The DNA base excision repair protein Ape1/Ref-1 as a therapeutic and chemopreventive target

Schistosomiasis is a major disease of public health importance in humans occurring in over 70 countries of the tropics and sub-tropics In this chapter, the history of the control of schistosomiasis is briefly discussed and current methods of control of schistosomiasis are reviewed; including mollusciciding, biological control of the intermediate snail hosts, the development of drugs to kill the adult worms, provision of clean water and health education, with a focus on the African situation Since an effective vaccine against schistosomiasis is lacking, the emphasis today is placed on the drug praziquantel (PZQ) The marked reduction in the cost of PZQ together with the support of the Bill and Melinda Gates Foundation has enabled the drug to be used more widely in sub-Saharan Africa Nevertheless, with the possibility of resistance to praziquantel emerging, the potential role of other drugs, such as artemether, in the control of schistosomiasis is examined The World Health Organization (WHO) anticipates that at least 75% of all schoolchildren at risk of morbidity from schistosomiasis will be treated by 2010, with the aim of reversing morbidity The importance of recent international initiatives such as the Schistosomiasis Control Initiative (SCI) working in Mali, Niger, Burkina Faso, Zambia, Tanzania and Uganda is recognised There are benefits to integrating the control of schistosomiasis with other disease control programmes, such as gastrointestinal helminths and/or lymphatic filariasis (LF), since this markedly reduces the cost of delivery of the treatment Countries that are situated on the perimeter of the distribution of schistosomiasis have either achieved or have made progress towards the elimination of the disease For control programmes to be successful in areas such as sub-Saharan Africa, it is absolutely essential that these programmes are sustainable Thus, it will be vital for Ministries of Health and Education to budget for the control of diseases of poverty in addition to school health, and to utilise funds from a range of sources, such as, government funds, pooled donor contributions, or bilateral and international agencies

Implementation of Human Schistosomiasis Control: Challenges and Prospects

The current approach of morbidity control of schistosomiasis, a helminth disease of poverty with considerable public health and socioeconomic impact, is based on preventive chemotherapy with praziquantel. There is a pressing need for new drugs against this disease whose control entirely depends on this single drug that has been widely used over the past 40 years. We argue that a broader anthelminthic approach supplementing praziquantel with new antischistosomals targeting different parasite development stages would not only increase efficacy but also reduce the risk for drug resistance. Repositioning drugs already approved for other diseases provides a shortcut to clinical trials, as it is expected that such drugs rapidly pass the regulatory authorities. The antischistosomal properties of antimalarial drugs (e.g., semisynthetic artemisinins, synthetic trioxolanes, trioxaquines and mefloquine) and of drugs being developed or registered for other purposes (e.g., moxidectin and miltefosin), administered alone or in combination with praziquantel, have been tested in the laboratory and clinical trials. Another avenue to follow is the continued search for new antischistosomal properties in plants. Here, we summarise recent progress made in schistosomiasis chemotherapy, placing particular emphasis on repositioning of existing drugs against schistosomiasis.

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Controlling schistosomiasis with praziquantel: How much longer without a viable alternative?

Schistosomiasis is a widespread helminthic disease. Treatment of schistosomiasis is based on chemotherapy with praziquantel, which is the drug of choice. Since resistance to praziquantel has been demonstrated, alternative drugs must be considered. Myrrh is an oleo-gum resin from the stem of the plant Commiphora molmol. This study was carried out on 204 patients with schistosomiasis. The drug was given at a dose of 10 mg/kg of body weight/day for three days, and induced a cure rate of 91.7%. Re-treatment of cases who did not respond with a dose of 10 mg/kg of body weight/day for six days gave a cure rate of 76.5%, increasing the overall cure rate to 98.09%. The drug was well tolerated, and side effects were mild and transient. Twenty cases provided biopsy specimens six months after treatment and none of them showed living ova.

A safe, effective, herbal antischistosomal therapy derived from myrrh

Schistosomiasis affects 200 million individuals in underdeveloped and developing regions and is a growing concern for travelers worldwide. There has been evidence of resistance to the praziquantel-based therapy and reports of acute-disease manifestation; therefore, other drugs affecting different stages of the schistosome parasites life cycle and alternative therapeutic regimens should be developed and become accessible. The present review results from a comprehensive search in the scientific literature for substances and compounds tested in the past centennial for schistosomiasis therapy. We gathered over 40 drugs providing information on therapeutic action in humans or animal model, toxicity, susceptible Schistosoma stages, species, etc. The drugs were grouped according to their known metabolic effects on the parasite, whether they are on membrane structure and function, carbohydrate metabolism, protein synthesis and function, or on nucleic acid metabolism. We discuss the current knowledge of drug–target interactions, their mechanism of action and possible therapy combinations. Furthermore, based in the literature and in our own experience with large-scale Schistosoma mansoni genome and transcriptome analyses, we put forward several recently described gene products that are promising target candidates for existing or new drugs.

Schistosomiasis—a century searching for chemotherapeutic drugs

Schistosomiasis, a grave and debilitating disease of socioeconomic importance, is increasing in incidence despite concerted efforts to control and contain the disease in all the endemic areas. While a multipronged method of control using health education, sanitation and snail control has been used, chemotherapy and chemoprophylaxis play the most important and crucial role in containing/preventing the transmission of the disease. Schistosomicides such as antimonials were introduced, as early as the 1990s as the drugs of choice and continued to be used until the early 1960s. The antimonials were administered intravenously, and produced severe side effects; the various variables that determined their effects at the site of action made their application difficult and adversely affected their use in large scale chemotherapy. The antimonials were then replaced by hycanthone and lucanthone which were administered intramuscularly. These drugs produced immediate side effects such as hepatotoxicity and gastrointestinal disturbances, and were consequently withdrawn. It was then decided that the alternative was to produce synthetic drugs that could be administered orally. Niridazole, oxamniquine, and metrifonate were introduced as schistosomicidal agents, with drugs like oltipraz and amoscanate still at clinical trial phase. Therapeutic doses of drugs like hycanthone, niridazole and amoscanate have been found to cause many major side effects. A significant advance in the control of schistosomiasis chemotherapy is the introduction of a relatively safe, effective, broad spectrum oral helminthic agent, praziquantel. Studies have also shown that oxamniquine is as effective as praziquantel in eliminating intestinal S. mansoni infection, and metrifonate is as effective as praziquantel in eliminating urinary S. haematobium and S. mansoni infections. Praziquantel has been found to be effective in treating S. haematobium infections compared with metrifonate and more effective in treating S. mansoni infection when compared with oxamniquine. Because the drug is effective even when treating advanced hepatosplenic schistosomiasis, with few side effects, praziquantel is currently the drug of choice for the treatment of any kind of schistosomiasis. The only limitation is the cost which restricts its use in many developing countries. While effective, safe drugs for mass chemotherapy are being developed, the problem of therapeutic failure and drug resistance is being reported from certain developing countries. Under these circumstances, alternative drugs must be resorted to. Mass treatment, a crucial goal in the eventual control of schistosomiasis, awaits a well-tolerated and nontoxic drug that will ultimately prove to be effective where cure is definite. Until such a time, while eradication of the disease is a near impossibility, reducing the intensity of infection can ultimately reduce morbidity and even mortality.(ABSTRACT TRUNCATED AT 400 WORDS)

Shekhar Kc

Papers

Schistosomiasis Drug Therapy and Treatment Considerations