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Biomedical subjects

Farhad Kamali

Publications and source records attributed to Farhad Kamali.

15 recordsLinked to original sources
PubMed2006

Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin.

Patients receiving warfarin who have unstable control of anticoagulation have a significantly lower intake of dietary vitamin K compared with their stable counterparts. We hypothesized that supplementation with oral vitamin K would improve stability in patients with previously unstable control of anticoagulation. Seventy warfarin-treated patients with unstable anticoagulation control were randomly assigned in a double-blinded fashion to receive a daily amount of 150 mug oral vitamin K or placebo orally for 6 months. Measures of stability of anticoagulation control in the 6-month study period were compared with those in the 6 months immediately prior to it. Vitamin K supplementation resulted in a significantly greater decrease in standard deviation of international normalized ratio (INR) compared with placebo (-0.24 +/- 0.14 vs -0.11 +/- 0.18; P < .001) and a significantly greater increase in percentage time within target INR range (28% +/- 20% vs 15% +/- 20%; P < .01). Anticoagulation control improved in 33 of 35 patients receiving vitamin K supplementation; of these, 19 fulfilled our criteria for having stable control of anticoagulation. However, only 24 of 33 patients receiving placebo demonstrated some degree of improvement, with only 7 patients fulfilling the criteria for having stable control. Concomitant supplementation of vitamin K, perhaps through reducing the relative day-to-day variability in dietary vitamin K intake, can significantly improve anticoagulation control in patients with unexplained instability of response to warfarin.

Aged↗
PubMed2006

Appraisal of current vitamin K dosing algorithms for the reversal of over-anticoagulation with warfarin: the need for a more tailored dosing regimen.

Warfarin is the most commonly prescribed oral anticoagulant in the UK for the treatment and prevention of thromboembolic disorders. Vitamin K administration is an effective way of reversing excessive anticoagulation. Over-anticoagulated patients present with a wide range of international normalized ratio (INR) values and may respond differently to a fixed dose of vitamin K. Current dosing algorithms for vitamin K administration in the non-urgent treatment of over-anticoagulation do not take this variability in response into account. Consequently, over a third of over-anticoagulated patients still remain outside their target INR 24 h after treatment. Such patients are therefore prone to either haemorrhage (if the patient is still over-anticoagulated) or thromboembolism (if the INR reversal is over-corrected). A number of factors such as patient age, body weight, co-morbidity, frailty, warfarin daily dose and CYP2C9 and VKORC1 polymorphism could affect response to vitamin K and thus the rate and extent of INR reversal. There is a need for a more individualized approach to the reversal of over-anticoagulation in asymptomatic or mildly haemorrhagic patients in order to improve the safety of warfarin therapy.

Aged↗
PubMed2006

APOE genotype makes a small contribution to warfarin dose requirements.

Alterations in vitamin K availability can significantly influence anticoagulation response to warfarin. Apolipoprotein E (APOE) plays a part in the hepatic uptake of lipid-soluble vitamin K. This study aimed to determine the influence of common polymorphisms in the APOE gene on warfarin dose requirements. patients with stable anticoagulation control and with a target International Normalized Ratio (INR) 2.0-3.0 were genotyped for the APOE epsilon2, epsilon3 and epsilon4 variants. Mean +/- SD daily warfarin doses were significantly lower in patients carrying at least one epsilon4 allele compared to the epsilon3epsilon3 reference genotype (3.3 +/- 1.9 versus 4.0 +/- 1.8; P = 0.03; 95% CI: 0.1-1.2). Multivariate regression analysis showed that patient age, height and CYP2C9, VKORC1 and APOE genotypes significantly contributed to warfarin dose requirement (R = 57%). only the epsilon4 allele of APOE was found to make a significant (P = 0.002) but small contribution to warfarin dose requirement. There was no significant difference in fasted plasma vitamin K concentration between patients with the different APOE genotypes. This study suggests that APOE genotype is unlikely to have a clinically significant effect on warfarin dose requirements.

Adult↗
PubMed2006

Genetic influences on the response to warfarin.

PURPOSE OF REVIEW: Warfarin has a narrow therapeutic index and there is wide interindividual variability in the drug dose requirement. Uncertainty of response renders currently used loading regimens inaccurate as they fail to take into account individual patient factors that have a major influence on anticoagulation response. This review focuses on recent research findings demonstrating the impact of genetics on warfarin sensitivity and dose requirement and the issues concerning the clinical utility of individualized therapy. RECENT FINDINGS: Single-nucleotide polymorphisms in cytochrome P450 2C9 and vitamin K epoxide reductase have been shown to make significant contributions to the variability in warfarin dose requirements. Polymorphisms in other genes that mediate the actions of warfarin make little or no contribution to the variability. Racial and cultural differences influence dose requirements, which can be explained at least in part by genetic and dietary factors. SUMMARY: Individualization of therapy based on genetic and environmental factors has the potential to reduce the adverse effects associated with the commencement of warfarin therapy. Prospective studies that incorporate both CYP2C9 and VKORC1 genes and environmental factors in warfarin dose calculation will be required to demonstrate the safety, cost-effectiveness, and feasibility of individualized dosing regimens.

Anticoagulants↗
PubMed2006

The future prospects of pharmacogenetics in oral anticoagulation therapy.

Coumarins are the mainstay of oral anticoagulation for the treatment and prophylaxis of thromboembolic disorders. They have a narrow therapeutic index and regular monitoring is therefore required to avoid serious adverse effects. There is wide interindividual variability in dosage requirements, which makes anticoagulation response unpredictable. Current dosing titrations are haphazard and inconvenient and poor initial control leads to morbidity, and occasional mortality, because of bleeding and further thromboembolism. Recent discoveries have helped to characterize the factors that contribute to the interindividual variability in responses to coumarins. Patient and environmental factors that affect anticoagulation response to coumarins include age, body size, dietary vitamin K status, concurrent disease and drug interactions. More recently, single nucleotide polymorphisms in the 2C9 isoform of cytochrome P450 (CYP2C9) and vitamin K epoxide reductase (VKOR) have been shown to make significant contributions to the variability in coumarin dosage requirements. Polymorphisms in other genes that mediate the actions of coumarins may also contribute to this variability. Racial and cultural differences influence dosage requirements, which can be explained, at least in part, by genetic and dietary factors. Incorporation of genetic and environmental factors could help in the prediction of more individualized loading and maintenance doses for safer anticoagulation therapy.

Administration, Oral↗
PubMed2005

The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen.

Current dosing algorithms do not account for genetic and environmental factors for warfarin dose determinations. This study investigated the contribution of age, CYP2C9 and VKORC1 genotype, and body size to warfarin-dose requirements. Studied were 297 patients with stable anticoagulation with a target international normalized ratio (INR) of 2.0 to 3.0. Genetic analyses for CYP2C9 (*2 and *3 alleles) and VKORC1 (-1639 polymorphism) were performed and venous INR and plasma R- and S-warfarin concentrations determined. The mean warfarin daily dose requirement was highest in CYP2C9 homozygous wild-type patients, compared with those with the variant *2 and *3 alleles (P < .001) and highest in patients with the VKORC1 (position -1639) GG genotype compared with those with the GA genotype and the AA genotype (P < .001). Mean warfarin daily dose requirements fell by 0.5 to 0.7 mg per decade between the ages of 20 to 90 years. Age, height, and CYP2C9 genotype significantly contributed to S-warfarin and total warfarin clearance, whereas only age and body size significantly contributed to R-warfarin clearance. The multivariate regression model including the variables of age, CYP2C9 and VKORC1 genotype, and height produced the best model for estimating warfarin dose (R2 = 55%). Based upon the data, a new warfarin dosing regimen has been developed. The validity of the dosing regimen was confirmed in a second cohort of patients on warfarin therapy.

Adult↗
PubMed2005

Patients with unstable control have a poorer dietary intake of vitamin K compared to patients with stable control of anticoagulation.

Evidence suggests that alterations in the dietary intake of vitamin K can affect anticoagulation response to warfarin. It is possible that a low and erratic intake of dietary vitamin K is at least partly responsible for the variable response to warfarin in patients with unstable control of anticoagulation. Twenty-six patients with unstable and twenty-six with stable control of anticoagulation completed dietary records of all foods and drinks consumed on a daily basis for two consecutive weeks. The mean daily intake of vitamin K in unstable patients was considerably lower than that for stable patients during the study period (29+/-17 microg v . 76+/-40 microg). The logarithm of vitamin K intake was consistently and significantly lower in the unstable patients than the stable patients over the two week period (5.9+/-0.4 microg v. 6.9+/-0.5 microg; p<0.001; 95% CI: 0.7-1.2). Changes in vitamin K intake between weeks 1 and 2 of the study were negatively correlated with changes in International Normalised Ratio (INR) amongst the unstable patients, however this failed to reach significance (r=-0.25; p=0.22). Daily supplementation with oral vitamin K in unstable patients could lead to a more stable anticoagulation response to warfarin.

Adult↗
PubMed2005

V-10153 (Vernalis).

Vernalis is developing V-10153, a recombinant plasminogen activator stimulator, for the potential treatment of thrombotic disorders and cardiovascular disease. By March 2004, a phase II trial in acute myocardial infarction had been completed, and by July 2005, Vernalis intended to initiate a phase II trial in stroke later that same year.

Animals↗
PubMed2004

Contribution of age, body size, and CYP2C9 genotype to anticoagulant response to warfarin.

OBJECTIVE: Our objective was to assess the contribution of CYP2C9 genotype, age, body size, and vitamin K and lipid status to warfarin dose requirements. METHODS: Patients with stable warfarin dose requirements and an international normalized ratio (INR) of the prothrombin time within the target range of 2.0 to 3.0 were recruited to the study. On arrival at the clinic in the morning, after an overnight fast, a blood sample was taken from each patient for CYP2C9 genotyping and for determination of venous INR and plasma vitamin K, R- and S-warfarin, and triglyceride concentrations. RESULTS: A total of 121 patients were recruited to the study. CYP2C9 genotyping showed that 74 patients were homozygous wild-type (*1/*1), 30 were heterozygous *1/*2, and 15 were heterozygous *1/*3 genotype. One patient was found to have the genotype *2/*3, and another was found to have the genotype *3/*3. The mean warfarin daily dose requirement in milligrams fell from 4.06 +/- 1.72 mg in homozygous wild-type patients to 3.63 +/- 1.78 mg for *1/*2-positive patients and 2.70 +/- 1.36 mg for *1/*3-positive patients. The multiple linear regression model for warfarin dose indicated significant contributions from age (r = 0.41, P <.001), genotype (r = 0.24, P <.005), and age and genotype together (r = 0.45, P <.005). Although there were significant linear correlations between warfarin dose and body surface area (r = 0.21, P =.02), body weight (r = 0.25, P =.005), and plasma vitamin K concentration (r = 0.18, P <.05), none of these variables made a significant contribution to the regression model for warfarin dose. CYP2C9 genotype had a significant effect on S-warfarin clearance (r = 0.34, P <.0001) but none on R-warfarin clearance. CONCLUSION: This study showed that age and CYP2C9 polymorphism affect warfarin dose requirements in patients receiving long-term therapy and having stable control of anticoagulation. It is anticipated that using dosing regimens modified to take into account the contribution of age and CYP2C9 genotype has the potential to improve the safety of warfarin therapy.

Adult↗
PubMed2004

Upstream and coding region CYP2C9 polymorphisms: correlation with warfarin dose and metabolism.

OBJECTIVES: To assess whether CYP2C9 alleles other than CYP2C9*2 and *3 are associated with a low-warfarin dose requirement and the relevance of upstream CYP2C9 polymorphisms to dose requirement and metabolism. METHODS: CYP2C9 exons, intron-exon boundaries and 3 kb of upstream sequence in 20 patients requiring or= 0.01, was obtained. In individuals negative for coding region polymorphisms, neither individual genotypes for T-1188C or DeltaG-2664DeltaT-2665 or particular combinations of haplotype pairs were predictive of dose requirement or S-warfarin total clearance, suggesting neither upstream polymorphism was functionally significant. Dose requirements in CYP2C9*11 heterozygotes were not statistically significantly different from homozygous wild-type individuals. CONCLUSIONS: The coding region non-synonymous polymorphisms associated with the CYP2C9*2 and CYP2C9*3 alleles are the major CYP2C9-related factor affecting warfarin dose in UK Caucasians. Upstream CYP2C9 polymorphisms do not appear to be important independent determinants of dose requirement.

Aged↗
PubMed2004

The value of education and self-monitoring in the management of warfarin therapy in older patients with unstable control of anticoagulation.

Of 125 patients aged 65 years or over, with atrial fibrillation taking warfarin for at least 12 months, with a standard deviation (SD) of prothrombin time, expressed as the International Normalized Ratio (INR) >0.5 over the previous 6 months, 40 were randomized to continue with usual clinic care and 85 to receive education about warfarin. Of these, 44 were randomized to self-monitor their INR and 41 returned to clinic. Compared with the previous 6 months there was a significant increase in percentage time within the therapeutic range for the 6 months following education [61.1 vs. 70.4; mean difference 8.8; 95% confidence interval (CI): -0.2-17.8; P = 0.054] and following education and self-monitoring (57 vs. 71.1; mean difference 14.1; 95% CI: 6.7-21.5; P < 0.001), compared with those patients following usual clinic care (60.0 vs. 63.2; mean difference 3.2; 95% CI: -7.3-13.7). Using the same comparative periods, the INR SD fell by 0.24 (P < 0.0001) in the group allocated to education and self-monitoring, 0.26 (P < 0.0001) in the group receiving education alone and 0.16 (P = 0.003) in the control group. Inter-group differences were not statistically significant (intervention groups 0.26 +/- 0.30 vs. control 0.16 +/- 0.3, P = 0.10). Quality-of-life measurements and health beliefs about warfarin were unchanged (apart from emotional role limitation) with education or education and self-monitoring. Patient education regarding anticoagulation therapy could be a cost-effective initiative and is worthy of further study.

Aged↗
PubMed2003

Warfarin sensitivity: be aware of genetic influence.

BACKGROUND: avoidance of over anticoagulation in response to warfarin therapy would reduce risk of associated bleeding. SUBJECTS: two elderly patients with venous thromboembolism exhibited extreme anticoagulant response to warfarin. Both were noted to have variant CYP2C9 alleles, which reduce the metabolic capacity of cytochrome P450 2C9. DISCUSSION: adverse outcomes with warfarin therapy could be explained and possibly avoided by identifying patients with variant alleles for CYP2C9 before initiation of therapy.

Aged↗
PubMed1998

Analgesic effects of lamotrigine and phenytoin on cold-induced pain: a crossover placebo-controlled study in healthy volunteers.

The analgesic activity of a single dose of lamotrigine (300 mg p.o.) and phenytoin (300 mg p.o.) was evaluated in a randomised, double-blind, placebo-controlled study in 12 healthy volunteers. A computerised cold-pressor test (CPT) was used to measure analgesia. Dihydrocodeine (90 mg p.o.) was used to validate the effectiveness of the CPT in measuring analgesia in the volunteers. On each study day the volunteers performed the CPT before study medication and at 1.25, 2.75, 4.25 and 5.75 h post-dose. Psychomotor tests were carried out before each CPT to determine possible drug-induced sedation. These included digit symbol substitution, critical flicker fusion and choice reaction time. Subjective feelings of concentration, vigilance and relaxation were also measured using visual analogue scales. All three active drugs significantly reduced pain scores. Maximum pain relief was achieved at 1.25 h post-dose for both dihydrocodeine and lamotrigine, whereas for phenytoin it occurred at 4.25 h post-dose. There was a significant association between analgesia and plasma concentrations of lamotrigine (P = 0.013) and phenytoin (P = 0.028). There were no significant differences in the sedation produced by any of the active drugs, compared to placebo. The findings of this study suggest that lamotrigine and phenytoin could have a wider clinical use as analgesics.

Adult↗