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|Year : 2011 | Volume
| Issue : 7 | Page : 208-210
Prof. Manjeet Singh Prize Paper Abstracts
|Date of Web Publication||13-Dec-2011|
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
. Prof. Manjeet Singh Prize Paper Abstracts. Indian J Pharmacol 2011;43, Suppl S1:208-10
Prof . Manjeet Singh Prize -1
Genetic polymorphisms of CYP2D6 increase the risk for recurrence of breast cancer in patients receiving tamoxifen as an adjuvant therapy
Damodaran SE , Pradhan SC, Umamaheswaran G, Kadambari D 1 , Reddy KS 2 , Adithan C.
Departments of Pharmacology, 1 Surgery, and 2 Radiotherapy, Jawaharlal Institute of Postgraduate Medical Education and Research, (JIPMER), Puducherry - 605 006, India.
Objectives: Tamoxifen is used as an adjuvant hormonal therapy in breast cancer. It is converted to the active metabolite endoxifen by CYP2D6. Variations in activity of CYP2D6 maybe a reason for the failure of tamoxifen therapy. Previous studies on the role of CYP2D6 genotype on tamoxifen therapy gave conflicting results and no such study has been performed in Indian population. Therefore, this study was done to evaluate the influence of CYP2D6 genetic polymorphisms on the recurrence of breast cancer in patients receiving tamoxifen. Materials and Methods: Patients receiving adjuvant tamoxifen were recruited for the study. Genotyping was carried out for CYP2D6 alleles *2, *4, *5 and *10. CYP2D6 activity score was calculated to determine the phenotype. The activity scores were compared between patients with recurrence and patients with no recurrence of breast cancer. Results: Of the 141 patients recruited, genotyping could be done only for 132 cases. CYP2D6 activity score ≤0.5 was associated with a statistically significant increased risk of recurrence (OR-12.37; 95% CI - 3.23, 47.33; p <0.001) and shorter recurrence free survival (52.68 ± 10.58 months, mean ± SEM; p <0.001), as was shown in Kaplan-Meir survival estimates, when compared to activity score ≥1. The hazard ratio for activity score ≤0.5 was 7.29 (p <0.001) when compared to activity score ≥1. The lower levels of endoxifen may be attributed to poor treatment outcomes in breast cancer patients. Conclusion: Reduced CYP2D6 activity is associated with increased risk of recurrence and shorter recurrence free survival in breast cancer patients on adjuvant tamoxifen therapy.
Prof. Manjeet Singh Prize -2
Salubrious role of modulator of nicotinamide adenine dinucleotide phosphate-oxidase (nadph-oxidase) in experimental hypertension induced vascular dementia
Bhupesh Sharma, Nirmal Singh
Pharmacology Division, Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala - 147 002, Punjab, India.
E-mail: [email protected]
Objectives: Vascular dementia (VaD) and hypertension are the conditions which are increasing at an alarming rate with a high degree of co-occurrence. We have investigated the effect of 4'-hydroxy-3'-methoxyacetophenone (HMAP), a selective inhibitor of nicotinamide adenine dinucleotide phosphate-oxidase (NADPH-Oxidase) in hypertension induced vascular dementia in Wistar Albino rats. Donepezil has served as positive control. Materials and Methods: Deoxycorticosterone acetate (DOCA) hypertension was used to induce VaD. Morris water-maze (MWM) was used for testing learning and memory. Endothelial function was assessed by acetylcholine induced endothelium dependent relaxation of aortic strips. Different biochemical estimations were used to assess oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species and brain glutathione), nitric oxide levels (serum nitrite/nitrate) and cholinergic activity (brain acetyl cholinesterase activity). Results: DOCA has increased mean arterial blood pressure in rats, these animals performed poorly on MWM hence reflecting impairment of learning & memory. DOCA also produced impairment of vascular endothelial function, and decrease in serum nitrite / nitrate levels, along with increase in aortic & brain oxidative stress levels and brain acetylcholinesterase activity. HMAP, a selective inhibitor of NADPH-oxidase as well as donepezil, an acetylcholinesterase inhibitor significantly attenuated, hypertension induced impairment of learning, memory, endothelial function, and changes in various biochemical parameters. Conclusion: Experimental hypertension has induced the VaD and NADPH-oxidase modulator may be considered as potential pharmacological agents for the management of hypertension induced vascular dementia. Key words: 4'-hydroxy-3'-methoxyacetophenone, deoxycorticosterone acetate, donepezil, endothelial dysfunction, Morris water maze.
Prof. Manjeet Singh Prize -3
Association of genetic polymorphisms of CYP2C9, VKORC1 with adverse effects of warfarin
Kannan S , Bendkhale S, Modi T, Gogtay NJ, Thatte UM
Department of Clinical Pharmacology, 1 st floor, New MS Building, Seth GS Medical College and KEM Hospital, Parel, Mumbai - 400 012, India.
Objectives: Various factors have been shown to increase the risk of bleeding with warfarin. This tudy aimed to assess the association of CYP2C9 and VKORC1 with the development of bleeding following warfarin. Materials and Methods: A case control study was initiated after obtaining institutional ethics committee clearance and written informed consent from patients. Cases were defined as those who bled within three months of warfarin initiation and controls as those who did not have any episode of bleeding within three months. Genotyping for CYP2C9 (*1, *2, *3) and VKORC1 1639 (GG, GA and AA) were performed by PCR-RFLP. Chi-square test was used to find out the association and trend of genotypes with odds ratio (95% CI) for strength of association. A binary logistic regression model was developed associating age, body weight, sex, CYP2C9 and VKORC1 with risk of bleeding. Results: A total of 100 controls and 38 cases studied from Oct 2009 to July 2011. A significant association (P < 0.0001) and trend (P = 0.027) of mutant alleles of CYP2C9 and VKORC1 were noted with bleeding with odds ratios of 7.8 (3.4, 17.9) and 2.683 (1.25, 5.74) respectively. Weekly dose requirement was significantly lower with the presence of *3 allele relative to *1 in CYP2C9 (P < 0.001). The regression model showed an accuracy of 80% and could explain 35.3% of the variability. Conclusion: A significant association between CYP2C9 (*1,*2,*3) genotype and VKORC1 (1639 G>A) haplotype status has been found with increased bleeding tendency to warfarin. This may help to individualize therapy.
Prof. Manjeet Singh Prize- 4
CYP2C9 and VKORC1 genetic polymorphisms decrease warfarin dose requirement in South Indian population
Madhan S , Krishna Kumar D, Dutta TK 1 , Balachander J 2, Adithan C.
Departments of Pharmacology, 1 Medicine, and 2 Cardiology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry - 605 006, India.
Objectives: Warfarin is an oral anticoagulant used in the prophylaxis and treatment of thromboembolisc disorder. CYP2C9 metabolises warfarin and Vitamin K epoxide reductase (VKOR) is the target enzyme for warfarin action. Previous studies have shown that genetic polymorphisms leading to variations in these enzymes result in interindividual variability in warfarin dose requirements. No study has been done in South Indian population. Therefore the study was done to evaluate the effect of CYP2C9 and VKORC1 genetic polymorphism on warfarin dosing requirements. Materials and Methods: Patients on warfarin with stable INR (2-3.5) for the past 3 months were recruited for the study. Patient characteristics and mean daily warfarin dose (MDWD) were obtained Genotyping was carried out for alleles CYP2C9*2 and *3 and VKORC1 -1639G>A. Genotype and MDWD were compared. Results: Of the 120 patients recruited for the study, genotyping could be done only for 116 of them. MDWD was significantly higher in CYP2C9 wild genotype when compared to the variant genotype (5.2±0.1 mg vs 4.5±0.3 mg, p<0.05). Similarly MDWD was significantly higher in normal genotype of VKORC1 -1639G>A when compared to the variant genotype (5.4±0.1 mg vs 3.6±0.3 mg, p<0.001). Multiple regression analysis for variables known to affect warfarin dose showed that only CYP2C9 and VKORC1 -1639G>A genotype were significantly associated and they together contributed to 30% variability in MDWD. Conclusion: The mean daily warfarin dose is higher in patients with normal genotypes of CYP2C9 and VKORC1 compared to those with variant genotypes and they together contribute to 30% variability in MDWD.
Prof . Manjeet Singh Prize -5
Interaction of diclofenac sodium and atorvastatin in rodent model of acute inflammationth
Tiwari S.A., Daswani B. R., Khalse M.S., Ghongane B.B.
Department of Pharmacology, B.J. Medical College, Pune - 411 001, Maharashtra, India.
Objectives: Diclofenac acts as anti-inflammatory via suppressing COX and Atorvastatin via mevalonate pathway but the outcome of the interaction between these two drugs has not been evaluated hence this study was planned to explore the same. Materials and Methods: 128 healthy albino rats divided in sixteen groups (n= 8) were used. These groups received a single dose of the following: Diclofenac 7.5, 15 or 30 mg/kg, Atorvastatin 2, 5 or 10 mg/kg either alone or in combination with each of the doses of Diclofenac orally as a suspension. These animals were subjected to acute inflammation by sub-plantar carrageenan injection and were evaluated for paw edema at 0, 3 and 6 hours. Results : Significant anti-inflammatory effect was noted with Diclofenac (15, 30 mg/kg) and Atorvastatin (10 mg/kg) (P< 0.005) whereas this was insignificant for Diclofenac 7.5 mg/kg and Atorvastatin 2 and 5mg/kg. Addition of Atorvastatin (2 or 5 mg/kg) to Diclofenac (7.5 mg.kg) increased its anti-inflammatory effect significantly as compared to Diclofenac 7.5 mg/kg alone (P< 0.005) and that was comparable to that of Diclofenac (15 mg/kg). However, addition of Atorvastatin 10 mg/kg to Diclofenac 15 or 30 mg/kg did not show any synergistic or additive effect. Conclusion: Combination of Atorvastatin (2 or 5 mg/kg) with Diclofenac (7.5 mg.kg) produced additive anti-inflammatory effect but this was not so with Atorvastatin 10mg/kg since this dose itself produced a ceiling anti-inflammatory effect. However, studies in chronic models of inflammation are needed to implement it clinically.
Prof . Manjeet Singh Prize -6
Effect of circadian rhythm disturbance on CFSO and CART peptide in the brain of rat
Gajanan P. Shelkar , Kartik T. Nakhate, Praful S. Singru 1 , Dadasaheb M. Kokare, Nishikant K. Subhedar 2
Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University Campus, Nagpur- 440 033, 1 School of Biological Sciences, National Institute of Science Education and Research (NISER), Institute of Physics Campus, Sachivalaya Marg, PO Sainik School, Bhubaneswar, 751 005, 2 Indian Institute of Science Education and Research (IISER), First Floor, Central Tower, Sai Trinity Building, Garware Circle, Sutarwadi, Pashan, Pune- 411 021, Maharashtra, India.
Objectives : To investigate the influence of circadian disturbance on endogenous cFos and cocaine- and amphetamine-regulated transcript peptide (CART) in association with feeding and anxiety-like behavior. Materials and Methods: Adult male rats were exposed to steady light environment for 14 days with a view to disrupt circadian rhythm. These rats were screened for feeding behavior and social interaction test for anxiety. Moreover, their brains were processed for immunohistochemical analysis of cFos and CART. Results : Constant light exposure caused anorexia for initial 3 days, although body weight was not affected. A significant reduction in social interaction time was observed on day 2 and 14. cFos containing cells were significantly increased following light exposure for day 2 or 14. In paraventricular nucleus (PVN), although cFos was increased in CART neurons on day 2, no significant change was noticed on day 14. Moreover, CART-immunoreactivity was reduced on day 2 in the fibers of central nucleus of amygdale (CeA), hypothalamic arcuate (ARC), PVN and suprachiasmatic (SCN) nuclei and in the cells of Edinger-Westphal nucleus (EW). Interestingly, on day 14, CART-immunoreactive fibers in PVN and ARC did not change, although immunoreactivity in ARC/EW cells and amygdala/SCN fibers was increased. CART-immunoreactive cells in PVN did not change across all the groups. Conclusions : Changes in cFos and CART activity in EW and SCN following constant light exposure may be associated with circadian disturbance. While the changes in ARC and PVN may reflects the diurnal disturbance related changes on feeding behavior, those in CeA might be associated with anxiety-related phenomenon.