Orientalist Perspectives in Ellis’s Breadwinner Trilogy: A Postcolonial Critique

The study critically engages with the issue of continuity of the orientalist rhetoric in the contemporary literary yields. To establish and substantiate the argument, the researchers have analyzed Deborah Ellis’s Breadwinner Trilogy (2009) that comprises Breadwinner, Parvana’s Journey, and Mud City. All the three fictional narratives claims to have represented the life of the Pakistani and Afghani characters who have been shown to face the existential threats in the wake of the insecurities that have engulfed the region. However, the study contends, the Canadian writer has also given way to the parochial psychological and sociological schema that has been held as the prime representational trope regarding the East, that is, Orientalism. The qualitative and textual approach has facilitated the researchers to negotiate the identified thematic patterns with the interpretive freedom. In this regard, framing the fictional representation into the Saidian critique of the orientalist discourse, the study explicates the reductive approach of the writer and exposes the latent ideological triggers working under the manifest humanist projections. Thus, the study strengthens the postcolonial stance and, therefore, will sharpen the Pakistani students’ understanding of the current socio-literary debates.

The Impact of Gender and Menopausal Status on the Pharmacokinetics of Omeprazole and Rosuvastatin

Gender difference and genotypic polymorphism may affect the clinical outcome and therapeutic effectiveness of drugs. Current study was based on the same concept. Physiologically, males and females differ in body composition, body mass index, body fats proportion, plasma volume, blood flow and organ size. Gender differences also exist in expression of drug transporters and drug metabolizing enzymes due to hormonal disparity that may affect plasma drug levels. Hormonal fluctuations during menstrual cycle are considered to be the underlying cause for differences in pharmacokinetics of drugs. Similarly, hormonal changes in menopause affect physiology of females that may lead to the variations in the pharmacokinetics of drugs. It has been reported that females experience frequent side effects of the drugs compared with the males. Genotype is also a potential determinant of enzymatic activity. Genetic polymorphism of CYP2C19 may affect metabolism of omeprazole and individuals are classified as homozygous poor metabolizers (Homz PMs), homozygous extensive metabolizers (Homz EMs) and heterozygous poor metabolizers (Htrz PMs). The prevalence of PMs is 19-23% in Asians. Omeprazole (5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulphinyl]-1H-benzimidazole) is a pyridinylsulfinylbenzimidazole compound and a prototype member of proton pump inhibitors. It is used for the treatmentof gastro esophageal reflux disease (GERD), Zollinger-Ellison syndrome and hyperacidity. Omeprazole is primarily metabolized by CYP2C19 and CYP3A4 to 5-hydroxy- viii omeprazole and omeprazole-sulphone, respectively. FDA warns that hip bone and spine fracture is associated with prolonged use of omeprazole that may accelerate osteoporosis in postmenopausal females. Rosuvastatin(3R,5S,6E)-7-[4-(4-fluorophenyl)-2-(Nmethylmethanesulfonamido)-6-(propan-2-yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid) is a 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitor that reduces blood cholesterol level. Rosuvastatin is used for the primary prevention of cardiovascular events. Rosuvastatin is only 10% metabolized by CYP2C9 and 90% is excreted unchanged through hepatobiliary secretion. Females are mostly underrepresented in most of the clinical trials arranged for Statin. Therefore, there is scarcity of data on the therapeutic effectiveness and safety of statins in females. In present study, the impact of gender, menopause and CYP2C19 genotype on pharmacokinetics of omeprazole and rosuvastatin was evaluated. Reversed phase High Performance Liquid Chromatography (RP-HPLC-UV) method was developed and validated for the quantitative analysis of omeprazole and rosuvastatin. Stock solutions (I mg/ml) of omeprazole, 5-hydroxy-omeprazole, omeprazole-sulphone and pantoprazole (internal standard) in methanol was prepared. Blood samples were collected in heparinized tubes and centrifuged at 5000 rpm at 0°C for 5 minutes in order to separate plasma that was stored at -20 °C until analysis. Plasma samples were thawed at room temperature extracted and analyzed using RP-HPLC coupled with UV detector. Genotyping of CYP2C19 was determined by Tetra primer polymerization chain reaction (PCR) assay. ix The single oral dose, open-label, clinical trial was designed to study PK parameters in all present studies. Pharmacokinetic study of omeprazole, 5-hydroxyomeprazole, omeprazole-sulphone and rosuvastatin was performed in general Pakistani population (n = 32) while comparative study was conducted between males (n = 16) and female (n = 16), premenopausal (n = 16) and postmenopausal females (n = 8) and during menstrual cycle where study was repeated for three time according to the menstrual phase. Pharmacokinetics of omeprazole and 5-hydroxy-omeprazol was also evaluated according to the CYP2C19 genotype. During the clinical trials, the volunteers fasted overnight and no juice, caffeine or food intake was allowed except water. At about 8.00 am, each volunteer received omeprazole capsule (40 mg) with a full glass of water (ca ≈ 250 ml). The blood samples (≈ 5 ml) were collected at 0.0, 0.5, 1.0, 2, 3, 4, 6 and 8 hours, centrifuged to separate the plasma and stored at -20°C till analysis. The samples were analyzed using RP-HPLC. The same protocol was adopted for rosuvastatin after one month of completion of omeprazole study. The plasma concentrations of omeprazole, 5-hydroxy-omeprazole, omeprazolesulphone and rosuvastatin were plotted on linear scale as a function of time while PK parameters were calculated using PK summit Soft-ware. Statistical analysis was performed to calculate mean ± SD values of PK parameters. Significant pharmacokinetic differences of omeprazole, 5-hydroxy-omeprazole and omeprazole sulphone were observed in male and female volunteers. The high AUC and low CL were observed in females compared with males. x During menstrual cycle, the AUC of omeprazole was high in follicular phase while metabolic ratios for 5-hydroxy-omeprazole and omeprazole-sulphone were insignificantly higher in luteal phase (high progesterone level). The finding suggests that progesterone stimulates CY2C19 and CYP3A4 activity. The AUC of omeprazole was high in postmenopausal compared with premenopausal females while CL was low in postmenopausal females. The metabolic ratios of 5-hydroxy-omeprazole and omeprazole-sulphone were higher in premenopausal females that reflect higher activities of CYP2C19 and CYP3A4 in premenopausal females, respectively. Pharmacokinetic differences based on CYP2C19 genotype were also observed. Higher AUC of omeprazole was observed in homozygous poor metabolizers (CYP2C19*3 in homozygous state) compared with homozygous extensive metabolizers whereas while higher AUC of 5-hydroxy-omeprazole was observed in homozygous extensive metabolizers. The finding showed that metabolism of omeprazole was high in homozygous extensive metabolizers carrying CYP2C19*1 allele in homozygous state while CYP2C19*3 was responsible for genetically deficient metabolism. The AUC of rosuvastatin was significantly higher in females while CL was slow compared with males however; AUC of rosuvastatin was low in postmenopausal females compared with premenopausal females. In current investigation, significant PK differences for omeprazole and rosuvastatin were observed in males and females, premenopausal and postmenopausal xi females and during menstrual cycle. The present results showed the variations in drug response (PK parameters) exist between males and females, in premenopausal and postmenopausal females and during menstrual cycle, these differences may have clinical impact particularly in multiple drug therapy where chances of drug-drug interaction increased.