Development of a detection algorithm for statin-induced myopathy using electronic medical records.

WHAT IS KNOWN AND OBJECTIVE: Demonstration of the utility of electronic medical records (EMRs) for pharmacovigilance (PV) has been highly anticipated. Analysis using appropriately selected EMRs should enable accurate estimation of adverse drug event (ADE) frequencies and thus promote appropriate regulatory actions. Statin-induced myopathy (SIM) is a clinically important ADE, but pharmacoepidemiological methodology for detecting this ADE with high predictability has not yet been established. This study aimed to develop a detection algorithm, highly selective for SIM using EMRs. METHODS: We collected EMRs on prescriptions, laboratory tests, diagnoses and medical practices from the hospital information system of Kobe University Hospital, Japan, for a total of 5109 patients who received a statin prescription from April 2006 to March 2009. The current algorithm for extracting SIM-suspected patients consisted of three steps: (i) event detection: increase in creatine kinase (CK) and subsequent statin discontinuation, (ii) filtration by exclusion factors (disease diagnosis/medical practices) and (iii) refinement by the time course of CK values (baseline, event and recovery). A causal relationship between the event and statin prescription (probable/possible/unlikely) was judged by review of patient medical charts by experienced pharmacists. The utility of the current algorithm was assessed by calculating the positive predictive value (PPV). In a comparative analysis, subjects screened in step 1 were extracted by the diagnostic term/code for 'myopathy/rhabdomyolysis', and the PPV of this diagnostic data approach was also estimated. RESULTS AND DISCUSSION: Five subjects with suspected SIM were identified using our proposed algorithm, giving a frequency of 0·1% for the adverse event. Review of the medical charts revealed that the causal association of SIM with statin use was judged as 'Likely (probable/possible)' for all five suspected patients; thus, the PPV was estimated as 100% (95% confidence interval: 56·6-100%). The higher utility of the current algorithm compared with the diagnostic data approach was also shown by assessing the PPV (100 vs. 33·3%). WHAT IS NEW AND CONCLUSION: We report on a detection algorithm with high predictability for SIM using EMRs. Combined use of exclusion criteria for disease, medical practice data and time course of CK values contributes to better prediction of SIM. The utility of the proposed algorithm should be further confirmed in a larger study.

Perfusion index derived from a pulse oximeter can predict the incidence of hypotension during spinal anaesthesia for Caesarean delivery.

BACKGROUND: Hypotension during spinal anaesthesia for Caesarean delivery is a result of decreased vascular resistance due to sympathetic blockade and decreased cardiac output due to blood pooling in blocked areas of the body. Change in baseline peripheral vascular tone due to pregnancy may affect the degree of such hypotension. The perfusion index (PI) derived from a pulse oximeter has been used for assessing peripheral perfusion dynamics due to changes in peripheral vascular tone. The aim of this study was to examine whether baseline PI could predict the incidence of spinal anaesthesia-induced hypotension during Caesarean delivery. METHODS: Parturients undergoing elective Caesarean delivery under spinal anaesthesia with hyperbaric bupivacaine 10 mg and fentanyl 20 µg were enrolled in this prospective study. The correlation between baseline PI and the degree of hypotension during spinal anaesthesia and also the predictability of spinal anaesthesia-induced hypotension during Caesarean delivery by PI were investigated. RESULTS: Baseline PI correlated with the degree of decreases in systolic and mean arterial pressure (r=0.664, P<0.0001 and r=0.491, P=0.0029, respectively). The cut-off PI value of 3.5 identified parturients at risk for spinal anaesthesia-induced hypotension with a sensitivity of 81% and a specificity of 86% (P<0.001). The change of PI in parturients with baseline PI ≤ 3.5 was not significant during the observational period, while PI in parturients with baseline PI>3.5 demonstrated marked decreases after spinal injection. CONCLUSIONS: We demonstrated that higher baseline PI was associated with profound hypotension and that baseline PI could predict the incidence of spinal anaesthesia-induced hypotension during Caesarean delivery.

Effects of ABCB1 3435C>T genotype on serum levels of cortisol and aldosterone in women with normal menstrual cycles.

ABCB1, also known as MDR1/P-glycoprotein, can transport cortisol and aldosterone. We examined the effects of ABCB1 polymorphisms on serum levels of cortisol and aldosterone among different phases of the normal menstrual cycle in 51 non-pregnant healthy Japanese female volunteers (22 +/- 1 years old). The menstrual cycle was divided into three phases: premenstrual phase (14 days preceding the onset of menstruation, N = 22; menstrual phase, N = 11, and postmenstrual phase, N = 18). ABCB1 -129T>C, 1236C>T, 2677G>A/T, and 3435C>T genotypes were determined. Serum levels of cortisol, aldosterone, estradiol, progesterone, and testosterone were measured. The serum levels of estradiol in the pre- and post-menstrual phases and of progesterone in the premenstrual phase were significantly increased when compared to their serum levels in the menstrual phase (P < 0.005). In the postmenstrual phase, the mean serum cortisol level in subjects with the 3435CT and 3435TT genotype was 7.6 +/- 3.4 microg/dL (mean +/- SD, N = 7), which was significantly lower than in women with the 3435CC genotype (9.9 +/- 1.8 microg/dL, N = 11) (P = 0.037). The opposite effect was observed in the serum aldosterone level during the postmenstrual phase (97.2 +/- 23.4 and 141.2 +/- 48.5 pg/mL for 3435CC and 3435CT + 3435TT, respectively; P = 0.041). These findings suggest that ABCB1 3435C>T genotype can influence serum levels of cortisol and aldosterone during the postmenstrual phase of the normal menstrual cycle.

Phase I and pharmacological study of paclitaxel given over 3 h with cisplatin for advanced non-small cell lung cancer.

BACKGROUND: To establish the toxicities and maximum tolerated dose of paclitaxel given over 3 h in combination with cisplatin, to determine the pharmacokinetic profiles of these two drugs and to observe their antitumor activity, we conducted a combination phase I study in non-small cell lung cancer. METHODS: Patients received paclitaxel doses of 150-210 mg/m2 given over 3 h and cisplatin doses of 60-80 mg/m2 as a 1 h infusion 2 h after the end of the paclitaxel infusion. RESULTS: A total of 25 patients with previously untreated non-small cell lung cancer were enrolled. Granulocytopenia was the most frequent hematological toxicity and the most prominent non-hematological toxicity was sensory dominant neuropathy. Two of six patients experienced dose limiting toxicities (leukopenia, infection and neuropathy) at a dose of paclitaxel 210 mg/m2 and cisplatin 60 mg/m2, which was considered the maximum tolerated dose. There were seven partial responses among 24 evaluable patients, for an overall response rate of 29%. The median survival time was 341 days and the 1 year survival rate was 45.8%. As the paclitaxel pharmacokinetic parameters in this study were consistent with those of our previous single agent study, we found no significant drug-drug interaction between the 3 h infusion paclitaxel and cisplatin. CONCLUSION: The recommended doses for further study are determined to be paclitaxel 180 mg/m2 and cisplatin 80 mg/m2. This is a well-tolerated and active regimen for non-small cell lung cancer. In view of the promising survival outcome, further evaluation in prospective randomized trials versus other regimens is warranted.

[Comparison of screening-detected and symptomatic lung cancer patients].

Survival rates were studied in 416/27 screening-detected and 1,099/188 symptomatic patients with non-small cell lung cancer (NSCLC)/small cell lung cancer (SCLC). Screening-detected patients with both NSCLC and SCLC had earlier stage disease, showed better PS distribution, and a greater part of the patients underwent standard therapy than the symptomatic cohort with a significant difference. Median survival time, 5- and 10-year survival rates were 1,220 days, 44.4% and 34.9%, respectively, in the screening-detected patients, and 248 days, 11.3% and 7.5%, respectively, in the symptomatic patients with NSCLC. They were 584 days, 21.2% and 15.9%, respectively, in the screening-detected patients, and 257 days, 4.8% and 2.3% in the symptomatic patients with SCLC.

Phase I and pharmacokinetic study of paclitaxel by 24-hour intravenous infusion.

Paclitaxel, a new antitubular agent, appears to be one of the most promising single agents for the chemotherapy of various solid tumors. The primary objectives of this phase I study of paclitaxel using 24-h continuous intravenous infusions were to determine the maximum tolerated dose of paclitaxel administered by this schedule to Japanese patients with solid tumors and to evaluate the pharmacokinetics of paclitaxel. Eighteen patients received one of five doses of paclitaxel, 49.5, 75, 105, 135 or 180 mg/m2. Premedication with diphenhydramine, dexamethasone, and ranitidine was used to prevent acute hypersensitivity reactions. Pharmacokinetic data were obtained from all 18 patients. Dose-limiting toxicities observed at 180 mg/m2 consisted of grade 4 granulocytopenia associated with grade 3 infection. No severe HSRs or cardiac toxicity were detected. Reversible toxicities observed included liver dysfunction, alopecia, peripheral neuropathy and myalgias. Pharmacokinetic studies performed using high-performance liquid chromatography demonstrated that plasma concentrations of paclitaxel increased during the 24-h infusion and declined immediately upon cessation of the infusion with a half life of 13.1-24.6 h (75-180 mg/m2). Less than 10% of paclitaxel was excreted in the urine within 72 h. The peak plasma concentrations and the areas under the concentration-versus-time curves increased linearly with the dose administered. Antitumor activity was observed in one patient with pulmonary metastasis from pharyngeal cancer. Based on these studies a phase II trial dose of 135 mg/m2 administered over 24 h was chosen.