DARU Journal of Pharmaceutical Sciences
Year:2013 | Volume:21 | Issue:5|Papers Count:11

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Background and purpose of the study: p38a is a member of mitogen-activated protein kinases (MAPK) considered as a prominent target in development of anti-inflammatory agents. Any abnormality in the phosphorylation process leads to the different human diseases such as cancer, diabetes and inflammatory diseases.Several small molecule p38a inhibitors have been developed up to now. In this regard, structural elucidation of p38 inhibitors needs to be done enabling us in rational lead development strategies.Methods: Various interactions of three potent inhibitors with p38a active site have been evaluated in terms of binding energies and bond lengths via density function theory and MD simulations.Results: Our comparative study showed that both ab initio and MD simulation led to the relatively similar results in pharmacophore discrimination of p38a inhibitors.Conclusion: The results of the present study may find their usefulness in pharmacophore based modification of p38a inhibitors.

Background and the purpose of the study: Modified androsterone derivatives are class of steroidal compounds with potential anticancer properties. Various steroidal derivatives containing substitution at position 16 have shown diversified pharmacological activities. In the present study, a new series of cytotoxic 16-(substituted benzylidene) derivatives of dehydroepiandrosterone (DHEA) were synthesized and evaluated against three different cancer cell lines.Methods: The cytotoxic 16-(substituted benzylidene) derivatives of DHEA were synthesized via aldol condensation of DHEA with corresponding benzaldehyde derivatives. The cytotoxic activity of synthesized derivatives was evaluated against three different cancer cells including KB, T47D and SK-N-MC cell lines by MTT reduction colorimetric assay.Results: The results indicated that 16-(substituted benzylidene) derivatives of DHEA could be served as a potent anti-cancer agent. The 3-cholro benzylidene derivatives of DHEA was the most potent synthesized derivative especially against KB and T47D cell lines (IC50 values were 0.6 and 1.7 mM; respectively).Conclusion: The cytotoxic potential of novel benzylidene derivatives of DHEA is mainly attributed to the position and nature of the substituted group on the benzylidene pendant.

Metformin as a biguanid drug entered to the market 50 years ago and now is generally recommended as the first-line treatment in type 2 diabetes, especially in overweight patients, however in recent years new indications for its use have emerged. It improves peripheral and liver sensitivity to insulin, reduces basal hepatic glucose production, increases insulin-stimulated uptake and utilization of glucose by peripheral tissues, decreases hunger and causes weight reduction.Recently, much attention has been made toward the possible kidney protective efficacy of metformin. Recent studies have proven that metformin, possesses antioxidant properties, too.

Poisoning morbidity and mortality is high in the developing world. Systems for care of poisoned patients differ markedly between countries. In this paper a comparison of two very different systems for the care of poisoned patients, is presented. Specifically, the role of poison centers and poison treatment centers in the US and Iran are contrasted. A systematic literature search was undertaken utilizing the PubMed, Scopus, and Google Scholar and the keywords “poison centers”, “treatment” “Iran” “United States of America” and 100 publications were identified.From these, relevant data were found in 23 publications. The information was double-checked and data were summarized herein.We find that the system of the care of poisoned patients relies heavily on certified poison centers in the US and that only a few hospitals have well developed medical toxicology services. In contrast, in Iran, the poison center system is somehow less developed and the care of poisoned patients is provided in centralized high volume hospital poison units.Although both the US and Iran have highly developed systems for the care of poisoned patients they are distinctly different. Comparative studies based on these systems could provide important data for developing countries with more rudimentary poison control and treatment facilities.

Phthalic acid esters (PAEs) have been employed in polymer materials as a plasticizer to form them more flexible, adhesive, and soluble. These compounds are mainly used in paints, varnishes, personal cares, cosmetics, paper coatings, and adhesives even in bottled waters, shampoo, body deodorant, hairspray, and gels. Phthalates are able to possess remarkable toxic variations depending on their structures. So far, Di- (2-EthylHexyl) Phthalate DEHP and Di-n-Butyl Phthalate DBP have been found to cause reproductive and developmental toxicities. The U.S. Environmental Protection Agency (EPA) classified DEHP as probable human carcinogen. To the best of our knowledge, phthalates showed diverse toxicity profiles according to their structures in the liver, kidneys, thyroid, and testes, which are involved in general toxicity. Furthermore, they are introduced as hormonally-active agents, because they can interfere with the endocrine system in human. Incidence of developmental abnormalities (like skeletal malformations and cleft palate, and undescended testes, lowering testes weight and anogenital distance) seems increasing via high exposure to phthalate metabolites. Although, increasing the capacity for phthalate free plasticizer productions is the first step to restrict the distribution of these toxic manmade compounds, finding the new ways for phthalate absorption from the soil in agricultural fields may have benefits. Also, evaluation and examination of diverse sources of medicinal and food plants to determine the level of phthalate accumulation in their organs are extremely recommended to avoid creating toxicity particularly in reproductive systems.

Human trypanosomiasis is a parasitic disease among poor people in Africa and Latin America. Therapy against African and American trypanosomiasis is based on a few drugs that often cause severe side-effects. Therefore, it is essential to develop drug discovery especially from natural origins. Sesquiterpenes, a diverse group of natural terpenoids, are found in essential oils of many plants and show a broad range of bioactivities. They act through multiple mechanisms in the chemotherapy of trypanosomiasis. Some of these active compounds contain hydroperoxides, aldehydes, alcohols, a, b-unsaturated  g-lactone and even halogenated moieties. Among the compounds reported, sesquiterpene lactones showed a potent anti-trypanosoma effect comparable with commercial trypanocidal drugs. Trypanocidal activity of sesquiterpene lactones mostly depends on the reaction between g-lactone moieties and nucleophile groups of trypanithione, which is essential for Trypanosoma defense against the oxidative stresses. Elatol is a sesquiterpenoid from marine algae, with a different structure and considerable trypanocidal activity which could be an interesting candidate for further antiprotozoal investigations. To develop novel drugs with higher efficacy and lower toxicity from natural products, this review summarizes the more recent information on trypanocidal activities of various sesquiterpenes.

ackground: Ferula species are reputed in folk medicine for the treatment of a variety of disorders. There have been sporadic reports on the chemopreventive and chemosensitizing activities of some terpenoid coumarin derivatives from the genus Ferula. The present study investigated the cytotoxic activity of 11 phytochemicals (conferone, farnesiferol A, acantrifoside E, mogoltadone, diversin, galbanic acid, herniarin, 7-isopentenyloxycoumarin, umbelliprenin, stylosin and tschimgine) from Ferula species together with a newly synthesized prenylated derivative of curcumin (gercumin II).Methods: Cytotoxic activity of phytochemicals was evaluated against ovarian carcinoma (CH1), lung cancer (A549) and melanoma (SK-MEL-28) cell lines using MTT assay.Results and conclusion: Overall, moderate cytotoxic activity was observed from the tested compounds with IC50 values in the micromolar range. The highest activity against CH1 and A549 lines was from conferone while stylosin and tschimgine were the most potent compounds against SK-MEL-28 line. In conclusion, the findings of the present investigation did not support a potent cytotoxic activity of the tested phytochemicals against CH1, A549 and SK-MEL-28 cell lines. With respect to previous reports, the beneficial impact of these phytochemicals in cancer therapy may be more attributable to their chemopreventive or chemosensitizing activity rather than direct cytotoxic effects.

Background of the Study: The propose of the present work was to develop chemically cross-linked polyvinyl alcohol-co-poly (methacrylic acid) hydrogel (PVA-MAA hydrogel) for pH responsive delivery of 5-Fluorouracil (5-FU).Methods: PVA based hydrogels were prepared by free radical copolymerization. PVA has been cross-linked chemically with monomer (methacrylic acid) in aqueous medium, cross-linking agent was ethylene glycol di-methacrylate (EGDMA) and benzoyl peroxide was added as reaction initiator.5-FU was loaded as model drug. FTIR, XRD, TGA and DSC were performed for characterization of copolymer. Surface morphology was studied by SEM. pH sensitive properties were evaluated by swelling dynamics and equilibrium swelling ratio at low and higher pH.Results: FTIR, XRD, TGA and DSC studies confirmed the formation of new copolymer. Formulations with higher MAA contents showed maximum swelling at 7.4 pH. High drug loading and higher drug release has been observed at pH 7.4.Conclusions: The current study concludes that a stable copolymeric network of PVA was developed with MAA. The prepared hydrogels were highly pH responsive. This polymeric network could be a potential delivery system for colon targeting of 5-FU in colorectal cancers.

Background: The possible mechanism (s) of inotropic and chronotropic effects of the extract from Rosa damascena (R. damascena) on heart was examined.Methods: Inotropic and chronotropic effects of four concentrations of the extract from R. damascena and isoprenaline were examined in isolated guinea-pig hearts perfused through aorta in a Langendorff model. All measurements were performed in three different groups: 1) In the presence and absence of propranolol, 2) In the presence and absence of methacholine and 3) In the presence of diltiazem (n=12 for each group).Results: In all groups both isoprenaline and the extract caused an increase in heart rate and contractility (p<0.05 to p<0.001). Only in group 1, the final concentration of isoprenaline in the absence of propranolol caused significant greater increase in heart rate compared to the extract (207.6 ± 11.0 compared to 162.6±11.8, p<0.01).The percent increase in heart contractility due to the final concentration of the extract in the absence (362.4±36.9 compared to 227.7±31.6, p<0.01) and presence of propranolol (577.1±62.9 compared to 357.5±45.6, p<0.001) in group 1 and absence (403.7±42.1 compared to 244.8± 18.9, p<0.005) and presence of methcholine (499.88±64.64 compared to 323.90±44.49, p<0.05) in groups 2 was significantly greater than the increase caused by isoprenaline.Conclusions: The results of this study suggest that inotropic and chornotropic effect of R. damascena is possibly due to the stimulatory effect of this plant on beta-adrenoceptors.

Background: In Japan, both incidence and mortality rates of cancers have continuously increased and medical costs are growing more rapidly than the overall economy of Japan. However, there is no consensus threshold for cost-effectiveness in medical care, and few studies have investigated cost-effectiveness of medical care in Japan.The present study was to determine the direct costs of molecular-targeting drugs that were recently approved in Japan through simple and quantitative calculations. Thus, we calculated an incremental cost-effectiveness ratio (ICER) and the cost per life-year gained (LYG) by using reported data from randomized clinical trials for various cancers.Methods: Between 2008 and 2011, we reviewed seven molecular-targeting drugs that were approved for treatment of five cancers in Japan. These drugs included Bevacizumab, sorafenib, sunitinib, temsirolimus, Lapatinib, and panitumumab. Direct cost, ICER, and LYG of the drugs were estimated from the randomized phase III clinical trial data referred to in package leaflets. Effectiveness was defined as the prolongation of both median overall survival (OS) and progression-free survival (PFS). Costs were calculated as those of molecular-targeting drugs.Subsequently, ICER was based on 1-month increases in both OS and PFS periods and 1% increases in OS, and LYG was determined.Results: Direct costs ranged from ¥724, 804 ($9, 060) to ¥1, 506, 628 ($18, 833). ICERs of the drugs ranged from ¥724, 804 ($9, 060) to ¥1, 506, 628 ($18, 833) for a 1-month increase in OS. For each month of PFS, ICERs ranged from ¥372, 243 ($4, 653) to ¥7, 399, 877 ($92, 498). The costs of Bevacizumab and sorafenib for treatment of HCC per 1% increase in OS were ¥376, 657 ($4, 708) and ¥313, 733 ($3, 922), respectively. LYG ranged from ¥8, 697, 650 ($108, 721) to ¥18, 079, 530 ($225, 994).Conclusions: Some molecular-targeting drugs are not cost-effective. Considering ethical and moral issues, we should establish economic endpoints to approve new drugs in Japan.