Schistosomiasis praziquantel

Piperazine fused polycyclic ring systems are unique in terms of structures and properties. Praziquantel 211 is the primary medication for human schistosomiasis, for which it is usually effective in a single dose treatment. As shown in Fig. 10, praziquantel consists of a ketopiperazine fused ring system. A co-crystal of praziquantel and glutathione-5-peroxidase of the helminth Schistosoma japonica was known [63]. Praziquantel binds in a channel joining the two xenobiotic substrate... 

Domling A, Khoury K (2010) Praziquantel and schistosomiasis. Angew Chem hit Ed (in press)... 

Roszkowski et have described a method for the enantioselective preparation of Praziquantel (PZQ) a pharmaceutical for the treatment of schistosomiasis and soil-transmitted helminthiasis. Starting with the imine (P) (readily available from phenylethyl amine, phthalyl anhydride and glycine) an asymmetric transfer hydrogenation yielded the chiral intermediate in 62 % ee, and the crude product was easily crystallized to the required high ee and converted into the Praziquantel as shown in Figure 1.34. 

The use of new transcriptome information for discovery of novel drug candidates is desirable, as the control of schistosomiasis relies mostly on the use of a single drug, praziquantel, a heterocyclic pyrazino-isoquinolone. This drug exerts multiple effects, such as damage to the tegumental membrane, changes in calcium flux and muscular contractions in the parasite by a mechanism or mechanisms that are not... 

The only internationally used drug effective for treating schistosomiasis is praziquantel. This drug induces a rapid influx into the worms of surrounding Ca2+, a process that leads to paralysis (Martin, 1997), and changes in the surface membrane architecture that lead to the exposure of worm antigens that are normally cryptic (Brindley and Sher, 1987). Parasites affected in this way become susceptible to antibody-mediated immune attack and are killed as a result of the synergistic actions of chemotherapy and the immune response (Doenhoff et al., 1987 Brindley etal., 1989). 

Observations on cattle schistosomiasis in the Sudan, a study in comparative medicine. V. The effect of praziquantel therapy on naturally acquired resistance to Schistosoma bovis. American Journal of Tropical Medicine and Hygiene 32, 1 370-1 374. 

Praziquantel was developed in the late 1970s (Gonnert and Andrews, 1 977) and tested in humans soon after (Katz et al., 1979 Santos et al., 1979). It has been identified by the World Health Organization (WHO) as the drug of choice for the treatment of schistosomiasis caused by S. mansoni, S. japonicum or 5. haematobium since 1982 (Andrews et al., 1983). The mechanism of praziquantel s anti-schistosomal activity remains unclear, but recent insights are reviewed in Chapter 14. More information about other uses for praziquantel for other flatworm diseases can be found in Chapter 12. 

Predecessors to praziquantel as the preferred treatment for schistosomiasis include oxamniquine, and the related compound hycanthone (Cioli et al., 1995). These drugs act by inhibiting nucleic acid synthesis, but only after parasite-mediated biotransformation of the drug by a schistosome enzyme (Cioli et al., 1993, 1985). Until relatively recently, oxamniquine continued to be the primary drug used to treat schistosomiasis in Brazil. 

The praziquantel-based programmes were very successful. The Ministry of Health estimated that throughout Egypt there was a decrease in S. mansoni prevalence from 39% in 1983 (Scott, 1937 Cline et al., 1989) to 12% in 1 996 (El-Khoby et al., 1 998). At present, the situation is even better in some historically endemic villages where prevalence rates are below 4% (El-Khoby et al., 2000). It is certain that praziquantel has dramatically reduced the human, social and economic impact of schistosomiasis in Egypt and other countries. As a testament to the impact of the drug, it is the cornerstone of a US 30 million Schistosomiasis Control Initiative targeting schistosomiasis-associated morbidity in sub-Saharan Africa (www.schisto.org). 

Degu, G., Mengistu, G. and Jones, J. (2002) Praziquantel efficacy against schistosomiasis mansoni in school-children in north-west Ethiopia. Transactions of the Royal Society of Tropical Medicine and Hygiene 96, 444-445. 

Dias, L.C., Pedro, R.J. and Debelardini, E.R. (1982) Use of praziquantel in patients with schistosomiasis mansoni previously treated with oxamniquine and/or hycanthone resistance of Schistosoma mansoni to schistosomicidal agents. Transactions of the Royal Society of Tropical Medicine and Hygiene 76, 652-659. 

Ernould, J.C., Ba, K. and Sellin, B. (1999) Increase of intestinal schistosomiasis after praziquantel treatment in a Schistosoma haematobium and Schistosoma mansoni mixed focus. Acta Tropica 73, 143-1 52. 

Fallon, P.G. and Doenhoff, M.J. (1 994) Drug-resistant schistosomiasis resistance to praziquantel and oxamniquine induced in Schistosoma mansoni in mice is drug specific. American journal of Tropical Medicine and Hygiene 51, 83-88. 

Gryseels, B., Nkulikyinka, F. and Coosemans, M.H. (1 987) Field trials of praziquantel and oxamniquine for the treatment of schistosomiasis mansoni in Burundi. Transactions of the Royal Society of Tropical Medicine and Hygiene 81, 641-644. 

Praziquantel (Fig. 14.1) is a pyrazinoiso-quinoline anthelmintic that was discovered in the 1970s and subsequently introduced for the treatment of schistosomiasis (reviewed by Andrews et al., 1983). It is an asymmetric molecule, and standard preparations are composed of equal proportions of levo (-) and... 

The effectiveness of praziquantel has been demonstrated repeatedly in large-scale schistosomiasis control efforts in various regions, but it has been severely underutilized in areas such as sub-Saharan Africa (reviewed by Fenwick... 

Wu, M.H., Wei, C.C., Xu, Z., Yuan, H.C., Lian, W.N., Yang, Q.J., Chen, M., Jiang, Q.W., Wang, C.Z. and Zhang, S.J. (1991) Comparison of the therapeutic efficacy and side effects of a single dose of levo-praziquantel with mixed isomer praziquantel in 278 cases of schistosomiasis japonica. American Journal of Tropical Medicine and Hygiene 45, 345-349. 

Schistosomiasis (bilharziasis) (see also p. 292). The causative organisms are trema-todes with a complex life cycle that need (aquatic) snails as intermediate hosts. Free-swimming larval cercariae penetrate the intact skin of humans. The adult worms (Schistosoma mansoni, D) live in the venous vasculature. Occurrence tropical countries rich in aquatic habitats. About 200 million humans are af icted. Therapy praziquantel, 10-40 mg/kg, single dose, is highly effective with minimal adverse effects. Substances released from decaying worms may cause problems. 

The treatment for all forms of schistosomiasis consists of praziquantel (30-45 mg/kg BW as a single dose). In severe courses of the disease or with an S. japonicum infection, 60 mg/kg BW daily, in 3 single doses, should be administered. A 6-day course of therapy with 30 mg/ kg BW/day is likewise recommended. S. mansoni is also effectively treated with oxamniquine (20 mg/kg BW/day for 3 days). (110, 114, 115, 121)... 

The Berkovitz group achieved the synthesis of praziquantel (164) (used to treat schistosomiasis) through an intramolecular imino Diels-Alder route (84JOC5269). They failed in the initial reaction using the methylol acetate. However, the less labile methoxy group of 162 worked reasonably well as a leaving group. Pyrolysis of precursor 162 in various solvents was unsuccessful, but succeeded in the gas phase (49%) (Scheme 23). 

Botros SS. Effect of praziquantel versus hycanthone on deoxyribonucleic acid content of hepatocytes in murine schistosomiasis mansoni. Pharmacol Res 1990 22(2) 219-29. 

Bloody diarrhea occurs in some patients, but it can be difficult to distinguish this as an adverse effect from pretreatment symptoms one Ethiopian study of the use of praziquantel in suspected schistosomiasis found that before treatment there was blood in the stool in 55% of cases, diarrhea in 61%, and abdominal discomfort in 80%, and the figures recorded the next day after treatment were not very different (21). 

It has been suggested that praziquantel can cause hepatomegaly and splenomegaly in children with schistosomiasis (22), but hepatomegaly and splenomegaly have also been described as complications of the disease in these young patients, and they regress with effective treatment (24). 

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