Pharmacology of Rasagiline, a New MAO-B Inhibitor Drug for the Treatment of Parkinson’s Disease With Neuroprotective Potential.
Pharmacology of Rasagiline, a New MAO-B Inhibitor Drug for the Treatment of Parkinson’s Disease with Neuroprotective Potential.
Rambam Maimonides Med J. 2010 Jul; 1(1): e0003
Finberg JP
Rasagiline (Azilect) is a highly selective and potent propargylamine inhibitor of monoamine oxidase (MAO) type B. Like other similar propargylamine inhibitors, rasagiline binds covalently to the N5 nitrogen of the flavin residue of MAO, resulting in irreversible inactivation of the enzyme. Therapeutic doses of the drug which inhibit brain MAO-B by 95% or more cause minimal inhibition of MAO-A, and do not potentiate the pressor or other pharmacological effects of tyramine. Metabolic conversion of the compound in vivo is by hepatic cytochrome P450-1A2, with generation of 1-aminoindan as the major metabolite. Rasagiline possesses no amphetamine-like properties, by contrast with the related compound selegiline (Deprenyl, Jumex, Eldepryl). Although the exact distribution of MAO isoforms in different neurons and tissues is not known, dopamine behaves largely as a MAO-A substrate in vivo, but following loss of dopaminergic axonal varicosities from the striatum, metabolism by glial MAO-B becomes increasingly important. Following subchronic administration to normal rats, rasagiline increases levels of dopamine in striatal microdialysate, possibly by the build-up of ?-phenylethylamine, which is an excellent substrate for MAO-B, and is an effective inhibitor of the plasma membrane dopamine transporter (DAT). Both of these mechanisms may participate in the anti-Parkinsonian effect of rasagiline in humans. Rasagiline possesses neuroprotective properties in a variety of primary neuronal preparations and neuron-like cell lines, which is not due to MAO inhibition. Recent clinical studies have also demonstrated possible neuroprotective properties of the drug in human Parkinsonian patients, as shown by a reduced rate of decline of symptoms over time. HubMed – drug
AIDS and drug rationing.
J Med Ethics Hist Med. 2010; 3: 1
Sharif PS, Noroozi M
Financial shortage in resource-limited and poor countries restricts treatment in HIV-infected patients especially in poor countries. Higher HIV prevalence in poorer countries makes drug rationing a real concern. Different countries solve the problem with different methods regarding WHO guidelines, but fairness and equity should be a major consideration in drug rationing. This paper is aimed at reviewing different strategic approaches to drug rationing in AIDS treatment and then discusses pharmacists’ role. In conclusion, there is no fair and equitable strategy, and in each society, cultural, ethical and socioeconomic issues along with considering a critical role for pharmacists must be taken into account. HubMed – drug
Epidermal growth factor receptor exon 20 mutation increased in post-chemotherapy patients with non-small cell lung cancer detected with patients’ blood samples.
Transl Oncol. 2013 Aug; 6(4): 504-10
Wang Y, Bao W, Shi H, Jiang C, Zhang Y
Patients with non-small cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR)-mutations have excellent response to EGFR tyrosine kinase inhibitors (TKIs), and exon 20 mutation accounts for most of TKI drug resistance. Nested polymerase chain reaction (PCR) was used to detect EGFR exon 20 mutations of patients with NSCLC after chemotherapy. The same is being analyzed with patients’ characteristics.Peripheral blood samples were collected from 273 patients with NSCLC, including 143 with adenocarcinoma (ADC) and 130 with squamous cell carcinoma (SCC), after chemotherapy. DNA was extracted from whole blood for nested PCR amplification and purification. Sequencing was carried out in an automated 3730 sequencer, followed by analysis of EGFR exon 20 mutations from nested PCR products.The mutations of EGFR exon 20 were mainly point mutations in rs1050171 (c.2361A>G) and rs56183713 (c.2457G>A). The point mutation was 28.21%, 28.46%, and 27.97% in patients with NSCLC, ADC and SCC, respectively. Men had an equivalent mutation (27.18%) to women (30.77%). The mutation in smokers and nonsmokers was 27.68% and 29.17%, respectively. In unselected patients, there was no correlation between EGFR exon 20 mutations and patients’ characteristics of age, gender, smoking history, histologic type, or tumor-node-metastasis (TNM) staging system. In subgroup analyses, the EGFR mutation of patients with SCC was correlated with TNM stage [P = .013; odds ratio = 1.758; 95% confidence interval (CI) = 1.125-2.747].The data indicate that the chemotherapy may induce EGFR-TKI-resistant mutation in NSCLC cells and EGFR-TKI should be used in the early stage of NSCLC but not after chemotherapy. HubMed – drug
Role of Intracellular and Extracellular MicroRNA-92a in Colorectal Cancer.
Transl Oncol. 2013 Aug; 6(4): 482-92
Yamada N, Nakagawa Y, Tsujimura N, Kumazaki M, Noguchi S, Mori T, Hirata I, Maruo K, Akao Y
Colorectal cancer is one of the leading causes of cancer-related death worldwide. Previous studies have shown that miR-92a has an oncogenic function in several cancers and that its up-regulation is correlated with malignant clinicopathologic behaviors of colorectal cancer. It also has been suggested that circulating miR-92a in patients’ plasma can be a potential biomarker for colorectal cancer. However, the precise roles of intracellular and extracellular miR-92a are not yet understood. In this study, we examined the expression levels of miR-92a in colorectal tumors (38 cancer specimens and 56 adenoma specimens) and paired adjacent nontumorous tissues. Increased expression of miR-92a was frequently observed in the cancers compared with that in the adenomas and was correlated with advanced clinical stages, tumor depth, and size. We also demonstrated that the levels of miR-92a within microvesicles (MVs) in the plasma of mice bearing colon cancer xenografts were significantly increased compared with those in control mice. One of the roles of intracellular and extracellular miR-92a was shown to be down-regulation of Dickkopf-3 (Dkk-3), a presumed tumor suppressor gene. Within the colon cancer cells, suppression of Dkk-3 by miR-92a contributed to the cell proliferation. Extracellular miR-92a packed within MVs secreted by colon cancer cells was delivered into endothelial cells and contributed to the proliferation and motility of these cells through down-regulation of the same target gene, Dkk-3. These data suggest that intracellular and extracellular miR-92a had important roles in tumor growth and the tumor microenvironment in colorectal cancer. HubMed – drug
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