Cardioprotection mechanism of mangiferin on doxorubicin-induced rats: Focus on intracellular calcium regulation

Context: The molecular mechanism of doxorubicin (DOX) cardiotoxicity involves overproduction of free radicals that leads to intracellular calcium dysregulation and apoptosis. Mangiferin (MGR), a naturally occurring glucosylxanthone, has antioxidant and cardioprotective properties. However, its cardioprotection mechanism has yet to be revealed.

Objective: This study determines whether the cardioprotective effect of MGR is caused by its effect on intracellular calcium regulation.

Materials and methods: Male Sprague–Dawley rats were induced by DOX intraperitoneally with a total dose of 15?mg/kg bw. MGR was given orally at the doses of 30 and 60?mg/kg bw/d for seven consecutive weeks. The parameters examined were mRNA expression levels of proinflammatory cytokine gene (TNF-α), calcium regulatory gene (SERCA2a) and proapoptotic genes (caspase-9 and caspase-12), as well as cytosolic and mitochondrial calcium levels.

Results: Treatment with MGR at 60?mg/kg bw/d significantly decreased the mRNA expression levels of TNF-α by 44.55% and caspase-9 by 52.79%, as well as the cytosolic calcium level by 24.15% (p?<?0.05). SERCA2a and caspase-12 expressions were only slightly affected (27.27% increase and 24.85% decrease for SERCA2a and caspase-12, respectively, p?>?0.05). Meanwhile, MGR 30?mg/kg bw/d gave insignificant results in all parameters.

Discussion and conclusion: MGR protected against DOX-induced cardiac inflammation and apoptosis via down-regulation of proapoptotic and proinflammatory gene expressions, upregulation of SERCA2a gene expression, and normalization of cytosolic calcium level. Thus, the cardioprotective effect of MGR is at least in part due to the regulation of intracellular calcium homeostasis.     

Current status of phase I clinical trials in Asia: an academic perspectives

Clinical trials increasingly occured in Asia during the past years as pharmaceutical industries embraced globalization in the clinical research fields. The trend is true with phase III clinical trials but not for early stage/phase I clinical trials in Asian countries is still under-represented. The conduct of phase I clinical trials is considered more sophisticated and difficult than the later stage clinical trials. There are continuing concerns from the pharmaceutical industries about the capacity of Asian countries in conducting this type of clinical trials. We highlighted several problems concerning the ethical and scientific issues, the implementation of ICH-GCP and local regulations, investigators and clinical trial subjects. The purpose of this paper is to give some perspectives addressing the problems in conducting phase I clinical trials. Improving collaboration and capacity building among the Asian countries is a solution that we proposed in order to increase the quality and quantity of phase I clinical trials in Asian countries.     

Open study on efficacy and safety of levofloxacin in treatment of uncomplicated typhoid fever

The main objective of this study was to determine the clinical efficacy and safety of levofloxacin in an open setting for typhoid fever cases. Patients with clinical signs and symptoms of typhoid fever without previous antimicrobial treatment admitted to affiliated hospitals of the Faculty of Medicine, University Indonesia were included in this study. Adults, 18 years or above, were screened for any serious underlying conditions, pregnancy or possible complications of typhoid fever before final enrollment. Fifty-three subjects were screened, 48 were enrolled. The final diagnosis of enteric fever was made by positive blood culture, polymerase chain reaction or serology, was obtained in 31 cases, in whom one had a concomitant sinus infection and had to be excluded. Thirty patients (11 males, 19 females) aged between 18-58 years (mean 31.7 years) with a history of fever between 1 and 10 days (mean 6.1 days) showed excellent clinical response, becoming afebrile at an average of 2.43 days (range 1-5 days). Adverse effects noted were nausea in 4 patients, vomiting in one and meteorism in another one, which were all difficult to distinguish from the enteric infection. A pruritic rash occurring in two patients may be related to levofloxacin, and insomnia in another patient may be related. Microbiological clearance was obtained both immediately after treatment and at one month. No carrier states were detected in the cases positive for Salmonella typhi or paratyphi. None of the treated typhoid fever cases experienced a clinical relapse. In this open study of levofloxacin 500 mg/day for one week in treatment of uncomplicated typhoid fever, a 100% clinical efficacy was obtained in 30 patients with minimal adverse reactions warranting more intensive studies for this new indication of an old but well known disease in the developing world.