Praziquantel and Oltipraz: the treatment of schoolchildren infected with<i>Schistosoma mansoni</i>and/or<i>Schistosoma haematobium</i>in Gezira, Sudan

Tayeb, Marawan El; Daffalla, Asim Abdelrahman; Kardaman, Mohamed; See, Raymond H.; Fenwick, Alan

doi:10.1080/00034983.1988.11812208

Cited by 11 publications

(6 citation statements)

References 3 publications

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“…Moreover, the NOAEL in chronic toxicity studies conducted in rats and dogs for 26 weeks and 39 weeks, respectively, was 5 mg/kg/day, consistent with a previous report [28] . Oltipraz had been applied to humans at a dose of 30 mg/kg/day as a potential schistosomicidal agent [29] . Moreover, other dose regimens, including 6 months of 125 mg daily dosing and 30 days of intermittent dosing (200 mg × 2 or 500 mg/week), were well tolerated with no serious toxicities in human chemopreventive studies [30,31] .…”

Section: Discussionsupporting

confidence: 89%

Oltipraz therapy in patients with liver fibrosis or cirrhosis: a randomized, double-blind, placebo-controlled phase II trial†

Kim

Choi

et al. 2011

Journal of Pharmacy and Pharmacology

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Section: Discussionsupporting

confidence: 89%

Oltipraz therapy in patients with liver fibrosis or cirrhosis: a randomized, double-blind, placebo-controlled phase II trial†

Kim

Choi

et al. 2011

Journal of Pharmacy and Pharmacology

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“…One‐year chronic toxicity studies in rats and dogs showed that the safe dosage level of oltipraz estimated was approximately 10–30 mg/kg/day (60). Oltipraz was originally used as a potential schistosomicidal agent in humans at the daily dose of 30 mg/kg (61). In the present study, oltipraz at the daily equivalent dose of 13 mg/kg or less was highly efficacious as a treatment for LC.…”

Section: Discussionmentioning

confidence: 99%

Oltipraz regenerates cirrhotic liver through CCAAT/enhancer binding protein‐mediated stellate cell inactivation

et al. 2002

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Liver cirrhosis (LC) is a chronic disease with high mortality rate. In the United States and Western world as well as Asian countries, LC is the major leading cause of death by disease. Yet, no effective therapeutic agent is available for LC treatment. Laboratory cirrhotic rats produced by dimethylnitrosamine administrations simulate the clinical features of human LC such as mortality, ascites, hepatic parenchymal cell destruction, and formation of connective tissue and nodular regeneration, providing a preclinical model to evaluate therapeutic efficacy of drugs and the underlying mechanisms. Oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione] has been used clinically and is of little toxicity. Comprehensive mechanistic and phase IIa clinical studies supported the notion that oltipraz exerts chemopreventive effects against chemical carcinogenesis. We report here that oltipraz within the clinical dose range regenerates cirrhotic liver in the established LC rats as a result of reduction of the intensities of cirrhotic nodules, elimination of accumulated extracellular matrix, and inactivation of stellate cells, thereby improving survival rate. We also reveal that activation of CCAAT/enhancer binding protein by oltipraz inhibits transforming growth factor b1 gene expression in stellate cells, which provides a molecular target for pharmacological treatment of LC. Oltipraz is the first therapeutic agent that regenerates cirrhotic liver.

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“…Oltipraz, originally studied as a schistosomicidal agent, has been applied to humans at a daily dose of 30 mg/kg (El Tayeb et al, 1988). Oltipraz at 3 to 100 M induced GSTA2 in H4IIE cells, and 30 M oltipraz was sufficient to almost maximally increase GSTA2 level (Kang et al, 2003), as confirmed by the present study.…”

Section: Effects Of Oltipraz's Metabolites On C/ebp␤ and Nrf2mentioning

confidence: 99%

DIFFERENTIAL EFFECTS OF THE OXIDIZED METABOLITES OF OLTIPRAZ ON THE ACTIVATION OF CCAAT/ENHANCER BINDING PROTEIN-β AND NF-E2-RELATED FACTOR-2 FOR GSTA2 GENE INDUCTION

Lee²,

Kim

et al. 2006

Drug Metab Dispos

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ABSTRACT:Comprehensive mechanistic studies suggest that oltipraz exerts cancer chemopreventive effects through the induction of glutathione S-transferase (GST). Previously, we have shown that the activation of CCAAT/enhancer binding protein-␤ (C/EBP␤), promoted by oltipraz, contributes to the transcriptional induction of the GSTA2 gene. Studies also indicated that exposure of animals to oltipraz triggers nuclear accumulation of NF-E2-related factor-2 (Nrf2) with an increase in Nrf2's antioxidant response element (ARE) binding activity. Given the previous reports that C/EBP␤ activation contributes to oltipraz's induction of the GSTA2 gene and that Nrf2 activation by oltipraz was variable depending on the concentrations, this study investigated whether the major oxidized metabolites of oltipraz induce GSTA2 through the activation of C/EBP␤ and/or Nrf2. Immunoblot analysis revealed that M1 Oltipraz [4-methyl-5-(2-pyrazinyl)-1,2-dithiol-3-thione] has been studied as a chemopreventive agent for malignancies, such as liver and colorectal cancer (Rao et al., 1993;Kensler, 1997). Comprehensive mechanistic studies indicate that oltipraz exerts cancer chemopreventive effects through the induction of glutathione S-transferases (GSTs) (Bolton et al., 1993;Kensler, 1997). GST induction also accounts for the cytoprotective effect of oltipraz against toxicantinduced injury (Jaitovitch-Groisman et al., 2000;Nelson et al., 2002). A phase IIa randomized chemoprevention trial of oltipraz in residents of Qidong, China, showed that oltipraz might be clinically active as a chemopreventive agent. In the human studies, oltipraz dosage regimens with higher doses and a long-dosing interval seemed to be more efficacious in preventing cancer, as supported by a significant decline in the levels of aflatoxin-albumin adduct in the individuals receiving a higher dose of oltipraz (500 mg/week) (Jacobson et al., 1997;Jackson and Groopman, 1999;Wang et al., 1999).Exposure of experimental animals to oltipraz triggers nuclear accumulation of NF-E2-related factor-2 (Nrf2) Iida et al., 2004) and enhances Nrf2's antioxidant response element (ARE) binding activity (Pietsch et al., 2003). Diminished expression of phase II enzyme genes by oltipraz in the Nrf2 Ϫ/Ϫ mice supports the role of Nrf2 activation in its cancer chemopreventive effects Ramos-Gomez et al., 2001). Molecular signals activated by oxidative stress stimulate translocation of Nrf2 to the nucleus, where it binds and activates the AREs located in the promoter regions of phase II enzyme genes (Moinova and Mulcahy, 1998;Venugopal and Jaiswal, 1998;Huang et al., 2000).Studies from this laboratory showed that oltipraz at clinically relevant concentrations marginally increased the band intensity of Nrf2 ARE binding and thus weakly enhanced the accumulation of Nrf2 in the nucleus. Our results suggested that GSTA2 induction by oltipraz might be mediated by the activation of other transcriptional Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.doi:10...

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Praziquantel and Oltipraz: the treatment of schoolchildren infected withSchistosoma mansoniand/orSchistosoma haematobiumin Gezira, Sudan

Cited by 11 publications

References 3 publications

Oltipraz therapy in patients with liver fibrosis or cirrhosis: a randomized, double-blind, placebo-controlled phase II trial†

Oltipraz therapy in patients with liver fibrosis or cirrhosis: a randomized, double-blind, placebo-controlled phase II trial†

Oltipraz regenerates cirrhotic liver through CCAAT/enhancer binding protein‐mediated stellate cell inactivation

DIFFERENTIAL EFFECTS OF THE OXIDIZED METABOLITES OF OLTIPRAZ ON THE ACTIVATION OF CCAAT/ENHANCER BINDING PROTEIN-β AND NF-E2-RELATED FACTOR-2 FOR GSTA2 GENE INDUCTION

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