eine homozygote Mutation für G320V und bewiesen eine juvenile Hämochromatose. Eine Aderlasstherapie führte innerhalb eines Jahres zur Normalisierung des Eisenstatus und der kardialen Pumpfunktio

§ 16 Digitaler Handel

Die Verhandlungsgeschichte des EU-VK Handels- und Kooperationsabkommen zeigt deutlich, wie wichtig Fragen des digitalen Handels nach dem Brexit sind. Dies wiederum spiegelt die wachsende strategische Bedeutung des digitalen Handels und des grenzüberschreitenden Datenverkehrs wider. Der vorliegende Beitrag untersucht den regulatorischen Kontext, kommentiert ausführlich die inhaltlichen Bestimmungen des TCA und nimmt eine vergleichende Analyse des TCA-Kapitels zum digitalen Handel mit anderen Handelsabkommen der EU und anderer wichtiger Akteure vor. Eine der Schlüsselfragen der Verhandlungen zwischen der EU und dem VK war das genaue Zusammenspiel zwischen der Verpflichtung der Vertragsparteien, grenzüberschreitende Datenströme zuzulassen, und dem Gebot, personenbezogene Daten und die Privatsphäre von Einzelpersonen zu schützen. Diese Thematik verdient daher besonders beleuchtet zu werden. Der Beitrag schließt mit einer Würdigung und einem Ausblick