Recent Developments in the Chemotherapy of Schistosomiasis

Archer, Sydney; Yarinsky, Allen

doi:10.1007/978-3-0348-7081-8_1

Cited by 14 publications

(7 citation statements)

References 93 publications

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“…The effects of thioxanthenone compounds on schistosomes are not reversible (SENFT et ah, 1976) and in the present study no evidence was seen from the morphology of the gastrodermis to suggest a recovery by the parasite after drug administration was stopped. Hycanthone produced much more intense changes in the gastrodermis than did Lucanthone, and this observation corresponds with reports that Hycanthone is three times more effective against schistosomes in mice than Lucanthone (ARCHER & YARINSKY, 1972).…”

Section: Discussionsupporting

confidence: 90%

Schistosoma mansoni: an in vivo study of drug-induced autophagy in the gastrodermis

Clarkson¹,

Erasmus²

1984

J. Helminthol.

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The effects of Astiban, Lucanthone, Hycanthone and Niridazole on autophagic activities in the gastrodermis of Schistosoma mansoni were determined in vivo, using different dosage levels and dosage times. With Astiban, high levels of autophagy were observed in the gastrodermis 2 hours after an injection of the drug into the mouse, and this response had declined by 20 hours, marking a recovery by the parasite from the drug. Hycanthone and Lucanthone produced an autophagic response several days after the onset of treatment, and no recovery was observed in the morphology of the gastrodermis after the drug was discontinued. The effects of Niridazole on the gastrodermis were to produce the most dramatic ultrastructural changes after high doses and over several days of treatment. With all the drugs examined, gastrodermal autophagy was characterized by the formation of vacuoles containing cell components, lipid droplets and sometimes hydrolytic enzyme reaction product. The autophagic vacuoles appeared to be formed by the sequestration of cytoplasmic material by the basal membrane infoldings, and the transfer of enzymes into the vacuole from within the limiting membrane. The residues from intracellular digestion appeared to be emptied into the caecal lumen.

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Section: Discussionsupporting

confidence: 90%

Schistosoma mansoni: an in vivo study of drug-induced autophagy in the gastrodermis

Clarkson¹,

Erasmus²

1984

J. Helminthol.

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“…As an exception to these parallel types of behavior, HC has been reported to be active against S. haematobium (Archer and Yarinsky 1972), whereas OXA has very little, if any, eect on this species (Foster and Cheetham 1973). In this report we present evidence to show that such a dierence is compatible with the proposed similarity in the mechanism of action of the two drugs and can be attributed to dierences in the activating enzymes of the two parasite species.…”

Section: Introductionsupporting

confidence: 75%

“…Since previous data regarding the eects of HC and OXA on Schistosoma haematobium were obtained in vivo (Archer and Yarinsky 1972;Foster and Cheetham 1973) and could thus, in principle, be related to a different metabolic processing of the two drugs in the host, we ®rst set out to determine whether similar results could be reproduced in an in vitro system. The survival of adult male schistosomes kept in culture after a 45-min period of exposure to OXA or HC is presented in Fig.…”

Section: Resultsmentioning

confidence: 99%

Enzymatic basis for the lack of oxamniquine activity in Schistosoma haematobium infections

Pica‐Mattoccia¹,

Novi²,

Cioli³

1997

Parasitology Research

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The notion that oxamniquine is active against Schistosoma mansoni but inactive against S. haematobium was confirmed using in vitro cultures of adult worms. Since oxamniquine and hycanthone have been shown to become effective upon activation by a schistosome enzyme, enzymatic tests were carried out to detect possible differences between the enzyme of S. mansoni and that of S. haematobium. It was found that the S. mansoni enzyme could activate hycanthone and, to a lesser extent, oxamniquine. The S. haematobium enzyme, on the other hand, was capable of activating hycanthone but virtually incapable of activating oxamniquine. It is concluded that the different activity of oxamniquine in the two species is due to differences in the drug-activating enzyme.

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“…OXA was used to treat millions of people with results comparable to those of PZQ, with respect to safety and efficacy. However, OXA is only effective against the adult worm stage of S. mansoni, HYC is effective against the adult worm stage of S. mansoni and S. haematobium but has been shown to be a carcinogen ( Archer and Yarinsky, 1972 ; Haese and Bueding, 1976 ; Hartman and Hulbert, 1975 ) and thus has fallen out of use. Drug resistance against OXA has been demonstrated in the laboratory and in the field ( Rogers and Bueding, 1971 ; Katz et al, 1973 ).…”

Section: Introductionmentioning

confidence: 99%

Rational approach to drug discovery for human schistosomiasis

LoVerde

Alwan

Taylor

et al. 2021

International Journal for Parasitology: Drugs and Drug Resistan

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Human schistosomiasis is a debilitating, life-threatening disease affecting more than 229 million people in as many as 78 countries. There is only one drug of choice effective against all three major species of Schistosoma , praziquantel (PZQ). However, as with many monotherapies, evidence for resistance is emerging in the field and can be selected for in the laboratory. Previously used therapies include oxamniquine (OXA), but shortcomings such as drug resistance and affordability resulted in discontinuation. Employing a genetic, biochemical and molecular approach, a sulfotransferase (SULT-OR) was identified as responsible for OXA drug resistance. By crystallizing SmSULT- OR with OXA, the mode of action of OXA was determined. This information allowed a rational approach to novel drug design. Our team approach with schistosome biologists, medicinal chemists, structural biologists and geneticists has enabled us to develop and test novel drug derivatives of OXA to treat this disease. Using an iterative process for drug development, we have successfully identified derivatives that are effective against all three species of the parasite. One derivative CIDD-0149830 kills 100% of all three human schistosome species within 5 days. The goal is to generate a second therapeutic with a different mode of action that can be used in conjunction with praziquantel to overcome the ever-growing threat of resistance and improve efficacy. The ability and need to design, screen, and develop future, affordable therapeutics to treat human schistosomiasis is critical for successful control program outcomes.

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Recent Developments in the Chemotherapy of Schistosomiasis

Cited by 14 publications

References 93 publications

Schistosoma mansoni: an in vivo study of drug-induced autophagy in the gastrodermis

Schistosoma mansoni: an in vivo study of drug-induced autophagy in the gastrodermis

Enzymatic basis for the lack of oxamniquine activity in Schistosoma haematobium infections

Rational approach to drug discovery for human schistosomiasis

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