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Two-sided P (two-sided + p)
Selected AbstractsAtazanavir and lopinavir with ritonavir alone or in combination: analysis of pharmacokinetic interaction and predictors of drug exposureHIV MEDICINE, Issue 4 2008S Di Giambenedetto Objectives Studies on the pharmacokinetic interaction between atazanavir and lopinavir with ritonavir (lopinavir/ritonavir) report contradictory results. We aimed to establish the in vivo interaction between these two protease inhibitors as well as the variables influencing drug exposure. Methods Pharmacokinetic parameters were investigated in HIV-infected patients treated with atazanavir 300 mg with ritonavir 100 mg q24h (group A) or lopinavir/ritonavir 400/100 mg q12h (group B) or atazanavir 300 mg q24h with lopinavir/ritonavir 400/100 mg q12h (group C). Patients receiving other concomitant protease inhibitors or non-nucleoside reverse transcriptase inhibitors were excluded. Results In group A (n=10), mean ± standard deviation atazanavir Cmin was 390 ± 460 ng/mL, Cmax 3051 ± 1996 ng/mL and AUC24 29 913 ± 17 686 ng/mL/h. In group B (n=9), lopinavir Cmin was 7562 ± 4292 ng/mL, Cmax 12 944 ± 4838 ng/mL and AUC0,12 122 313 ± 38 225 ng/mL/h. In group C (n=7), atazanavir Cmin was 876 ± 460 ng/mL (P=0.039 vs. group A), Cmax 3421 ± 3399 ng/mL and AUC0,24 65 055 ± 49 843 ng/mL/h (two-sided P>0.05 for each comparison with group A), lopinavir Cmin was 7471 ± 3745 ng/mL, Cmax 10 143 ± 5217 ng/mL and AUC0,12 104 501 ± 43 565 ng/mL/h (P>0.05 for each comparison with group B). When analysing all the groups, including controls from routine clinical practice, higher body mass index was associated with lower atazanavir Cmin and with lower lopinavir Cmax. Atazanavir Cmin showed a correlation with total bilirubin levels. Conclusions Combination with lopinavir/ritonavir provides higher atazanavir Cmin than combination with ritonavir alone, possibly because of an effect of the additional ritonavir dose. Low BMI may be associated with higher drug exposure. [source] DOSE,RESPONSE OF ROPIVACAINE ADMINISTERED CAUDALLY TO CHILDREN UNDERGOING SURGICAL PROCEDURES UNDER SEDATION WITH MIDAZOLAMCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 7 2004F Tonatiu Aguirre-Garay SUMMARY 1.,In a double-blind randomized controlled design, 50 children were allocated to receive bupivacaine 0.25% or ropivacaine 0.25%, 0.32%, 0.40% or 0.50% by caudal block. 2.,Caudal block was performed after induction of anaesthesia with 2,5% sevoflurane, atropine 10 µg/kg and midazolam 100,300 µg/kg. During the surgical procedure, patients were maintained under spontaneous ventilation and no intravenous or inhalatory anaesthetic agent was administered. For transoperative sedation, midazolam 100,300 µg/kg was administered every 0.5,1.0 h. Transoperative cardiovascular response, postoperative analgesia and local and systemic complications were evaluated. 3.,Groups were similar (P > 0.05) in sex, age, weight and in the time elapsed from caudal block to the beginning of the surgical procedure. The surgical time was significantly lower in the ropivacaine 0.25% group. The duration of analgesia was 24 h with ropivacaine 0.25% and approximately 10 h in the other four groups (P < 0.001). Linear regression analysis revealed a significant relationship between the postoperative analgesic period produced by ropivacaine and the surgical time (r = , 0.48, two-sided P = 0.002). Systolic and diastolic blood pressures remained in the physiologically normal range for the duration of the transoperative period. Vomiting was present in only one patient receiving ropivacaine 0.50%. 4.,In children, the duration of analgesia produced by caudal block with ropivacaine may be affected by surgical time. At surgical times of 0.5,1 h, ropivacaine 0.25% produced at least 24 h postoperative analgesia. At similar surgical times, ropivacaine 0.32%, 0.40% and 0.50% produced similar analgesic times to bupivacaine 0.25%. [source] From Adjuvant Therapy to Breast Cancer Prevention: BCPT and STARTHE BREAST JOURNAL, Issue 3 2001Barbara K. Dunn MD Abstract: The continued widespread prevalence of breast cancer supports placing a high priority on research aimed at its primary prevention, particularly among women who are at increased risk for developing this disease. The suggestion of potential agents for the primary chemoprevention of breast cancer evolved out of the treatment setting. Extensive experience with tamoxifen, a first-generation selective estrogen receptor modulator (SERM) showing efficacy, first, in the treatment of advanced breast cancer and, subsequently, as adjuvant therapy for early stage disease established the safety of this agent. Cumulative data from multiple adjuvant studies documented the efficacy of tamoxifen in reducing second primary breast cancers in the contralateral breast, supporting its potential as a chemopreventive agent for breast cancer. The safety and second primary data on tamoxifen, together with extensive information on its pharmacokinetics, metabolism, and antitumor effects, as well as its potentially beneficial effects on lipid metabolism and osteoporosis, led the National Surgical Adjuvant Breast and Bowel Project (NSABP) to select tamoxifen for testing in the first prospective randomized phase III trial of the efficacy of a chemopreventive agent for preventing breast cancer in women at increased risk of the disease. Accordingly, in 1992 the NSABP started the Breast Cancer Prevention Trial (P-1) in which 13,388 women 35 years of age who were at increased risk of breast cancer according to Gail model risk factors [family history, age, and personal history (i.e., age at first birth, age at menarche, previous breast biopsies)] were randomized to tamoxifen 20 mg/day or placebo for 5 years. Through 69 months of follow-up tamoxifen reduced the risk of invasive breast cancer, primarily estrogen receptor-positive tumors, by 49% (two-sided p < 0.00001). Tamoxifen reduced the risk of noninvasive breast cancer by 50% (two-sided p < 0.002). In addition, tamoxifen reduced fractures of the hip, radius, and spine, but it had no effect on the rate of ischemic heart disease. As previously shown, the rates of endometrial cancer and vascular events increased with tamoxifen. With the P-1 results establishing tamoxifen as the standard of care for the primary chemoprevention of breast cancer in high-risk women, concern over the side effects of tamoxifen has prompted a continuing search for an agent that displays a more desirable efficacy/toxicity profile. Raloxifene, a second-generation SERM approved for the prevention of osteoporosis in postmenopausal women, displays antiestrogenic properties in the breast and possibly the endometrium, and estrogenic effects in the bone and on the lipid profile, suggesting it as a candidate for comparison with the chemopreventive standard, tamoxifen. Raloxifene will be compared to tamoxifen in an equivalency trial, the Study of Tamoxifen and Raloxifene (STAR) NSABP P-2, which began in July 1999 at almost 500 centers in North America. The plan is to randomize 22,000 postmenopausal women 35 years of age at increased risk of breast cancer by Gail criteria to tamoxifen 20 mg/day or raloxifene 60 mg/day for 5 years. Study endpoints include invasive and noninvasive breast cancer, cardiovascular disease, endometrial cancer, bone fractures, and vascular events. [source] Trimmed Weighted Simes' Test for Two One-Sided Hypotheses With Arbitrarily Correlated Test StatisticsBIOMETRICAL JOURNAL, Issue 6 2009Werner Brannath Abstract The two-sided Simes test is known to control the type I error rate with bivariate normal test statistics. For one-sided hypotheses, control of the type I error rate requires that the correlation between the bivariate normal test statistics is non-negative. In this article, we introduce a trimmed version of the one-sided weighted Simes test for two hypotheses which rejects if (i) the one-sided weighted Simes test rejects and (ii) both p -values are below one minus the respective weighted Bonferroni adjusted level. We show that the trimmed version controls the type I error rate at nominal significance level , if (i) the common distribution of test statistics is point symmetric and (ii) the two-sided weighted Simes test at level 2, controls the level. These assumptions apply, for instance, to bivariate normal test statistics with arbitrary correlation. In a simulation study, we compare the power of the trimmed weighted Simes test with the power of the weighted Bonferroni test and the untrimmed weighted Simes test. An additional result of this article ensures type I error rate control of the usual weighted Simes test under a weak version of the positive regression dependence condition for the case of two hypotheses. This condition is shown to apply to the two-sided p -values of one- or two-sample t -tests for bivariate normal endpoints with arbitrary correlation and to the corresponding one-sided p -values if the correlation is non-negative. The Simes test for such types of bivariate t -tests has not been considered before. According to our main result, the trimmed version of the weighted Simes test then also applies to the one-sided bivariate t -test with arbitrary correlation. [source] | ||||||||||