PEGylated Interferon Beta-1a in the Treatment of Multiple Sclerosis – an Update.

PEGylated interferon beta-1a in the treatment of multiple sclerosis – an update.

Biologics. 2013; 7: 131-138
Reuss R

Current standard immunomodulatory therapy with interferons (IFNs) for relapsing-remitting multiple sclerosis (MS) exhibits proven, but limited, efficacy and increased side effects due to the need of frequent application of the drug. Therefore, there is a need for more effective and tolerable drugs. Due to their small size, optimization of therapy with IFNs in MS by PEGylation is feasible. PEGylation of an IFN means that at least one molecule of polyethylene glycol (PEG) is covalently added. This modification is a standard procedure to increase the stability, solubility, half-life, and efficacy of a drug, and is applied in several drugs and diseases. Currently, a therapy regimen applying PEG-IFN beta-1a in MS is being developed to achieve an optimized relationship between therapy-related side effects and pharmacokinetic/pharmacodynamic efficacy. Phase I studies demonstrated that subcutaneous PEG-IFN beta-1a at a dose of 125 ?g every 2 or 4 weeks might be at least as efficient and safe as the current standard therapy with IFN beta-1a. A global Phase III clinical study is investigating the efficacy of PEG-IFN beta-1a in terms of reduction of the relapse rate in relapsing-remitting MS patients. The latest primary safety and efficacy analysis after 1 year has revealed a favorable risk-benefit profile with no significant difference between dosing regimens. Compared to placebo, the annualized relapse rate was reduced by about one-third and new or newly enlarging T2 brain lesions were reduced by about one-third when dosing every 4 weeks or by two-thirds when dosing every 2 weeks. This presents a significant effect of the dosing interval, favoring administration every 2 weeks. Chronic administration of PEGylated proteins mostly at toxic concentrations causes vacuolation of renal epithelium in animals, which – along with the issue of occurrence of anti-PEG antibodies – has to be addressed by Phase IV studies. HubMed – drug


Application of Plant Metabonomics in Quality Assessment for Large-Scale Production of Traditional Chinese Medicine.

Planta Med. 2013 Jun 27;
Ning Z, Lu C, Zhang Y, Zhao S, Liu B, Xu X, Liu Y

The curative effects of traditional Chinese medicines are principally based on the synergic effect of their multi-targeting, multi-ingredient preparations, in contrast to modern pharmacology and drug development that often focus on a single chemical entity. Therefore, the method employing a few markers or pharmacologically active constituents to assess the quality and authenticity of the complex preparations has a number of severe challenges. Metabonomics can provide an effective platform for complex sample analysis. It is also reported to be applied to the quality analysis of the traditional Chinese medicine. Metabonomics enables comprehensive assessment of complex traditional Chinese medicines or herbal remedies and sample classification of diverse biological statuses, origins, or qualities in samples, by means of chemometrics. Identification, processing, and pharmaceutical preparation are the main procedures in the large-scale production of Chinese medicinal preparations. Through complete scans, plants metabonomics addresses some of the shortfalls of single analyses and presents a considerable potential to become a sharp tool for traditional Chinese medicine quality assessment. HubMed – drug


Condurango-glycoside-A fraction of Gonolobus condurango induces DNA damage associated senescence and apoptosis via ROS-dependent p53 signalling pathway in HeLa cells.

Mol Cell Biochem. 2013 Jun 27;
Bishayee K, Paul A, Ghosh S, Sikdar S, Mukherjee A, Biswas R, Boujedaini N, Khuda-Bukhsh AR

Gonolobus condurango plant extract is used as an anticancer drug in some traditional systems of medicine including homeopathy, but it apparently lacks any scientific validation. Further, no detailed study is available to suggest whether condurango-glycoside-A (CGA), a major ingredient of condurango serves as a potent anticancer compound. Therefore, we investigated apoptosis-inducing ability of CGA against cervix carcinoma cells (HeLa). ?-galactosidase-activity and DNA damage were critically studied at different time points; while induced DNA-damage was observed at 9-12th hours, senescence of cells appeared at a later stage (18th hour after CGA treatment), implicating thereby a possible role of DNA damage in inducing pre-mature cell senescence. Concurrently, the number of cells undergoing apoptosis increased along with increase in reactive oxygen species (ROS) generation. Expression of p53 was also up-regulated, indicating that apoptosis could have been mediated through p53 pathway. DCHFDA (4′,6-Diamidino-2-phenylindole dihydrochloride) assay, acridine orange/ethidium bromide staining and annexin V/PI assay results collectively confirmed that apoptosis was induced by increased ROS generation. Reduction in proliferation of cells was further evidenced by the cell cycle arrest at G0/G1 stage. Expression profiles of certain relevant genes and proteins like p53, Akt, Bcl-2, Bax, cytochrome c and caspase 3 also provided evidence of ROS mediated p53 up-regulation and further boost in Bax expression and followed by cytochrome c release and activation of caspase 3. Overall results suggest that CGA initiates ROS generation, promoting up-regulation of p53 expression, thus resulting in apoptosis and pre-mature senescence associated with DNA damage. HubMed – drug


Demethylzeylasteral exhibits dose-dependent inhibitory behaviour towards estradiol glucuronidation.

Eur J Drug Metab Pharmacokinet. 2013 Jun 27;
Liu SL, Zhang SY, Wang MJ, Jiang H, Yang YX, Chen L

The disturbance of estradiol level might induce the occurence of some diseases, including cancer. Estradiol is mainly metabolized through the conjugation reactions, including the sulfation and glucuronidation reactions. The present study tried to evaluate the inhibition of estradiol glucuronidation by the major ingredients of Tripterygium wilfordii Hook F. demethylzeylasteral. Selective ion monitoring at negative ion mode ([M + H](-) = 447) was employed to monitor the two glucuronides of estradiol. The reaction rate was determined through comparison of peak area of these two glucuronides. Lineweaver-Burk plot and Dixon plot were utilized to determine the inhibition kinetic type, and the inhibition kinetic parameters (K i ) were calculated using the second plot. Competitive inhibition of demethylzeylasteral towards the formation of two glucuronides of estradiol was demonstrated, and the K i values were calculated to be 453.3 and 110.9 ?M, respectively. All these results will remind us the risk of elevated serum concentrations of estradiol due to the inhibition of estradiol glucuronidation by demethylzeylasteral. HubMed – drug



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