Cyclosporine is a marketed immunosuppressive agent and a known substrate for CYP3A. Micafungin is an antifungal agent and a mild inhibitor of CYP3A‐mediated metabolism in vitro. The objectives of ...this study were to evaluate the pharmacokinetics of cyclosporine and micafungin before and with concomitant administration. The pharmacokinetics of single‐dose oral cyclosporine (5 mg/kg) were estimated on days 1, 9, and 15 (n = 27). Subjects received micafungin (100 mg/d over 1 hour) on days 7, 9, and 11 through 15. Micafungin pharmacokinetics were estimated on days 7, 9, and 15. Mean apparent oral cyclosporine clearances were estimated to be 645 ± 236 mL/h/kg, 546 ± 101 mL/h/kg (P = .01), and 540 ± 104 mL/h/kg (P = .02) for days 1, 9, and 15, respectively. Micafungin appears to be a mild inhibitor of cyclosporine metabolism.
Objective
The goal of this study was to define the haplotype structure of the cytochrome P450 (CYP) 2C9 gene in a European American population and evaluate associations between CYP2C9 haplotypes and ...anticoagulation‐related outcomes.
Methods
Genomic deoxyribonucleic acid from 192 European American patients stabilized on warfarin therapy was resequenced across 60 kilobases of the CYP2C9 genomic region, including all exons, dense sampling of introns, approximately 10 kilobases of the 5′‐flanking region, and approximately 1.7 kilobases of the 3′‐untranslated region.
Results
A total of 132 single nucleotide polymorphisms (SNPs) were detected, of which 47 were present in the 5′‐flanking promoter region, 11 in the exonic coding region, and 74 in the intron regions. Nine nonsynonymous SNPs in the coding region consisted of CYP2C9*2, *3, *9, *11, and *12; R125H; and 3 new structural variants. Sixty SNPs were present at a minor allele frequency of greater than 5%, and from this subpopulation, 23 haplotypes were inferred. Clustering analysis identified 6 major groups of related haplotypes that were further designated 1A, 1B, 1C, 1D, 2, or 3. The *2 and *3 SNPs appeared exclusively in groups 2 and 3, and these groups combined were associated with significantly reduced warfarin maintenance doses, longer time to stable dosing, and increased risk of bleeding. In contrast, combinations of haplotypes 1A, 1B, 1C, and 1D were not associated with differences in any of these outcomes.
Conclusion
These data establish a whole‐gene, high‐resolution haplotype structure for CYP2C9 in a European American patient population and suggest that genetic variation in exons, rather than the promoter or other regulatory regions, is largely responsible for warfarin sensitivity associated with CYP2C9 variants in this population.
Clinical Pharmacology & Therapeutics (2005) 77, 353–364; doi: 10.1016/j.clpt.2005.01.019
Tacrolimus is an approved immunosuppressive agent and a known substrate for CYP3A. Micafungin is an echinocandin antifungal agent and a mild inhibitor of CYP3A metabolism in vitro. The objectives of ...this study were to evaluate the pharmacokinetics of tacrolimus (5 mg oral) and micafungin (100 mg intravenous) alone and with concomitant administration (n = 26). Tacrolimus area under the concentration‐time curve was 298 ± 135 μg•h/L when tacrolimus was administered alone, 305 ± 129 μg•h/L (P = .8; confidence interval 89%, 118%) when tacrolimus was given with single‐dose micafungin, and 282 ± 138 μg•h/L (P = .4; confidence interval 82%, 107%) when tacrolimus was given with steady‐state micafungin. Despite the mild inhibition of CYP3A in vitro by micafungin, there does not appear to be a drug interaction with tacrolimus and micafungin either with single‐dose or steady‐state micafungin administration.
Personalizing intravenous (IV) busulfan doses in children using therapeutic drug monitoring (TDM) is an integral component of hematopoietic cell transplant. The authors sought to characterize initial ...dosing and TDM of IV busulfan, along with factors associated with busulfan clearance, in 729 children who underwent busulfan TDM from December 2005 to December 2008. The initial IV busulfan dose in children weighing ≤12 kg ranged 4.8‐fold, with only 19% prescribed the package insert dose of 1.1 mg/kg. In those children weighing >12 kg, the initial dose ranged 5.4‐fold, and 79% were prescribed the package insert dose. The initial busulfan dose achieved the target exposure in only 24.3% of children. A wide range of busulfan exposures were targeted for children with the same disease (eg, 39 target busulfan exposures for the 264 children diagnosed with acute myeloid leukemia). Considerable heterogeneity exists regarding when TDM is conducted and the number of pharmacokinetic samples obtained. Busulfan clearance varied by age and dosing frequency but not by underlying disease. The authors— group is currently evaluating how using population pharmacokinetics to optimize initial busulfan dose and TDM (eg, limited sampling schedule in conjunction with maximum a posteriori Bayesian estimation) may affect clinical outcomes in children.
Background Patients who screen positive for alcohol misuse on the Alcohol Use Disorder Identification Test Consumption Questionnaire (AUDIT-C ≥5 points) have significantly increased postoperative ...complications. Severe alcohol misuse (AUDIT-C ≥9 points) is associated with increased postoperative health care use; however, little is known about the prevalence of alcohol misuse in demographic and clinical subgroups of surgical patients. Methods The prevalence of alcohol misuse was evaluated among 10,284 patients (9,771 men and 513 women) who underwent major noncardiac surgery in Veterans Affairs (VA) hospitals during the fiscal years 2004 to 2006 and completed the AUDIT-C. Sex-stratified analyses evaluated prevalence rates of alcohol misuse (AUDIT-C ≥5) and severe misuse (AUDIT-C ≥9) across demographic and clinical subgroups. Results Overall, 1,607 (16%) men and 24 (5%) women screened positive for alcohol misuse (AUDIT-C ≥5) in the year before operation, with 4% and 2% screening positive for severe misuse (AUDIT-C ≥9), respectively. Alcohol misuse was more common among men who were <60 years of age, divorced or separated, current smokers, or American Stoke Association class 1 or 2, and those with cirrhosis/hepatitis or substance use disorders. Among patients with alcohol misuse, 36% of men and 58% of women were American Society of Anesthesiologists class 1 or 2, and most did not have diagnoses that were commonly associated with alcohol misuse. Conclusion Alcohol misuse is relatively common in male surgical patients. Moreover, surgical patients undergoing operation who screen positive for alcohol misuse are often relatively healthy, without health problems that might alert providers to their alcohol misuse in the absence of screening.
This study projects prosthetic- and assistive-device costs for veterans with limb loss from Vietnam and injured servicemembers returning from Operation Iraqi Freedom (OIF) and Operation Enduring ...Freedom (OEF) to inform the Department of Veterans Affairs (VA) for these veterans' future care. The 2005 Medicare prosthetic device component prices were applied to current prosthetic and assistive-device use obtained from a national survey of 581 veterans and servicemembers with major traumatic amputations. Projections were made for 5-year, 10-year, 20-year, and lifetime costs based on eight Markov models. Average 5-year projected costs for prosthetic and assistive-device replacement for the Vietnam group are lower than for the OIF/OEF cohort due in part to use of fewer and less technologically advanced prosthetic devices and higher frequency of prosthetic abandonment. By limb-loss level, for the Vietnam group and OIF/OEF cohort, 5-year projected unilateral upper limb average costs are $31,129 and $117,440, unilateral lower limb costs are $82,251 and $228,665, and multiple limb costs are $130,890 and $453,696, respectively. These figures provide the VA with a funding estimate for technologically advanced prosthetic and assistive devices within the framework of ongoing rehabilitation for veterans with traumatic limb loss from the Vietnam and OIF/OEF conflicts.
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Dostopno za:
DOBA, FSPLJ, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
To measure agreement between women's self-administered risk factor questionnaire and their providers' evaluation of their medical eligibility for hormonal contraceptive use.
This was an anonymous ...cross-sectional study. Participants were women 15–45 years old who completed a 20-item self-administered questionnaire. Women were recruited from six public health family planning clinics in the Seattle Metropolitan area. A matching medical evaluation questionnaire was completed concurrently by each participant's health care provider. Using provider evaluation as the “gold standard” against which we compared self-reported medical history, we calculated participant–provider agreement with point estimates and 95% confidence interval (CI).
Of 399 participant and provider pairs, participant–provider agreement was obtained for 392 participant pairs. The majority of the participants (90.3%) were 15–30 years old and 77.7% had used a hormonal contraceptive method for more than 1 year. The estimated proportion of the overall agreement was 96% (95% CI, 0.92–0.98). Women were more likely to report severe headaches (12.4% vs. 3.3%), possible pregnancy (7.3% vs. 3.5%) and smoking (6.2% vs. 2.1%) than providers, but less likely to report smoking more than 15 cigarettes per day (2.6% vs. 9.2%) and irregular menses (6.5% vs. 9.9%).
Overall, a high proportion of the women in this study completed our medical history questionnaire in concordance with their health care providers' same-day medical evaluation. Agreement on critical medical eligibility criteria such as hypertension was well above 90%. For criteria on which there was disagreement, women were more likely to identify contraindications than were their providers.
OBJECTIVESThe calcineurin inhibitors (CNIs) cyclosporine A (CsA) and tacrolimus (Tac) help prevent allograft rejection but are associated with nephrotoxicity. Cytochrome P450 2C8 (CYP2C8) and CYP2J2 ...are polymorphic enzymes expressed in the kidney that metabolize arachidonic acid (AA) to epoxyeicosatrienoic acids, promoting kidney homeostasis. This study examined the association between CNI-induced nephrotoxicity in liver transplant patients and CYP2C8 and CYP2J2 polymorphisms.
METHODSLiver transplantation patients receiving CNIs for at least 3 years were genotyped for CYP2C8*3, CYP2C8*4, CYP2C8 Haplotypes B and C, and CYP2J2*7 and evaluated for nephrotoxicity (serum creatinine ≥1.6 mg/dl) 3-year post-transplantation. CYP2C8 proteins were also engineered in E. coli and their activity towards AA and inhibition by CNIs was investigated in vitro.
RESULTSThe risk of kidney disease post-transplantation was positively associated with CYP2C8*3 genotype. Odds ratios for all participants carrying at least one CYP2C8*3 allele were significant odds ratio=2.38 (1.19–4.78). Stratification by CNI indicated a significant association between CYP2C8*3 and nephrotoxicity among patients receiving Tac but not CsA. The risk of renal dysfunction was not significantly influenced by CYP2C8*4, CYP2J2*7, or CYP2C8 haplotype B genotypes although inheritance of haplotype C seems to be protective. In vitro, the gene products of CYP2C8*3 and CYP2C8*4 were deficient in AA epoxidation, retaining 26 and 18% of wild-type activity, respectively. Circulating plasma concentrations of CsA and Tac inhibited CYP2C8 wild-type in vitro epoxidation of AA by 17 and 35%, respectively.
CONCLUSIONInheritance of CYP2C8*3 is associated with a higher risk of developing renal toxicity in patients treated chronically with CNIs, and especially Tac, possibly by reducing formation of kidney protecting vasodilatory epoxyeicosatrienoic acids.
Abstract Background Several therapy options are available for symptomatic, treatment-naïve chronic lymphocytic leukemia (CLL). Many of these therapies have been compared against chlorambucil, but ...have not been directly compared against each other. There is currently no agreed upon standard therapeutic regimen for treatment-naïve CLL. Methods We performed a systematic literature review to identify randomized controlled trials (RCTs) published prior to November 2011 of therapies for previously untreated CLL. We conducted a network meta-analysis using fixed and random effect statistical models to estimate differences between shape and scale parameters of progression-free survival (PFS) curves for each competing therapy. We used the parameter estimates and a Weibull distribution to project mean PFS for each therapy option. Results Five RCTs were included in our comparison network. Overall, patients were younger (59–65 years), had good performance status based on the Eastern Cooperative Oncology Group scale (ECOG 0-1), and earlier stage disease (Rai 0–II or Binet A or B). The combination regimen fludarabine with cyclophosphamide and rituximab (FCR) was estimated to yield mean PFS of 76 months (95% CrI: 60, 91), FC 60 months (46, 73), fludarabine 38 months (27, 49), alemtuzumab 24 months (15, 32), and chlorambucil 23 months (15, 32). Conclusion Our results suggest that FCR has relatively higher potential of preventing disease progression in younger, healthier, treatment-naïve CLL patients and should be considered an optimal initial treatment strategy for this patient population. However, because estimates are based on model simulation, additional studies of FCR are necessary to clinically validate its therapeutic potential.
To examine variables influencing colony-stimulating factor (CSF) prescription as primary prophylaxis versus other use during patients' initial chemotherapy course among a large sample of health ...insurance records.
Retrospective cohort study.
Adults 25 years or older with a diagnosis of breast, colorectal, or non-small cell lung cancer (NSCLC) between January 1, 2002, and December 31, 2005, were identified from the western Washington State Surveillance, Epidemiology, and End Results Seattle Puget Sound registry. We linked these records to health insurance claims. Chemotherapy regimens identified from insurance claims were categorized as carrying high, intermediate, or low risk of myelosuppression according to the National Comprehensive Cancer Network guidelines and the literature. Colony-stimulating factor use was described as primary prophylaxis, other use, or no use, and logistic regression analysis identified factors associated with CSF use.
For patients with breast cancer, colorectal cancer, and NSCLC, respectively, 58%, 0%, and 28% received CSFs as primary prophylaxis in conjunction with high-risk chemotherapy regimens, whereas 10%, 7%, and 21% did so in conjunction with low-risk chemotherapy regimens. Prophylactic CSF use increased from 2002 to 2005 for breast cancer but remained constant for colorectal cancer and for NSCLC.
As primary prophylaxis, CSF use is underutilized based on recommendations for patients having cancer who receive chemotherapy regimens carrying high febrile neutropenia risk and may be overutilized for patients who receive chemotherapy regimens carrying low febrile neutropenia risk. Further research is needed to understand the barriers to implementing guidelines in clinical practice.
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