Association of CYP2C8, CYP3A4, CYP3A5, and ABCB1 polymorphisms with the pharmacokinetics of paclitaxel.

PURPOSE: To retrospectively evaluate the effects of six known allelic variants in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes on the pharmacokinetics of the anticancer agent paclitaxel (Taxol). EXPERIMENTAL DESIGN: A cohort of 97 Caucasian patients with cancer (median age, 57 years) received paclitaxel as an i.v. infusion (dose range, 80-225 mg/m(2)). Genomic DNA was analyzed using PCR RFLP or using Pyrosequencing. Pharmacokinetic variables for unbound paclitaxel were estimated using nonlinear mixed effect modeling. The effects of genotypes on typical value of clearance were evaluated with the likelihood ratio test within NONMEM. In addition, relations between genotype and individual pharmacokinetic variable estimates were evaluated with one-way ANOVA. RESULTS: The allele frequencies for the CYP2C8*2, CYP2C8*3, CYP2C8*4, CYP3A4*3, CYP3A5*3C, and ABCB1 3435C>T variants were 0.7%, 9.2%, 2.1%, 0.5%, 93.2%, and 47.1%, respectively, and all were in Hardy-Weinberg equilibrium. The population typical value of clearance of unbound paclitaxel was 301 L/h (individual clearance range, 83.7-1055 L/h). The CYP2C8 or CYP3A4/5 genotypes were not statistically significantly associated with unbound clearance of paclitaxel. Likewise, no statistically significant association was observed between the ABCB1 3435C>T variant and any of the studied pharmacokinetic variables. CONCLUSIONS: This study indicates that the presently evaluated variant alleles in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes do not explain the substantial interindividual variability in paclitaxel pharmacokinetics.     

Disability and quality of life in individuals with postpolio syndrome

Purpose : The purpose of the study is to investigate disability and quality of life in individuals with the characteristic symptoms of postpolio syndrome. Method : Disability is assessed by means of the self-report activities of daily living instrument, and quality of life by means of Kaasa's questionnaire and the quality of life profile. Results : The 39 subjects have on average lived with polio sequelae for 52 years. Their main difficulties are with moving, lifting and carrying. This means restricted mobility, sedentary activities and a need to prioritize. Half of them feel that polio has lessened their possibilities in life, and a quarter have still not accepted the limitations polio has involved. Nevertheless the majority report a high level of psychosocial well-being, and almost a quarter say that living with polio has meant personal development and strength. We found a significant correlation between on the one hand disability with regard to ambulation, arm strength and finger strength on the self-report ADL, and on the other hand the number of negative problems on the quality of life profile (0.33-0.45). Conclusion : The latter instrument needs further testing before its validity can be determined with certainty.     

Cost description of clinical examination and MRI in wrist ligament injuries

Objective: The total number and cost of wrist MRIs in the catchment area of the Västra Götaland Region in Sweden (population 1 723 000) during 1 year was analysed, together with the number and content of referrals.

Methods: Six radiology departments reported the numbers and rate of all MRI investigations intended to diagnose wrist ligament injuries (n?=?411) and other injuries to the wrist.

Results: The additional cost of the difference between MRIs and a clinical examination by a hand surgeon, plus indirect costs for patients with suspected wrist ligament injuries, was calculated as 957 000 euros.

Conclusions: It is recommended that MRI should only be used in patients in whom there are clinical difficulties in terms of diagnosing wrist ligament injuries. It is suggested that patients with suspected wrist ligament injuries should be referred directly to an experienced hand surgeon, capable of performing a standardised wrist examination and, when needed, diagnostic arthroscopy and final treatment. The proposed algorithm for the diagnosis and treatment of suspected wrist ligament injuries presented in the present study could save time for the patient and for the radiology departments, as well as reducing costs. The ability to implement the early and appropriate treatment of acute ligament injuries could be improved at the same time.