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Treatment Exposure (treatment + exposure)
Selected AbstractsExposure to opioid maintenance treatment reduces long-term mortalityADDICTION, Issue 3 2008Amy Gibson ABSTRACT Aims To (i) examine the predictors of mortality in a randomized study of methadone versus buprenorphine maintenance treatment; (ii) compare the survival experience of the randomized subject groups; and (iii) describe the causes of death. Design Ten-year longitudinal follow-up of mortality among participants in a randomized trial of methadone versus buprenorphine maintenance treatment. Setting Recruitment through three clinics for a randomized trial of buprenorphine versus methadone maintenance. Participants A total of 405 heroin-dependent (DSM-IV) participants aged 18 years and above who consented to participate in original study. Measurements Baseline data from original randomized study; dates and causes of death through data linkage with Births, Deaths and Marriages registries; and longitudinal treatment exposure via State health departments. Predictors of mortality examined through survival analysis. Findings There was an overall mortality rate of 8.84 deaths per 1000 person-years of follow-up and causes of death were comparable with the literature. Increased exposure to episodes of opioid treatment longer than 7 days reduced the risk of mortality; there was no differential mortality among methadone versus buprenorphine participants. More dependent, heavier users of heroin at baseline had a lower risk of death, and also higher exposure to opioid treatment. Older participants randomized to buprenorphine treatment had significantly improved survival. Aboriginal or Torres Strait Islander participants had a higher risk of death. Conclusions Increased exposure to opioid maintenance treatment reduces the risk of death in opioid-dependent people. There was no differential reduction between buprenorphine and methadone. Previous studies suggesting differential effects may have been affected by biases in patient selection. [source] Liver damage underlying unexplained transaminase elevation in human immunodeficiency virus-1 mono-infected patients on antiretroviral therapy,HEPATOLOGY, Issue 2 2009Patrick Ingiliz Liver damage associated with chronic unexplained high serum transaminases in human immunodeficiency virus (HIV)-infected patients under combined antiretroviral therapy is unknown. Liver histology was prospectively investigated in patients presenting serum transaminase elevation for more than 6 months, after exclusion of alcohol abuse, hepatitis C virus (HCV) or hepatitis B virus (HBV) infection, autoimmune, and genetic liver diseases. In a subgroup of patients, liver mitochondrial activities were measured by spectrophotometry and mitochondrial DNA (mtDNA) by real-time polymerase chain reaction (PCR). Thirty patients were included with median values of alanine aminotransferase (ALT) levels: 80 U/L, age: 46 years, body mass index: 23 kg/m2, HIV RNA: 200 copies/mL, CD4 count: 365/mm3, duration of HIV infection: 13 years, and duration of treatment exposure: 118, 41, and 53 months for nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, respectively. Histological anomalies were found in 22 of 30 patients. Steatosis was present in 18 patients, severe in nine patients, and associated with inflammation in 16 patients with a diagnosis of non-alcoholic steatohepatitis (NASH). Fibrosis was found in 18 patients, severe in six patients and associated with steatosis in 13 patients. Significant liver respiratory complex I defect, contrasting with high complex IV activity and normal mitochondrial DNA content, was observed in the group of patients compared with controls. The presence of NASH was correlated with high fasting glycemia and insulin levels, not with liver mitochondrial function or mitochondrial DNA content. Conclusions: HIV-infected patients on combined antiretroviral therapy with chronic transaminase elevation of unknown origin have a high rate of liver lesions, mostly consistent with NASH related to insulin resistance. (HEPATOLOGY 2008.) [source] Increased rate of prematurity associated with antenatal antiretroviral therapy in a German/Austrian cohort of HIV-1-infected womenHIV MEDICINE, Issue 1 2008I Grosch-Woerner Objective The aim of the study was to assess the risk of adverse pregnancy outcomes after antenatal antiretroviral therapy in a well-defined prospective cohort of nontransmitting HIV-infected women. Methods Prospective monitoring of 183 mother,child pairs from 13 centres in Germany and Austria, delivering between 1995 and 2001, was carried out. Following German,Austrian guidelines recommending an elective Caesarean section (CS) at 36 weeks, prematurity was defined as <36 weeks' gestation for these analyses. Results Of 183 mother,child pairs, 42% were exposed to antenatal monotherapy and 17% to dual therapy. Of the 75 women exposed to highly active antiretroviral therapy (HAART), 21 (28%) received protease inhibitor (PI)-based HAART and the remaining 54 received nonnucleoside reverse transcriptase inhibitor-based HAART. In multivariable analysis (176 pregnancies), PI-based HAART exposure during pregnancy was associated with an increased risk of premature delivery [adjusted odds ratio 3.40; 95% confidence interval (CI) 1.13,10.2; P=0.029, compared with monotherapy]. Congenital abnormalities affected 3.3% infants. Perinatally, 18.9% of children (34 of 179) had respiratory problems requiring interventions, which were associated with prematurity but not with type of treatment exposure. From adjusted regression analysis, the mean birth weight z -score for children exposed to HAART with PI (+0.46; 95% CI 0.01,0.92; P=0.047) or dual therapy (+0.43; 95% CI 0.03,0.82; P=0.034) was slightly but significantly higher than that for those exposed to monotherapy; head circumference was appropriate for gestational age and there were no significant differences between treatment groups. Conclusions Use of antenatal PI-based HAART initiated before or during pregnancy was associated with a significantly increased risk of premature delivery at <36 weeks' gestation. The overall crude prematurity rate was 34% (63 of 183; 95% CI 28,42). [source] Effect of Teriparatide {rhPTH(1-34)} on BMD When Given to Postmenopausal Women Receiving Hormone Replacement TherapyJOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2006Louis G Ste-Marie Abstract The effects of teriparatide when given in combination with HRT were studied in postmenopausal women with low bone mass or osteoporosis. The data provide evidence that the adverse event profile for combination therapy with teriparatide + HRT together is consistent with that expected for each treatment alone and that the BMD response is greater than for HRT alone. Introduction: Teriparatide {rhPTH(1-34)}, given as a once-daily injection, activates new bone formation in patients with osteoporosis. Hormone replacement therapy (HRT) prevents osteoporosis by reducing bone resorption and formation. Combination therapy with these two compounds, in small clinical trials, increased BMD and reduced vertebral fracture burden. The purpose of this study was to determine whether teriparatide provided additional effect on BMD when given in combination with HRT. Materials and Methods: A randomized, double-blind, placebo-controlled study was conducted in postmenopausal women with either low bone mass or osteoporosis. Patients were randomized to placebo subcutaneous plus HRT (n = 125) or teriparatide 40 ,g/day (SC) plus HRT (TPTD40 + HRT; n = 122) for a median treatment exposure of 13.8 months. Approximately one-half of the patients in each group were pretreated with HRT for at least 12 months before randomization. Patients received 1000 mg calcium and 400,1200 IU of vitamin D daily as oral supplementation. BMD was measured by DXA. Results: Compared with HRT alone, TPTD40 + HRT produced significant (p < 0.001) increases in spine BMD (14% versus 3%), total hip (5.2% versus 1.6%), and femoral neck (5.2% versus 2%) at study endpoint. BMD, in whole body and ultradistal radius, was higher, and in the one-third distal radius was lower, in the combination therapy but not in the HRT group. Serum bone-specific alkaline phosphatase and urinary N-telopeptide/Cr were increased significantly (p < 0.01) in the women receiving TPTD40 + HRT compared with HRT. A similar profile of BMD and bone markers was evident in both randomized patients as well as in subgroups of patients not pretreated or pretreated with HRT. Patients tolerated both the treatments well. Nausea and leg cramps were more frequently reported in the TPTD40 + HRT group. Conclusions: Adding teriparatide, a bone formation agent, to HRT, an antiresorptive agent, provides additional increases in BMD beyond that provided by HRT alone. The adverse effects of teriparatide when added to HRT were similar to the adverse effects described for teriparatide administered alone. Whether teriparatide was initiated at the same time as HRT or after at least 1 year on HRT, the incremental increases over HRT alone were similar. [source] Quantifying the impact of survivor treatment bias in observational studiesJOURNAL OF EVALUATION IN CLINICAL PRACTICE, Issue 6 2006Peter C. Austin PhD Abstract Rationale, Observational cohort studies are frequently used to measure the impact of therapies on the time to a particular outcome. Treatment often has a time-variant nature since it is frequently initiated at varying times during a patient's follow-up. Studies in the medical literature frequently ignore the time-dependent nature of treatment exposure. Survivor treatment bias can arise when the time dependent nature of treatment exposure is ignored since patients who survived to receive treatment may be healthier than patients who died prior to receipt of treatment. Aims and objectives, The objective of the current study was to explicitly quantify the magnitude of survivor-treatment bias. Methods, Monte Carlo simulations using parameters obtained from an analysis of patients admitted to hospital with a diagnosis of acute myocardial infarction in Ontario, Canada. Results and conclusions, When the true treatment was null (hazard ratio of 1), estimated treatment effects varied from a 4% reduction in mortality to a reduction in mortality of 27% when the time varying nature of the treatment was ignored. Furthermore, survivor-treatment bias increased as the time required foe exposed patients to receive treatment increased. Similarly, survivor treatment bias was amplified as exposure was defined to be exposure at any time prior to mortality compared to exposure within a fixed time interval starting at the time origin. Ignoring the time-dependent nature of treatment results in overly optimistic estimates of treatment effects. Depending on the period required for patients to initiate therapy, treatments with no effect on survival can appear to be strongly associated with improved survival. The current study is the first to explicitly quantify the magnitude of bias that results from ignoring the time-varying nature of treatment exposure in survival studies. [source] Effects of salt stress on purslane (Portulaca oleracea) nutritionANNALS OF APPLIED BIOLOGY, Issue 1 2009M. Teixeira Abstract The objective of this study was to determine the influence of saline stress on the chemical composition of purslane (Portulaca oleracea), in particular the mineral composition. Four salinity levels were investigated using irrigation solutions with electrical conductivity values of 0.8, 6.8, 12.8 and 24.2 dS m,1 and two planting dates (May and July) were tested. Samples of full-grown leaf and stems of purslane were harvested after 7 and 15 days of the saline treatment exposure. Chemical analysis (dry matter basis) of leaves showed significant differences among the different saline treatments for all the characteristics measured. Salinity levels, planting date and harvest time significantly influenced (P < 0.05) the levels of crude protein, total lipids, ash and carbohydrate content. Salinity treatments did not significantly (P > 0.05) affect the water content of purslane leaves. The crude protein content of purslane leaves decreased with increasing salinity levels and time of exposure to treatment. However, carbohydrates and mineral residue content increased. An unusual phenomenon was noted for intermediate salinity levels, whereby an increase in total lipid content was measured in leaves of plants exposed to salinity treatments of 6.8 and 12.8 dS m,1. The highest mineral residue content was seen in leaves of purslane exposed to the highest salinity treatment. The mineral composition was also affected by salinity levels, Na and Cl uptake, and accumulation increased with increasing salinity in irrigation solution; Mg concentration was not significantly (P > 0.05) affected by salinity levels, although a slight increase was seen, and Ca, K and Zn levels significantly (P < 0.05) decreased. Ca and Zn preferentially accumulated in the leaves, while K and Na values were higher in the stems. A significant increase (P < 0.05) in relative ratio of Na/K, Mg/K, Na/Ca and Mg/Ca was observed with increasing salinity levels. A decrease in the yield of purslane was only observed for the most severe saline treatment, where the highest ratio of Mg/Ca was seen. This study reveals that purslane is relatively tolerant to conditions of moderate salinity, thus improving its potential to become a key vegetable crop for animal and human consumption. [source] Long-term complications in survivors of advanced stage neuroblastoma,PEDIATRIC BLOOD & CANCER, Issue 3 2005Caroline Laverdière MD Abstract Background Few studies have assessed late effects in neuroblastoma (NB) survivors, particularly those with advanced stage disease. Methods Retrospective analysis of a cohort of advanced stage NB survivors followed in a late effect clinic at a single institution. Screening tests to detect late effects were tailored depending on the individual's treatment exposures. Results The study included 63 survivors (31 males). The median age at diagnosis was 3.0 years. The median follow-up from diagnosis was 7.06 years. All patients had surgery and received chemotherapy, 89% received radiation therapy (RT), 62% immunotherapy, and 56% autologous stem cell transplant. Late complications were detected in 95% of survivors and included: hearing loss (62%), primary hypothyroidism (24%), ovarian failure (41% of females), musculoskeletal (19%), and pulmonary (19%) abnormalities. The majority of complications were moderate, with only 4% being life-threatening. Survivors who received cisplatin were at greater risk to develop hearing loss compared to those not so treated (OR 9.74; 95% CI: 0.9,101.6). A total dose of cyclophosphamide greater than 7.4 g was associated with ovarian failure (P,=,0.02). Conclusions Late complications occur frequently in survivors of advanced stage NB. The majority of these problems are of mild-moderate severity. Long-term follow-up (LFTU) and screening of this population is essential. © 2005 Wiley-Liss, Inc. [source] The utility of mixed-effects covariate analysis in rapid selection of doses in pediatric subjects: A case study with fexofenadine hydrochlorideBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 9 2004Rajesh Krishna Abstract Fexofenadine hydrochloride is a non-sedating antihistamine that is used in the treatment of symptoms associated with seasonal allergic rhinitis and chronic idiopathic urticaria. A pooled analysis of pharmacokinetic data from children 6 months to 12 years of age and adults was conducted to identify the dose(s) in children that produce exposures comparable to those in adults for the treatment of seasonal allergic rhinitis. The pharmacokinetic parameter database included peak and overall exposure data from 269 treatment exposures from 136 adult subjects, and 90 treatment exposures from 77 pediatric allergic rhinitis patients. The data were pooled and analysed using NONMEM software, version 5.0. A covariate model based on body weight and age and a power function model based on body weight were identified as appropriate models to describe the variability in fexofenadine oral clearance and peak concentration, respectively. Individual oral clearance estimates were on average 44%, 36% and 61% lower in children 6 to 12 years (n = 14), 2 to 5 years (n = 21), and 6 months to 2 years (n = 42), respectively, compared with adults. Trial simulations (n = 100) were carried out based on the final pharmacostatistical models and parameter estimates to identify the appropriate dose(s) in children relative to the marketed dose of 60 mg fexofenadine hydrochloride in adults. The trials were designed as crossover studies in 18 subjects comprising various potential dosing regimens with and without weight stratification. Pharmacokinetic parameter variability was assumed to have a log-normal distribution. Individual weights and ages were simulated using mean (SD) estimates derived from the studies used in this analysis and proportional measurement/model mis-specification errors derived from the analysis were incorporated into the simulation. The results indicated that a 30 mg dose of fexofenadine hydrochloride administered to children 1 to 12 years of age and weighing >10.5 kg and a 15 mg dose administered to children 6 months and older and weighing ,10.5 kg produces exposures similar to those seen with the 60 mg dose in adults. Copyright © 2004 John Wiley & Sons, Ltd. [source] | ||||||||||