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.     

Improved Lipid Lowering Activity of Bezafibrate Following Continuous Gastrointestinal Administration: Pharmacodynamic Rationale for Sustained Release Preparation of the Drug

Purpose. To evaluate the role of different routes and modes of administration of bezafibrate (BZF) on its hypolipidemic activity. We hypothesize that the major sites of BZF action are located presystemically as in other 'gastrointestinal (GI) drugs.' Thus, continuous administration of the drug to the GI tract is expected to augment its efficacy and provides a rationale for an oral sustained release preparation of the drug. Methods. The hypothesis was investigated in three experimentally induced-hyperlipidemia rat models. Models A and B were based on cholesterol-enriched diets and Model C on induced acute hyperlipidemia by triton 225 mg/kg. The pharmacokinetics and the pharmacodynamics of the drug following various modes of administration were examined. Results. In all cases, continuous administration of the drug into the duodenum (IGI) at a dose of 30 mg/kg/day for 3 days (Models A and B) or over 18 hr (Model C) reduced significantly both total cholesterol and triglycerides levels and elevated HDL cholesterol levels in comparison to bolus oral administration of the same dose, as well as in comparison to equivalent intravenous infusion (Model C). Infusion of the drug directly into the portal vein produced an equivalent activity to IGI administration. The pharmacokinetic study showed 100% oral bioavailability, good colonic absorption properties and an indication for an enterohepatic cycle. Conclusions. The results confirm that BZF has a first pass hepatic pharmacodynamic effect. Administration of BZF in a slow release matrix tablet to the rats produced the same magnitude of effect as IGI administration, thus proving the pharmacodynamic rationale for this mode of administration for GI drugs.     

Muscle pain and serum creatine kinase are not associated with low serum 25(OH) vitamin D levels in patients receiving statins

Objective Vitamin D deficiency has been associated in some studies with nonspecific musculoskeletal pain and, more specifically, with statin‐induced myalgia, which was ameliorated by high‐dose vitamin D supplements. Our objective was to explore the association between vitamin D status and statin‐induced myalgia and elevation of serum creatine kinase (CK). Design Retrospective cohort study, based on the electronic database of a health maintenance organization. Patients Six thousand eight hundred and eight patients (71·5% women) to whom statins were dispensed during 2008 and who had ≥1 CK and 25‐hydroxy vitamin D (25OHD) levels measured during statin exposure. Of these, 376 patients (5·5%) had switched from a first‐line statin to atorvastatin because of muscle pain (n = 220) or other reasons (n = 156). Measurements In the entire cohort, we compared serum CK levels among serum 25OHD quartiles. In addition, we compared CK and 25OHD levels among patients with myalgia, other switchers and nonswitchers. Results The median 25OHD level in the entire cohort was 21·8 ng/ml [interquartile range (IQR), 16·3–27·4]. CK levels were marginally lower in patients in the lowest 25OHD quartile [median CK (IQR) in 25OHD quartiles 1–4, 87 (61–130), 90 (65–131), 91 (65–132) and 91 (67–131) IU/ml, respectively; P = 0·007]. 25OHD levels in statin switchers were similar to those in nonswitchers; moreover, there were no differences in 25OHD among switchers with muscle pain and other switchers. Conclusion Our findings do not support an association between low 25OHD levels and statin‐induced myalgia or CK elevation.     

Database assessment of the effectiveness of brand versus generic rosiglitazone in patients with type 2 diabetes mellitus.

BACKGROUND: To compare the effectiveness of brand rosiglitazone maleate (BRM) versus generic rosiglitazone HCl (GRH) in patients with type 2 diabetes mellitus, using computerized records of a healthcare organization. Retrospective, longitudinal database analysis. MATERIAL/METHODS: Comparison of HbA1C reduction in patients starting treatment with either BRM (n=740) or GRH (n=306) in the years 2004-2005. RESULTS: BRM users were older (63.5+/-11 vs. 61.7+/-10 years p<0.001) and presented more cardiovascular disorders (38% vs. 25%, p<0.001) with no differences in gender distribution, rates of hypertension or use of concomitant oral hypoglycemic drugs. Use of concomitant insulin was more frequent (17.7% vs. 6.2%, p<0.0001), rates of dispensed rosiglitazone doses >4 mg/d (65.3% vs. 48.5%, p<0.001) and treatment duration was longer (9.3+/-6.2 vs. 5.2+/-2.2 months, p<0.001) with the generic formulation. Baseline HbA1C levels were higher (9.0+/-1.5 vs. 8.6+/-1.2%, p<0.001) and the absolute decrease in HbA1C levels was greater in the GRH group (-1.2+/-1.6% vs. -0.5+/-1.7%, p<0.001). On multiple regression analysis, the decrease in HbA1C (dependent variable) was associated mainly with initial HbA1C level (partial r2=0.30). Rosiglitazone formulation (partial r2=0.02), age, treatment duration and concomitant insulin (partial r2=0.006) were all significant but minor predictors, with no effect of rosiglitazone daily dose. Mean regression-predicted decreases in HbA1C (with 95% CL) were not significantly different between the two rosiglitazone formulations: -1.6% (-4.3% to +1.1%) for GRH and -1.1% (-3.8% to +1.6%) for BRM. CONCLUSIONS: In this retrospective database analysis, we found no evidence of different effectiveness of generic vs. brand rosiglitazone in lowering HbA1C levels.     

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.     

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.     

Pharmacodynamic effects of bezafibrate and niacin combination: implications of the mode of administration

The goal of this investigation was to optimize antilipid therapy by utilizing the combined activity of two lipid-lowering agents, niacin and bezafibrate, and improve their efficacy by targeting them to their presumed presystemic site(s) of action. Thus, continuous duodenal (IGI) administration of the drug combination should augment their efficacy in comparison with intermittent oral treatment. Three hyperlipidemic rat models were studied: Models A and B were based on cholesterol-enriched diets and Model C was based on on acute hyperlipidemia induced by triton injection. Continuous IGI administration of the drug combination [bezafibrate, 30mg/kg/day, and niacin, 40 mg/kg/day for 3 days (Models A and B) or for 18 h (Model C)] produced significantly greater lowering of total cholesterol and triglycerides and elevation of high-density lipoprotein (HDL) cholesterol in comparison with intermittent oral administration of the same doses either given individually or in combination (Models A and B). Similar results were found in Model C for the IGI administration of the drug combination in contrast to oral and also to intravenous infusions. The results indicate that the combination of bezafibrate and niacin produces a significant hypolipidemic response, with major site(s) of action located presystemically. Because a slow-release matrix tablet of the drug combination resulted in a similar magnitude of effect as the IGI administration, the present study provides a pharmacodynamic rationale for the use of a slow-release low-dose niacin-bezafibrate combination.