Risk of stroke in CYP2C19 LoF polymorphism carrier coronary artery disease patients undergoing clopidogrel therapy: An ethnicity-based updated meta-analysis.

BACKGROUND: Antiplatelet agent clopidogrel has been widely used for stroke management for many years, although resistance to clopidogrel may increase the chance of stroke recurrence. CYP2C19 loss-of-function (LoF) polymorphism is assumed to be responsible for the poor metabolism of clopidogrel that ultimately turns to resistance. Previous publications could not provide firm evidence due to highly conflicting and heterogeneous outcomes. AIM: To get clear evidence from an updated meta-analysis on CYP2C19 LoF polymorphism association with stroke risk in clopidogrel treated patients, this study has been performed. METHODS: We conducted a meta-analysis with 72 selected studies from authentic databases, including 40,035 coronary artery disease patients treated with clopidogrel. RESULTS: This analysis showed that the worldwide carrier of one or more CYP2C19 LoF alleles had a significantly higher risk of stroke and composite events than the non-LoF carriers (RR=1.78, 95% CI=1.52-2.07, p<0.00001 and RR=1.39, 95% CI=1.26-1.54, p<0.00001, respectively). Besides, subgroup analysis showed that Asian CYP2C19 LoF carriers had a significantly increased risk of stroke (RR=1.91, 95% CI=1.60-2.28, p<0.00001) while the risk of composite events was significantly higher in all ethnic populations (Asian: RR=1.58, 95% CI=1.32-1.89, p<0.00001; Caucasian: RR=1.27, 95% CI=1.08-1.50, p=0.003; Hispanic and others: RR=1.21, 95% CI=1.09-1.34, p=0.0003). CONCLUSION: Our meta-analysis confirmed that the presence of CYP2C19 LoF alleles increases the risk of stroke and composite events recurrence in the worldwide population, especially in Asians undergoing clopidogrel treatment. Alternative antiplatelet therapy should be investigated thoroughly for the intermediate and poor metabolizers.

Pharmacological investigation of analgesic and antipyretic activities of methanol extract of the whole part of Aeginetia indica.

ETHNOPHARMACOLOGICAL RELEVANCE: Aeginetia indica (Linn.), commonly known as aankuri bankuri, guan-jen-huang, forest ghost flower, dok din daeng, dapong tubo; is a root parasitic plant of the Orobanchaceae family native to South and South-East Asian region. Different parts of the plant are traditionally used to treat fever, pain, inflammation, arthritis, cough, diabetes, and chronic liver disease. Local practitioners often recommend this plant as a folk remedy for dermal swelling, painful menstrual periods, wounds, and knee pain. However, the antipyretic and analgesic activity of A. indica have never been investigated. AIM OF THE STUDY: The present study was aimed to evaluate the analgesic and antipyretic potential of Aeginetia indica plant extract to verify its effectiveness as reported in traditional uses. MATERIALS AND METHODS: Preliminary phytochemical analysis of Aeginetia indica crude extract was performed using previously established methods and antioxidant capacity was determined by phosphomolybdenum assay. In vivo analgesic activity of Aeginetia indica methanol extract (AiME) was evaluated by acetic acid-induced writhing test, formalin-induced paw licking test, and hot plate test model. The antipyretic activity was studied in Baker's yeast induced pyrexia model. RESULTS: Phytochemicals screening revealed cardiac glycosides, saponins, phenols, tannins, and flavonoids in the crude extract of Aeginetia indica. Total phenolic and flavonoid content were recorded as 101 ± 1.1 mg GAE/g of the extract and 35 ± 0.8 mg QE/g of the extract, respectively. The total antioxidant capacity observed in phosphomolybdenum assay was 68.3 ± 1.3 mg ascorbic acid equivalent per gram of the extract. AiME showed significant dose-dependent analgesic activity against acetic acid-induced writhing, formalin-induced paw licking, and hot plate pain model. A higher dose of A. indica (200 mg/kg) produced significant (P < 0.001) inhibition of writhing by 69% whereas, standard aspirin showed maximum 85.6% inhibition. AiME at all doses showed a significant (P < 0.001) decrease of paw licking time in both early neurogenic and late inflammatory pain phase of formalin-induced licking test. In the hot plate test, AiME at a 200 mg/kg dose produced antinociceptive activity (55.18%) higher than the standard ketorolac (49.88%) at 1 h. However, after 2 h, ketorolac showed a maximum effect of 62.66% and AiME 200 mg/kg showed a 60.24% effect. A significant (P < 0.001) reduction of rectal temperature (4.54 °F↓) was recorded for AiME 200 mg/kg, which was higher than the standard paracetamol (3.86 F°↓) after 24 h of treatment. CONCLUSION: The in vivo investigational studies' results demonstrated promising analgesic and antipyretic activities of A. indica, which supported the claim of its folk uses.

Antidiabetic and hepatoprotective potential of whole plant extract and isolated compounds of Aeginetia indica.

BACKGROUND: Aeginetia indica, a perennial herb from the Orobanchaceae family, generally grows as a root parasite and is widely distributed in the forests of South and South-Asian countries. The plant has valuable uses in herbal medicine against various diseases, such as diabetes, liver diseases, and arthritis. AIM OF THE STUDY: The present study was designed to investigate the antidiabetic and hepatoprotective effects of the methanol extract of the whole plant of A. indica in a mouse model followed by the isolation of bioactive compounds and their in-silico studies. METHODS: The hepatoprotective effects were evaluated in a paracetamol-induced hepatotoxicity mouse model. The antidiabetic effects were examined by an oral glucose tolerance test and in an alloxan-induced diabetes mouse model. RESULTS: The plant extract, at a dose of 400 mg/kg, caused a significant reduction (p < 0.001) in liver enzyme concentrations, including alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, similar to the effects of standard drug silymarin. The plant extract, at 400 mg/kg, also significantly reduced (p < 0.001) the fasting blood glucose concentration by 27.33 % after 3 h, compared with a reduction of 45.31 % in response to glibenclamide. In the alloxan-induced diabetes model mice, significant reductions (p < 0.05) in elevated glucose concentrations were observed on days 10 and 20 in mice treated with plant extract and glibenclamide. Chromatographic analyses and nuclear magnetic resonance (NMR) studies identified the presence of ß-sitosterol, stigmasterol, and oleic acid in the extract. The possible mechanism underlying the antidiabetic effects was revealed by molecular docking analyses examining the binding of ß-sitosterol and stigmasterol with sirtuin 4, an NAD-dependent deacylase enzyme that downregulates leucine-induced and glutamate dehydrogenase-induced insulin secretion. The binding affinities between sirtuin 4 and ß-sitosterol, stigmasterol, and NAD were found to be -8.6 kcal/mol, -7.2 kcal/mol and -9.5 kcal/mol, respectively, indicating the probable competition between NAD and the isolated components for sirtuin 4. CONCLUSION: The present study revealed that A. indica exerted protective effects against alloxan-induced diabetes and paracetamol-induced hepatotoxicity in mice, which supports the findings regarding the use of A. indica during traditional medical practice.

Association of TP53 Codon 72 Arg>Pro Polymorphism with Breast and Lung Cancer Risk in the South Asian Population: A Meta-Analysis.

BACKGROUND: A transversion missense polymorphism of the TP53 tumor suppressor gene at the codon 72 codes proline instead of arginine causes an altered p53 protein expression and has been found to be associated with an elevated risk of various cancer; especially breast and lung cancer. As the previous case-control studies on the South Asian population have shown controversial results, we performed a meta-analysis to evaluate a precise estimation of the relationship between the TP53 Arg72Pro polymorphism with breast and lung cancer. METHODS: A total of 12 related studies on the South Asian population have been included through comprehensive database searching. Six studies were selected for breast cancer meta-analysis involving 950 cases and 882 controls; the other six studies were for lung cancer meta-analysis including 975 cases and 1397 controls. The results have been determined by using the Review Manager (RevMan) 5.3. Additionally, the stability of our analysis was assessed by heterogeneity, publication bias analysis and sensitivity testing. RESULTS: A significantly increased risk of breast cancer was found in Pro allele (Pro vs. Arg), co-dominant model 2 (Pro/Pro vs. Arg/Arg), dominant model (Pro/Pro + Arg/Pro vs. Arg/Arg). In case of lung cancer, significantly increased risk was found in the allele, co-dominant 1, co-dominant 2, co-dominant 3, dominant, and recessive models. No association with other genetic models with breast and lung cancer risk was found in the South Asian population. CONCLUSIONS: Our results indicate that TP53 Arg72Pro polymorphism is a risk factor for the development of breast cancer and lung cancer in the South Asian population.