Effects of imatinib on glycemic and lipid profiles: a retrospective cohort study.

Despite a favorable effect of imatinib on glucose metabolism in animal models, human reports are inconsistent. We retrospectively studied the long-term effect of imatinib on fasting plasma glucose (FPG), glycated hemoglobin (HbA1C), LDL-cholesterol (LDL), and triglycerides (TGs) in a large HMO cohort of patients initiating therapy. In patients with diabetes (n = 118), significant reductions in HbA1c (0.53%, IQR 0.09, 1.19; p < .001) and FPG (10.2 mg/dL, IQR -3.5, 32.2; p < .001), independent of demographics and of glucose-lowering drugs utilization, were observed during the first year of imatinib treatment. Significant reductions in LDL (17.8 mg/dL, IQR -1.3, 34.0; p < .001) and TG (25.0 mg/dL, IQR -2.3, 58.3; p < .001), also independent of demographics and of statin utilization, were evident in the entire cohort (n = 611) during the first imatinib year. All reductions persisted during the second treatment year. To conclude, imatinib is associated with durable metabolic benefits, which may guide TKI choice in patients with cardiovascular co-morbidities.

Database evaluation of the association between serum magnesium levels and the risk of atrial fibrillation in the community.

BACKGROUND: In population studies, mild hypomagnesemia, determined by a single measurement, was associated with incident atrial fibrillation, over ~20 years of follow-up. We sought to determine whether mild (≤ 1.7 mg/dL) and moderate (≤ 1.5mg/dL) hypomagnesemia are temporally associated with increased incidence of atrial fibrillation (AF) in the community. METHODS: Health Maintenance Organization (HMO) database cohort study including beneficiaries with ≥ 1 serum magnesium measurement between 2004 and 2013. The follow-up period was defined from the first magnesium measurement to first listing in an AF registry (for cases) and December 2013 or date of death or loss to follow-up (for controls). We analyzed the association between serum magnesium quintiles, as well as the above clinically relevant hypomagnesemia thresholds, and incident AF using Cox proportional hazard regression analysis, adjusting for confounders. The association between serum magnesium and AF occurring within 3 months was also examined. RESULTS: Among 162,162 subjects, 2228 (1.4%) developed AF over a median follow-up of 25.3 months. Compared to the middle quintile the lowest magnesium quintile (≤ 1.9 mg/dL) had a significantly higher risk of AF (HR, 1.21; 95% CI: 1.07-1.37). Increased AF risk was also associated with mild (HR, 1.44; 95% CI: 1.20-1.73) and moderate hypomagnesemia (HR, 1.57; 95% CI: 1.14-2.15). No association was found when limiting the follow-up period to 3 months. CONCLUSIONS: In our study, hypomagnesemia was associated with incident AF over prolonged but not short-term follow-up periods, suggesting that this association may not be causal.

Potent CYP2D6 Inhibiting drugs do not increase relapse rate in early breast cancer patients treated with adjuvant tamoxifen.

Endoxifen, the most active metabolite of the prodrug tamoxifen, is produced by cytochrome P450 CYP2D6. Breast cancer patients treated with tamoxifen who have reduced CYP2D6 activity, related to either genetic variation or drug inhibition, may have inferior outcomes. To assess the effect of concomitant CYP2D6 inhibiting drug use on clinical outcomes of breast cancer patients treated with adjuvant tamoxifen. We conducted a retrospective database analysis. Women with non-metastatic estrogen receptor positive tumors who had completed adjuvant tamoxifen therapy for 2 years, without treatment with adjuvant aromatase inhibitors or early relapse, were included. Patients were classified as users of CYP2D6 inhibitors if they purchased strong CYP2D6 inhibiting drugs for ≥ 4 consecutive months during tamoxifen treatment. Tumors were classified as "high risk" if adjuvant chemotherapy was prescribed. Primary endpoint was disease free (DFS) and secondary endpoint was overall survival (OS). 902 patients treated with tamoxifen (median duration, 4.9 years) were followed for a median period of 5.9 years. Fifty-nine (6.5%) patients were users of CYP2D6 inhibitors (median duration, 23 months). DFS at 3 years (corresponding to 5 years after tamoxifen initiation) did not differ between users and non-users of CYP2D6 inhibiting drugs (92.7 vs. 93.0%, respectively; adjusted P = 0.44). OS at 3 years was lower in the patients using CYP2D6 inhibiting drugs: 89.4 vs. 93.8%, but after adjustment for age and comorbidities this difference was not significant (P = 0.20). Overall recurrence rates did not differ between users and non-users of CYP2D6 inhibiting drugs (11.8 vs. 19.0% respectively, P = 0.23). Concomitant prolonged therapy with strong CYP2D6 inhibiting drugs does not affect adversely DFS and recurrence rates in tamoxifen-treated early breast cancer patients.

Physician speciality and adherence to guidelines for the treatment of unsubstantiated uncomplicated urinary tract infection among women.

PURPOSE: To evaluate the variance in rates of physician adherence to guidelines for the empiric treatment of uncomplicated urinary tract infection (UTI) in women recommending either trimethoprim-sulfamethoxazole (TMP-SMX) or nitrofurantoin, in all relevant physician subspecialities practising in a managed care community setting in Israel. METHODS: Data were derived from the computerised medical records of Maccabi Healthcare Services, a health maintenance organisation (HMO) in Israel providing care to more than 1.6 million members nation-wide. The study population included women aged 18-75 years without risk factors for complicated UTI who were treated empirically with antibiotics for a diagnosis of acute cystitis or UTI. The data set consisted of 64,236 initial physician-patient encounters from July 2000 to June 2002. Physician adherence to guidelines was calculated by comparing the proportion of cases treated with each individual drug. A binary regression model was used to evaluate factors associated with suboptimal adherence to the guidelines. RESULTS: Nitrofurantoin was the most frequently prescribed drug (18.51%), followed by TMP-SMX (17.04%) for a crude rate of adherence of 35.6%. Adherence was observed to be highest in cases treated by urologists (OR=2.8, 95%CI: 2.4, 3.3), followed by gynaecologists (OR=1.9, 95%CI: 1.7, 2.31), with family practice as the referent speciality. The medical school attended was also found to be significant. CONCLUSIONS: Physician speciality was found to be significantly associated with rate of adherence to guidelines, with higher rates being observed amongst specialities such as urologists who presumably have greater familiarity with the subject matter.

Development and validation of a stability-indicating high performance liquid chromatographic assay for benoxinate.

Benoxinate is a local anaesthetic used for ophthalmic applications. The aim of this study was to develop a rapid and simple stability-indicating method for the determination of benoxinate formulated for ophthalmic use, evaluate its long-term stability and identify its major degradation product. Benoxinate was eluted on a 10 microm Spherisorb phenyl column, 250 x 3.2 mm, with a mobile phase consisting of acetonitrile-buffer (pH 3.5) (35:65, v/v), pumped at 0.8 ml min(-1) flow rate. The buffer was composed of sodium dihydrogen phosphate (50 mM), sodium hydrogen sulfate (2.5 mM) and 1-heptanesulfonic acid sodium salt (5 mM). The analyte was quantified spectrophotometrically at 308 nm. The chromatograms of benoxinate formulations obtained by this method showed benoxinate (t = 4.5 min) well resolved from its degradation product (t = 2.3 min), which was separately identified by means of HPLC-MS as 4-amino-3-butoxybenzoic acid. The assay was demonstrated to have high accuracy, precision and linearity. The method was implemented in investigating the long-term stability of benoxinate 0.4% ophthalmic solutions. The method was found to be simple, quick and selective in determining benoxinate concentrations in fresh and aged preparations.