Drug resistance to schistosomicides and other anthelmintics of medical significance.

It is usual for people to be infected for some period in life with parasitic worms, which may cause morbidity or even kill. Anthelmintics are used for the treatment and control of the human helminthiases, since no vaccines are yet available. Despite the widespread use of these compounds, drug resistance has become apparent only with antischistosomal chemotherapy, in contrast to the situation with other anti-infective agents in human medicine and with veterinary anthelmintics, where resistance is widespread. This paper reviews research on drug resistance in human helminthiasis with emphasis on schistosomicidal drugs.

Evaluation of external-beam radiation therapy plus 5-fluorouracil (5-FU) versus external-beam radiation therapy plus hycanthone (HYC) in confined, unresectable pancreatic cancer.

From March 1981 to November 1987, 87 patients with histologically confirmed pancreatic adenocarcinoma, unresectable but confined to the pancreatic region, were randomized to two treatments. The standard treatment was 40-50 Gy external-beam radiation therapy (RT) to gross tumor plus potential microscopic tumor with a 5 Gy boost to gross tumor plus a 1.5-2.0 cm margin, using multiple fields and 5-fluorouracil (5-FU) 500 mg/m2/d intravenously by rapid infusion. The 5-FU was given each of the initial 3 days of each of three 20 Gy radiation courses. The experimental treatment used identical radiation fields, but the two Gy daily radiation fractions were administered in a continuous course to a total dose of 50 Gy. Hycanthone was administered 60 mg/m2 intravenously within 2 to 4 hr during each day of the 5-day course of infusions during the first and fifth weeks of radiation therapy. There was no statistically significant difference between treatment arms in survival (p = 0.82) or disease-free survival (p = 0.27). Seven percent of hycanthone-treated patients demonstrated hepatic toxicity which was usually mild in nature. There was, however, one death due to hepatic toxicity.

Estudio clínico, laparoscópico e histológico en 60 pacientes con esquistosomiasis mansoni / Clinical, laparoscopic and histologic study in 60 patients with schistosomiasis mansoni

Se estudiaron 60 pacientes procedentes del continente africano a los que se les diagnosticó esquistosomiasis mansoni. Se realizó estudio coproparasitológico por la técnica de Knight y se demostró la presencia de huevos del parásito. El estudio hematológico mostró eosinofilia y el del perfil hepático resultó normal. Para la administración del tratamiento se formaron 3 grupos que recibieron diferentes drogas. A todos los casos se les realizó estudio laparoscópico y biopsia hepática, a su ingreso y al año posterior al tratamiento. El Praziquantel fue efectivo en el 95% de los casos, el Oxamniquine en el 75% y el Etrenol en el 55

Estudio clínico, laparoscópico e histológico en 60 pacientes con esquistosomiasis mansoni / Clinical, laparoscopic and histologic study in 60 patients with schistosoiasis mansoni

Se estudiaron 60 pacientes procedentes del continente africano a los que se les diagnosticó esquistosomiasis mansoni. Se realizó estudio coproparasitológico por la técnica de Knight y se demostró la presencia de huevos del parásito. El estudio hematológico mostró eosinofilia y el del perfil hepático resultó normal. Para la administración del tratamiento se formaron 3 grupos que recibieron diferentes drogas. A todos los casos se les realizó estudio laparoscópico y biopsia hepática, a su ingreso y al año posterior al tratamiento. El Praziquantel fue efectivo en el 95

de los casos, el Oxamniquine en el 75

y el Etrenol en el 55

Schistosoma mansoni-induced mesangiocapillary glomerulonephritis: influence of therapy.

Schistosomiasis mansoni has been well documented as one of the causes of infectious glomerulopathy, with mesangiocapillary glomerulonephritis being the most frequent lesion observed in this condition. Twenty-one patients with hepatosplenic schistosomiasis mansoni and biopsy-documented mesangiocapillary glomerulonephritis (MCGN) were studied and compared with 19 patients with the idiopathic form of MCGN. Nephrotic syndrome was the most frequent clinical presentation in both groups. At the time of diagnosis nine patients with hepatosplenomegaly (4 with associated arterial hypertension) and 12 (8 with arterial hypertension) among the patients with idiopathic MCGN had renal insufficiency. At the end of the follow-up period 16 patients with hepatosplenic schistosomiasis and MCGN (75.2 months) and 15 with the idiopathic form (52.1 months) had renal failure. Also, when compared at 48 months of follow-up, no difference in renal function could be detected in both groups. No benefits related to anti-parasitic treatment in the schistosomiasis group and immunosuppression therapy in either group could be documented. The progression of the renal disease, as assessed by the reciprocal of serum creatinine versus time, and the survival curve, were not different between the two groups. It is concluded that MCGN in patients with the hepatosplenic form of schistosomiasis mansoni is a progressive disease not influenced by anti-parasitic or immunosuppressive therapy, and presents a clinical course similar to that of the idiopathic form.

Tratamento em massa como medida de controle da esquistossomose no Brasil

Apóss considerqçöes acerca da situaçäo epidemiológica da esquistossomose mansônica no Brasisl e dos principais dados relativos as drogas esquistossomicidas em uso atualmetne, säo revistos os aspectos mais relevantes com relaçäo ao uso da quimioterapis em massa, como forma de controle dessa endemia

Experimental chemotherapy of Schistosoma curassoni in mice.

Mice experimentally infected with Schistosoma curassoni were treated with different dose regimens of praziquantel, metrifonate, oxamniquine and hycanthone. Praziquantel was the most effective drug; a dose of 100 mg/kg given orally for 5 days resulted in a 95% reduction in worm burdens. The drug produced oogram changes in all animals. Metrifonate did not result in a reduced worm burden but caused oogram changes even on a low-dose (150 mg/kg during 2 consecutive days) schedule. Oxamniquine proved to be ineffective; no reduction in worm burdens or alterations in oograms were observed. Hycanthone (80 mg/kg for 1 day) resulted in a significant reduction in worm burdens.

Preparation and antischistosomal and antitumor activity of hycanthone and some of its congeners. Evidence for the mode of action of hycanthone.

The synthesis of a series of esters of hycanthone (HC) and 7-hydroxyhycanthone, their antitumor activity, and their antischistosomal effects on HC-sensitive and HC-resistant schistosomes are reported. Binding studies using tritium-labeled HC and hycanthone N-methylcarbamate (HNMC) with calf thymus DNA provided evidence that HNMC but not HC alkylated the DNA. Tritiated HNMC also bound to the DNA of intact HeLa cells exposed to the drug while very little tritiated HC bound to DNA under the same conditions. The mechanism proposed previously to account for the antischistosomal action of HC, namely, drug esterification followed by alkylation of DNA, applies also to the antitumor action of the drug as shown in Scheme I.

Effect of chemotherapy on hepatic collagen and glycosaminoglycan metabolism in Schistosoma mansoni-infected mice.

The dynamics of biosynthesis and accumulation of collagenous proteins and glycosaminoglycans (GAGs) in liver granulomas induced by eggs of Schistosoma mansoni were studied in mice following eradication of adult worms by chemotherapy. The relatively synchronous granulomas around parasite eggs were isolated from the livers at ensuing 2-week intervals; the number of recoverable granulomas per liver gradually decreased and was 7% of initial values at 20 weeks. Hepatic or granuloma-associated extracellular matrix components increased for 4 weeks after treatment despite cessation of ova deposition. At 12 weeks after chemotherapy the rate of GAG biosynthesis per total liver granuloma fraction, measured by 3H-glucosamine incorporation, decreased dramatically; this was followed by a decrease in the amount of GAGs present. The rate of collagen biosynthesis per total liver granuloma fraction, measured by 3H-proline incorporation, began to decline at 14 weeks and a decrease in the amount of collagen present was noted at 16 weeks. Our results demonstrated that liver granulomas induced by S. mansoni eggs synthesize collagens and GAGs for about 4-6 weeks following parasitological cure. The subsequent resolution of granulomas proceeds first by a reduction in GAG biosynthesis followed 4-8 weeks later by decreased collagen biosynthesis, followed by accelerated resolution of both collagen and GAGs.

Efeito da quimioterapia sobre os ovos do Schistosoma mansoni / Effect of chemotherapy on the Schistosoma mansoni eggs

A administraçäo de praziquantel a camundongos infectados pelo Schistosoma mansoni(50 cercarias/8 semanas) causou necrose de coagulaçäo e/ou lítica, e por vezes calcificaçäo dos miracídios nos tecidos a partir do 4§ dia do início do tratamento. A administraçäo conjugada de oxamniquine/hycanthone, embora muito efetiva para eliminar os vermes adultos, näo teve açäo sobre os miracídios no interior dos granulomas, tendo os testes de eclosäo sido positivos até o 15§ dia após o tratamento curativo. A açäo do praziquantel sobre os ovos do S. mansoni pode ter repercussäo sorológica ou patogênica, facilitando uma mais rápida reabsorçäo dos granulomas pelos tecidos do hospedeiro

The influence of anti-parasitic therapy on the course of the glomerulopathy associated with Schistosomiasis mansoni.

Although several aspects of the association between S. mansoni infection and renal disease are well known, the influence of the anti-parasitic therapy on the clinical course of the glomerulopathy remains undefined. With the aim of studying this aspect, 16 patients with glomerulopathy associated with schistosomiasis mansoni were evaluated (proteinuria and levels of BUN and creatinine) before therapy, 1 week, 1 month, 2-3 months and 6 months after therapy of the parasitic infections. During the follow-up of such cases no benefit could unquestionably be demonstrated in the patients. Also, no permanent deterioration of renal function related to anti-parasitic therapy could be documented. It is concluded that the treatment of the S. mansoni infection, once the consequent glomerulopathy is clinically apparent, does not influence the clinical course of the disease.

[Ectopic cutaneous schistosomiasis caused by Schistosoma mansoni]. / Esquistossomose cutânea ectópica por Schistosoma mansoni.

A case of cutaneous schistosomiasis with lesions on the trunk caused by eggs of Schistosoma mansoni is described. A brief review of the reported cases of cutaneous ectopic schistosomiasis by S. mansoni in made. The different forms of cutaneous lesions caused by schistosoma are considered.

Anti-schistosomal drugs: observations on the mechanism of drug resistance to hycanthone, and on the involvement of host antibodies in the mode of action of praziquantel.

This paper reports recent observations from our laboratory dealing with the anti-schistosome drugs hycanthone (HC) and praziquantel (PZQ). In particular, we discuss a laboratory model of drug resistance to HC in Schistosoma mansoni and show that drug sensitive and resistant lines of the parasite can be differentiated on the basis of restriction fragment length polymorphisms using homologous ribosomal gene probes. In addition, we summarize data demonstrating that effective chemotherapy of S. mansoni infection with PZQ in mice requires the presence of host anti-parasite antibodies. These antibodies bind to PZQ treated worms and may be involved in an antibody-dependent cellular cytotoxicity reactions which result in the clearance of worms from the vasculature.

Evolution of the schistosomal hepatic lesions in mice after curative chemotherapy.

Mice with 64-day-old Schistosoma mansoni infection (+/- 27 worms, 8-12 pairs) were treated simultaneously with oxamniquine and hycanthone. The cure rate was 100%, and changes occurring thereafter in the liver were sequentially followed by means of histologic, ultrastructural, and immunofluorescence methods. Soon after treatment, hepatitic changes cleared up and periovular granulomas diminished in size. The predominant Type III collagen in granulomas was reduced, and the Type I showed no apparent increase, whereas Type IV did not seem to participate in the process. Collagen fibrils in periovular granulomas changed in texture from dense and more oriented to loose and disorganized. Fibroblasts, at first with marked signs of hyperfunction, became less so at a time when collagen fragments appeared within secondary lysosomes in macrophages and fibroblasts. Schistosomal ovular antigens remained sequestered inside the fibrotic granulomas up to the final, 39th day after treatment. Thus, specific treatment of schistosomiasis showed a beneficial effect upon the hepatic lesions from the very beginning and promoted changes in the periovular granulomas that indicated a rapid, although incomplete, resorption of fibrosis.

Schistosoma mansoni: chemotherapy of infections of different ages.

Mice were treated with potassium antimony tartrate, hycanthone, oxamniquine, niridazole, or praziquantel at different times after infection with Schistosoma mansoni. The rate of cure was assessed by perfusion of surviving worms approximately 4 weeks after treatment, and the percentage reduction in worm burden was estimated relative to the number of adult worms perfused from control mice, comparably infected but untreated. All six drugs were relatively inactive against S. mansoni between 3 and 4 weeks after infection when compared with treatment at 5 to 6 weeks. However, the drugs differed in the patterns of cure they achieved in the 2-week period after administration of cercariae and in the period around the onset of patency. Worms that had been subjected to amoscanate or hycanthone in the third week after infection showed evidence of this as adults in having a reduced fecundity. Factors such as worm or host physiology, or host immune status may have had roles in the outcome of chemotherapy at different stages of maturation of S. mansoni.

Schistosoma mansoni: reduced efficacy of chemotherapy in infected T-cell-deprived mice.

The effect of host immunosuppression on the efficacy of schistosomicidal chemotherapy has been tested in T-cell-deprived CBA mice infected with Schistosoma mansoni. The drugs hycanthone, oxamniquine, and praziquantel were found to kill fewer adult S. mansoni worms in deprived mice than in comparably infected strain-, age-, and sex-matched, immunologically intact controls. Inconsistent results were obtained with niridazole, and amoscanate was as effective in deprived mice as in controls. The possibility that hycanthone, oxamniquine, praziquantel, and previously studied antimony act synergistically with immune effector mechanisms in killing adult schistosomes is discussed.

The effect of repeated targeted mass treatment on the prevalence of schistosomiasis mansoni and the intensity of infection in Machakos, Kenya.

In a valley in Machakos District, Kenya, the entire population was surveyed in 1976 for the presence and number of eggs of Schistosoma mansoni in their faeces. All persons with 300 or more eggs g-1 faeces were then treated with a single dose of hycanthone, 1.5 mg kg-1 body-weight. A re-survey was carried out in 1977, followed by the treatment of all persons with 200 or more eggs g-1 faeces. After another re-survey in 1978, all persons with 100 or more eggs g-1 were treated. The final survey was carried out in 1981. It was found that the treatment of persons with a high egg output had a pronounced effect on the intensity of infection in the total population, but that, after a first considerable drop in the prevalence rate, further decreases were much smaller. Continuing moderate prevalence rates in very young children were an indication of continuing transmission.