CYP2D6 genotype predicts tamoxifen discontinuation and drug response: a secondary analysis of the KARISMA trial.

BACKGROUND: Guidelines regarding whether tamoxifen should be prescribed based on women's cytochrome P450 2D6 (CYP2D6) genotypes are conflicting and have caused confusion. This study aims to investigate if CYP2D6 metabolizer status is associated with tamoxifen-related endocrine symptoms, tamoxifen discontinuation, and mammographic density change. PATIENTS AND METHODS: We used data from 1440 healthy women who participated the KARISMA dose determination trial. Endocrine symptoms were measured using a modified Functional Assessment of Cancer Therapy - Endocrine Symptoms (FACT-ES) questionnaire. Change in mammographic density was measured and used as a proxy for tamoxifen response. Participants were genotyped and categorized as poor, intermediate, normal, or ultrarapid CYP2D6 metabolizers. RESULTS: The median endoxifen level per mg oral tamoxifen among poor, intermediate, normal and ultrarapid CYP2D6 metabolizers were 0.18 ng/ml, 0.38 ng/ml, 0.56 ng/ml and 0.67 ng/ml, respectively. Ultrarapid CYP2D6 metabolizers were more likely than other groups to report a clinically relevant change in cold sweats, hot flash, mood swings, being irritable, as well as the overall modified FACT-ES score, after taking tamoxifen. The 6-month tamoxifen discontinuation rates among poor, intermediate, normal, and ultrarapid CYP2D6 metabolizers were 25.7%, 23.6%, 28.6%, and 44.4%, respectively. Among those who continued and finished the 6-month tamoxifen intervention, the mean change in dense area among poor, intermediate, normal, and ultrarapid CYP2D6 metabolizers were -0.8 cm2, -4.5 cm2, -4.1 cm2, and -8.0 cm2 respectively. CONCLUSIONS: Poor CYP2D6 metabolizers are likely to experience an impaired response to tamoxifen, measured through mammographic density reduction. In contrast, ultrarapid CYP2D6 metabolizers are at risk for exaggerated response with pronounced adverse effects that may lead to treatment discontinuation.

Blood pressure of infants of hypertensive mothers: a two-year follow-up.

This study was designed to determine if the blood pressure (BP) of infants in the first two years of life relates to the presence of maternal hypertension during pregnancy. The BP of infants was measured at birth, and at 9, 18, and 24 months after delivery. Women with elevated BP in pregnancy or labor (n = 190) were enrolled as cases. Two-hundred-and-one normotensive women served as controls. The cases were divided according to the time BP became elevated, i.e., before or after 24 weeks of pregnancy, and intrapartum only. The largest of the case groups was hypertensive intrapartum only. A minority of the case mothers had proteinuria in association with elevated BP. There were no differences in BP between case and control infants at bith or at 9 and 18 months of age. However, by 24 months of age, the systolic BP of the infants of case mothers was higher (p less than .05) than that of the infants of control mothers. No differences in systolic BP could be attributed to the time of onset of maternal hypertension.

Antibiotic efficacy in odontogenic infections.

Cultures and antibiotic sensitivities were determined for 84 patients in the oral surgery clinic who had diagnoses of odontogenic infections. Data tabulated from the results of the bacteriologic cultures and antibiotic sensitivities disclosed the five organisms most frequently involved. Antibiotic efficacy for each of the antibiotics used in sensitivity determinations was calculated on the basis of the percent sensitivity of a given organism to the given antibiotic, and the percent of patients with infections resulting from the given organism, both expressed as decimals. Antibiotics were then arranged in order of greatest to least efficacy on the basis of chloramphenicol as 100 percent. Efficacy values, sigma and lambda, were compared for the antibiotics. It was concluded that those antibiotics below penicillin on the efficacy table were less useful in the initial antibiotic treatment of odontogenic infections. Chloramphenicol was effective against every microorganism isolated during this investigation, but its use should be tempered with clinical judgment. Erythromycin should be given consideration as a replacement for penicillin as the preferred drug in the initial treatment of odontogenic infections on the basis of its high efficacy rating and freedom from potentially serious allergic or other untoward manifestations.