[Praziquantel in the treatment of opisthorchiasis in Southeast Asian refugees. Evaluation of 153 cases]. / Le praziquantel dans le traitement des opisthorchiases chez des réfugiés du Sud-Est asiatique. Bilan de 153 cas.

153 patients coming to France from Southeast Asia were treated with Praziquantel for Opisthorchiasis. All these patients, 52 children and 101 adults were examined 30 to 90 day after arrival in France. They came from Laos (118 cases), Vietnam (10 cases) and Cambodia (25 cases), generally via Thailand. 7 heavy (10.000-29.999 Eggs Per Gram of faeces, EPG), 55 moderate (1.000-9.999 EPG) and 91 light infections (1-999 EPG) were detected. Praziquantel was given at a dose of 25 mg/kg body weight, orally, three times on a single day at intervals of 4-6 hours. Clinical tolerability was perfect in 59 patients and pretty good in the 94 remaining cases. We only observed, for one or two days, lassitude, headache, drowsiness, nausea, epigastric pain or arthralgia-myalgia, always of weak or moderate intensity and for 1 or 2 days. The biological tolerability was excellent without any variation of the biological norm values (47 parameters). The therapeutic efficacy was remarkable with 100% cure in all patients, who were followed-up for 40 days. All earlier controls (7th, 20th days) were always negative except for two patients who were completely negative on day 40th and later.

The profile of the trematodicidal compound praziquantel.

From the start onwards of testing praziquantel (2 - cyclohexyl - carbonyl - 1,2,3,6,7,11 b - hexahydro - 4H - pyrazino[2,1-a]isoquinolin-4-one, EMBAY 8440, Biltricide) proved to be very promising. By testing numerous trematode species in different host animals, high efficacy was established. There were no limitations due to the geographical origin of all those parasite species. Pharmacokinetic studies in animals and man showed similarly favourable results. The compound passes the blood-liquor barrier into the brain. No toxic alterations of vital functions and organs were revealed. After demonstrating satisfactory tolerability in healthy volunteers, therapeutic trials were begun. As to schistosomiasis, studies started double-blind in close cooperation with WHO, Geneva, with emphasis on future large scale treatment campaigns. Up to now safe and successful treatment of over 25,000 patients has been documented in Africa, Asia and South America with single dose or single day dosage schemes against all five schistosome species pathogenic to man. The analysis of allegedly drug-related adverse reactions often revealed their presence before treatment already, particularly in intestinal schistosomiasis. Irrespective of origin all symptoms and reactions were generally mild, transient and did not require additional treatment. No drug-related risks were detectable in patients with hepatosplenic and other complications of advanced stages of infection. High cure rates were also obtained in infections due to C. sinensis, O. viverrini and Paragonimus species. Infections with Metagonimus yokogawai, Fasciolopsis buski and Heterophyes heterophyes responded well to treatment, too.(ABSTRACT TRUNCATED AT 250 WORDS)

Trial designs for multicentre clinical studies of investigational phases I B to III with praziquantel.

Following very promising results with 2-cyclohexylcarbonyl-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a] isoquinolin-4-one (praziquantel, EMBAY 8440, Biltricide) in animal experiments on toxicity and efficacy and after confirming excellent tolerability in healthy volunteers, WHO could be won over to the further clinical development of this compound. In close cooperation trial protocols and case report sheets standardised as far as possible were set up for intercontinental multicentre trials in investigational phases II A, II B, and III, respectively. Thus, in investigational phase II A, studies were conducted simultaneously in Africa, Asia and South America. In all those endemic areas not only good tolerability in patients but also high efficacy against local Schistosoma species could be confirmed in double blind trials. In the extended phase II B, patients were allotted to 3 strata of different intensity of infection in order to find out if differentiating dosages would be necessary according to degree of worm burden, patient's age, and occurrence of more frequent and/or severe adverse reactions in patients with hepatolienal complications. There is not yet a satisfactory answer to all of these questions. In the investigational phase III already under way we hope to fill those gaps and also to find the optimum dosage for large scale use under field conditions. The profile of praziquantel, however, has already been established to an extent that first community health projects have been successfully started and others are in an advanced stage of planning.

[Clinical trial of niclofolan (Bay 9015) in the treatment of human opisthorchiasis. Apropos of 51 cases]. / Essais de traitement des opistorchiases humaines par le niclofolan (Bay 9015). A propos de 51 cas.

51 refugees from South east Asia infected with Opisthorchis viverrini or Clonorchis sinensis were included in a therapeutic study with Niclofolan (Bay 9015) at a dose of 1 mg/kg body weight given three times at intervals of 48 hours. Clinical and biological tolerance was carefully controlled and in all cases proved to be very good or excellent particularly in several patients with various haemoglobinopathies or erythrocytal enzymopathies (G-6-PD deficiency). Of the total of 51 cases, 17 were cured. These comprised mainly those with light or moderate infections (less than 10,000 eggs/gram stool). Treatment was, however, not effective in the more severe infections, even when repeated after an interval of 30 days. Between day 30 and 60 after treatment, only a transitory reduction of eggs/gram stool was observed, these values increasing again after day 90. Niclofolan did not reveal to be the ideal treatment of opisthorchiasis. Nevertheless its excellent tolerance should be pointed out which justifies its tentative application in light infections and above all its use in the treatment of paragonimiasis against which it appears to be one of the best drugs available at present.

Multicentre trials of praziquantel in human schistosomiasis: design and techniques.

This paper outlines the experimental design and techniques used in the initial multicentre clinical experiences with praziquantel in the treatment of human infections due to Schistosoma haematobium, S. mansoni, and S. japonicum. Trials were conducted in Brazil, Japan, the Philippines, and Zambia.Close professional cooperation between informed representatives of the manufacturers of the drug and WHO led to the use of a standard clinical trial design and agreed technical protocols, although parasitological methods of therapeutic assessment varied with the species of infecting parasite. Double-blind studies of tolerance were conducted at three different dose levels and subsequently, in Brazil and Zambia, single-blind trials of parasiticidal efficacy were carried out. The results of the various trials are reported separately.This type of close professional cooperation is a useful model for initial clinicopharmacological studies of parasiticidal drugs-an area beset with difficulties for both industry and international agencies.

Clinical pharmacology in normal volunteers of praziquantel, a new drug against schistosomes and cestodes. An example of a complex study covering both tolerance and pharmacokinetics.

The tolerance of Praziquantel (2-cyclohexylcarbonyl-1, 3, 4, 6, 7, 11b-hexahydro-2H-pyrazino-[2, 1-a]isoquinoline-4-one) in oral doses of 1 X 20 mg/kg, 1 X 50 mg/kg, 3 X 10 mg/kg and 3 X 25 mg/kg body weight (tau = 4 h) was tested in a complex study involving 36 healthy volunteers. In addition to the usual assessment of clinical chemistry, haematology, coagulation physiology, urinalysis, clinico-physiological examination including EEG, and medical examination, clinico-psychological parameters were also recorded and special neurological investigations were performed. No clinically relevant changes were found in any of the laboratory parameters, nor in the medical-neurological or clinico-physiological examinations. Based on a few clinico-psychological parameters and subjective comments, the largest daily dose tested (3 X 25 mg/kg = 75 mg/kg) produced a slight, transient disturbance in general well-being, which was barely detectable on objective clinical examination. The pharmacokinetic behaviour was dominated by rapid metabolism and pronounced first-pass metabolism of praziquantel, which greatly limits the value of results obtained by GC analysis of unchanged drug in serum. The peak concentration in serum was reached after 1--2 h, and the elimination half-life for the period 2--8 h was 1--1.5 h.