-
1.
Randomised single centre double-blind placebo controlled phase II trial of Tocovid SupraBio in combination with pentoxifylline in patients suffering long-term gastrointestinal adverse effects of radiotherapy for pelvic cancer: The PPALM study.
Andreyev, HJN, Matthews, J, Adams, C, Gothard, L, Lucy, C, Tovey, H, Boyle, S, Anbalagan, S, Musallam, A, Yarnold, J, et al
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2022;:130-137
Abstract
BACKGROUND Preclinical data suggest that combined gamma-tocotrienol with pentoxifylline ameliorates radiotherapy-induced gastrointestinal damage. AIM: To test whether gastrointestinal symptoms arising after radiotherapy, and persisting after maximal medical therapy, can be improved using Tocovid SupraBio 200 mg and pentoxifylline 400 mg orally twice daily for one year. Patients stratified by severity of symptoms, and randomised to active treatment or matched placebo were assessed after 12 months. The primary end point was improvement in gastrointestinal symptoms measured using the Inflammatory Bowel Disease Questionnaire, bowel subset score. Changes in bio-markers of fibrosis were assessed. RESULTS 62 patients, median age 66, 34(55%) treated for prostate, 21(34%) gynaecological, 6(10%) anal and one(1%) rectal cancer were recruited; 40(65%) randomised to treatment, 22(35%) to placebo, 39 months (median) after radiotherapy completion. Gamma tocotrienol was not detected in serum in 41% of treated patients, despite good compliance with study medication. Treatment was completed in 28(70%) and 17(77%) patients in the treatment and placebo groups respectively. No improvement in symptom scores nor in quality of life was identified. Thirteen serious adverse events occurred. A transient ischaemic attack, was possibly related to pentoxifylline, others were assessed as unlikely to be related to treatment. Levels of EGF, PDGF and FGF were significantly reduced and consistent trends in reduced inflammation were seen during treatment but were not sustained once treatment ended. SUMMARY This single centre study closed prematurely and therefore data interpretation is of necessity limited. No clinical benefit was demonstrated. However, biochemical data suggest that this intervention does have anti-inflammatory and anti-fibrotic effects.
-
2.
Volume of Plasma Expansion and Functional Outcomes in Stroke.
Miller, JB, Lewandowski, C, Wira, CR, Taylor, A, Burmeister, C, Welch, R
Neurocritical care. 2017;(2):191-195
Abstract
BACKGROUND Plasma expansion in acute ischemic stroke has potential to improve cerebral perfusion, but the long-term effects on functional outcome are mixed in prior trials. The goal of this study was to evaluate how the magnitude of plasma expansion affects neurological recovery in acute stroke. METHODS This was a secondary analysis of data from the Albumin in Acute Stroke Part 2 trial investigating the relationship between the magnitude of overall intravenous volume infusion (crystalloid and colloid) to clinical outcome. The data were inclusive of 841 patients with a mean age of 64 years and a median National Institutes of Health Stroke Scale (NIHSS) of 11. In a multivariable-adjusted logistic regression model, this analysis tested the volume of plasma expansion over the first 48 h of hospitalization as a predictor of favorable outcome, defined as either a modified Rankin Scale score of 0 or 1 or a NIHSS score of 0 or 1 at 90 days. This model included all study patients, irrespective of albumin or isotonic saline treatment. RESULTS Patients that received higher volumes of plasma expansion more frequently had large vessel ischemic stroke and higher NIHSS scores. The multivariable-adjusted model revealed that there was decreased odds of a favorable outcome for every 250 ml additional volume plasma expansion over the first 48 h (OR 0.91, 95 % CI, 0.88-0.94). CONCLUSIONS The present study demonstrates an association between greater volume of plasma expansion and worse neurological recovery.
-
3.
The study to understand the genetics of the acute response to metformin and glipizide in humans (SUGAR-MGH): design of a pharmacogenetic resource for type 2 diabetes.
Walford, GA, Colomo, N, Todd, JN, Billings, LK, Fernandez, M, Chamarthi, B, Warner, AS, Davis, J, Littleton, KR, Hernandez, AM, et al
PloS one. 2015;(3):e0121553
Abstract
OBJECTIVE Genome-wide association studies have uncovered a large number of genetic variants associated with type 2 diabetes or related phenotypes. In many cases the causal gene or polymorphism has not been identified, and its impact on response to anti-hyperglycemic medications is unknown. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH, NCT01762046) is a novel resource of genetic and biochemical data following glipizide and metformin administration. We describe recruitment, enrollment, and phenotyping procedures and preliminary results for the first 668 of our planned 1,000 participants enriched for individuals at risk of requiring anti-diabetic therapy in the future. METHODS All individuals are challenged with 5 mg glipizide × 1; twice daily 500 mg metformin × 2 days; and 75-g oral glucose tolerance test following metformin. Genetic variants associated with glycemic traits and blood glucose, insulin, and other hormones at baseline and following each intervention are measured. RESULTS Approximately 50% of the cohort is female and 30% belong to an ethnic minority group. Following glipizide administration, peak insulin occurred at 60 minutes and trough glucose at 120 minutes. Thirty percent of participants experienced non-severe symptomatic hypoglycemia and required rescue with oral glucose. Following metformin administration, fasting glucose and insulin were reduced. Common genetic variants were associated with fasting glucose levels. CONCLUSIONS SUGAR-MGH represents a viable pharmacogenetic resource which, when completed, will serve to characterize genetic influences on pharmacological perturbations, and help establish the functional relevance of newly discovered genetic loci to therapy of type 2 diabetes. TRIAL REGISTRATION ClinicalTrials.gov NCT01762046.
-
4.
Pooled individual data analysis of 5 randomized trials of infant nevirapine prophylaxis to prevent breast-milk HIV-1 transmission.
Hudgens, MG, Taha, TE, Omer, SB, Jamieson, DJ, Lee, H, Mofenson, LM, Chasela, C, Kourtis, AP, Kumwenda, N, Ruff, A, et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2013;(1):131-9
-
-
Free full text
-
Abstract
BACKGROUND In resource-limited settings, mothers infected with human immunodeficiency virus type 1 (HIV-1) face a difficult choice: breastfeed their infants but risk transmitting HIV-1 or not breastfeed their infants and risk the infants dying of other infectious diseases or malnutrition. Recent results from observational studies and randomized clinical trials indicate daily administration of nevirapine to the infant can prevent breast-milk HIV-1 transmission. METHODS Data from 5396 mother-infant pairs who participated in 5 randomized trials where the infant was HIV-1 negative at birth were pooled to estimate the efficacy of infant nevirapine prophylaxis to prevent breast-milk HIV-1 transmission. Four daily regimens were compared: nevirapine for 6 weeks, 14 weeks, or 28 weeks, or nevirapine plus zidovudine for 14 weeks. RESULTS The estimated 28-week risk of HIV-1 transmission was 5.8% (95% confidence interval [CI], 4.3%-7.9%) for the 6-week nevirapine regimen, 3.7% (95% CI, 2.5%-5.4%) for the 14-week nevirapine regimen, 4.8% (95% CI, 3.5%-6.7%) for the 14-week nevirapine plus zidovudine regimen, and 1.8% (95% CI, 1.0%-3.1%) for the 28-week nevirapine regimen (log-rank test for trend, P < .001). Cox regression models with nevirapine as a time-varying covariate, stratified by trial site and adjusted for maternal CD4 cell count and infant birth weight, indicated that nevirapine reduces the rate of HIV-1 infection by 71% (95% CI, 58%-80%; P < .001) and reduces the rate of HIV infection or death by 58% (95% CI, 45%-69%; P < .001). CONCLUSIONS Extended prophylaxis with nevirapine or with nevirapine and zidovudine significantly reduces postnatal HIV-1 infection. Longer duration of prophylaxis results in a greater reduction in the risk of infection.
-
5.
Clinical pharmacology of multiple doses of lasofoxifene in postmenopausal women.
Gardner, M, Taylor, A, Wei, G, Calcagni, A, Duncan, B, Milton, A
Journal of clinical pharmacology. 2006;(1):52-8
Abstract
Lasofoxifene, a next-generation selective estrogen receptor modulator, is undergoing phase 3 clinical development for osteoporosis. This study evaluated daily lasofoxifene for 14 days in healthy postmenopausal women. A loading dose of 5 times the daily dose was followed by daily doses of 0.01 mg (n = 8), 0.03 mg (n =8), 0.1 mg(n = 16), 0.3 mg (n =9), 1 mg (n = 8), or placebo (n = 16). Samples were collected for pharmacokinetic and pharmacodynamic assessments. Lasofoxifene was well tolerated; study drug-associated adverse events were mild and unrelated to dose. There was a predictable increase in plasma concentrations of lasofoxifene with dose. Pharmacokinetic parameters included mean half-life of 165 hours, mean area under the plasma concentration-time curve from time 0 to 24 hours ranging from 1.67 ng x h/mL to 137 ng x h/mL, and mean maximum observed plasma concentration ranging from 0.09 ng/mL to 6.43 ng/mL. Lasofoxifene partially suppressed luteinizing hormone, follicle-stimulating hormone, low-density lipoprotein, and N-telopeptide.
-
6.
Comparison of indirect methods of measuring intra-abdominal pressure in children.
Davis, PJ, Koottayi, S, Taylor, A, Butt, WW
Intensive care medicine. 2005;(3):471-5
Abstract
OBJECTIVE To determine the most accurate indirect method of measuring intra-abdominal pressure (IAP) in children. DESIGN AND SETTING Single-centre, prospective, clinical study in a 23-bed specialist paediatric intensive care unit in Australia. PATIENTS AND PARTICIPANTS 20 children admitted to paediatric intensive care with a peritoneal dialysis catheter in situ following congenital cardiac surgery. INTERVENTIONS IAP was measured directly via the peritoneal dialysis catheter and by intragastric manometry via an indwelling nasogastric tube, and by intravesical manometry via an indwelling transurethral urinary catheter, using volumes of 0, 1, 3 and 5 ml/kg body weight of sterile saline instilled into the bladder. MEASUREMENTS AND RESULTS Across the range of IAPs of 1-8 mmHg the Bland-Altman method for assessing agreement between two methods of clinical measurement showed bladder pressure measured via the urinary catheter with 1 ml/kg body weight of saline instilled to be the most accurate indirect measurement technique, tending to give pressures between 0.07 and 1.23 mmHg higher than the direct measurement (95% CI for bias). Measuring bladder pressure with either no saline instilled or more saline per kilogram body weight instilled was less accurate over the same range of pressures, as was measuring the gastric pressure. CONCLUSIONS The most accurate indirect method of measuring IAP in children over the normal range of IAPs involves measuring bladder pressure via a transurethral urinary catheter with 1 ml/kg body weight of sterile saline instilled into the bladder.
-
7.
Diet but not aerobic exercise training reduces skeletal muscle TNF-alpha in overweight humans.
Ferrier, KE, Nestel, P, Taylor, A, Drew, BG, Kingwell, BA
Diabetologia. 2004;(4):630-7
Abstract
AIMS/HYPOTHESIS Our aim was to test the hypothesis that TNF-alpha protein levels in skeletal muscle are important in mediating the improvements in glucose homeostasis that are associated with diet and exercise regimens intended to reduce cardiovascular risk. METHODS We recruited 20 people with a body mass index of 32.1 +/- 1.2 kg/m2 (mean +/- SEM) and one other component of the metabolic syndrome. The average age was 51.2 +/- 8.1 years (mean +/- SD). Of the 20 subjects, 6 were men and 14 were women. All subjects completed an 8-week control period, followed by randomisation to 8 weeks of moderate cycling exercise (30 min, three times per week) or to a diet with the following characteristics: low in saturated fat, high in fibre, low glycaemic index, rich in complex carbohydrates. RESULTS Diet induced a small reduction in body mass index (3.0 +/- 0.7%, p<0.05), although weight loss was not intended. Exercise training increased maximum oxygen consumption by 12 +/- 6% (p<0.05). Both interventions reduced fasting plasma insulin levels by about 20%. Diet reduced skeletal muscle TNF-alpha protein by 54 +/- 10% (p<0.05), an effect that was independent (p=0.94 in covariate analysis) of the small concurrent weight loss (-2.8 +/- 0.7 kg). Levels of GLUT4 protein were unchanged in the diet group. In contrast, exercise training did not significantly change TNF-alpha protein expression, but GLUT4 protein expression increased by 105 +/- 37% (p<0.05). CONCLUSIONS/INTERPRETATION These data indicate that the metabolic benefits of a diet aimed at cardiovascular risk reduction are associated with a decrease in skeletal muscle TNF-alpha protein.
-
8.
Cardiovascular safety profile of combretastatin a4 phosphate in a single-dose phase I study in patients with advanced cancer.
Cooney, MM, Radivoyevitch, T, Dowlati, A, Overmoyer, B, Levitan, N, Robertson, K, Levine, SL, DeCaro, K, Buchter, C, Taylor, A, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2004;(1 Pt 1):96-100
Abstract
PURPOSE The purpose of our study was to review and determine the cardiovascular safety profile of combretastatin A4 phosphate (CA4P) in a Phase I study in 25 patients with advanced solid tumors. EXPERIMENTAL DESIGN CA4P was administered in a dose-escalating fashion starting at 18 mg/m(2) i.v. every 21 days, and the maximal dosage was 90 mg/m(2). Continuous evaluation included bedside blood pressure and pulse monitoring, 12-lead electrocardiogram (ECG) at fixed time points for measured QT interval determination, determination of the corrected QT interval (QTc) using Bazett's formula QTc = QT/(R-R interval)(1/2), and chart review. Pharmacodynamic correlations of CA4P dose, CA4P/CA4 area under the curve, and C(max) versus heart rate (HR), blood pressure, QT, and QTc intervals, over the first 4 h postdosing were analyzed. RESULTS After CA4P administration, there were significant increases in QTc interval at the 3-h and 4-h time points [27.2 ms (P < 0.0001) and 30.8 ms (P < 0.0001), respectively] and HR at the 3- and 4-h time points [13.2 beats per minute (bpm; P < 0.01) and 15.1 bpm (P < 0.001), respectively]. Three of 25 patients had prolonged QTc intervals at baseline, whereas 15 (60%) of 25 and 18 (75%) of 24 patients had prolonged QTc intervals at 3 and 4 h. The slope of HR and QTc increasing as a function of time during the first 4 h was correlated to dose (in milligrams) of CA4P (P = 0.01 and r = 0.49 for HR, P = 0.005 and r = 0.55 for QTc) and to CA4 area under the curve (P = 0.04 and r = 0.41 for HR, P = 0.02 and r = 0.44 for QTc); blood pressure and uncorrected QTc interval dose-response correlations were not significant. Two patients had ECG changes consistent with an acute coronary syndrome within 24 h of CA4P infusion. CONCLUSIONS CA4P prolongs the QTc interval. There was a temporal relationship with the CA4P infusion and with ECG changes consistent with an acute coronary syndrome in two patients. It is advisable that future trials with CA4P have eligibility guidelines limiting patients with known coronary artery disease or those with multiple coronary artery disease risk factors until more experience is gained regarding potential cardiovascular toxicity with this agent.
-
9.
Unidentified acids of strong prognostic significance in severe malaria.
Dondorp, AM, Chau, TT, Phu, NH, Mai, NT, Loc, PP, Chuong, LV, Sinh, DX, Taylor, A, Hien, TT, White, NJ, et al
Critical care medicine. 2004;(8):1683-8
Abstract
OBJECTIVE To calculate, using the Stewart approach to acid-base disorders, the strong anion gap as an estimate for the contribution of unmeasured plasma anions other than lactate to the metabolic acidosis that characterizes severe falciparum malaria and to assess its relative prognostic significance. DESIGN Cohort study. SETTING The intensive care unit of an infectious diseases hospital in southern Vietnam. PATIENTS Consecutive adult patients (n = 268) with severe falciparum malaria. INTERVENTIONS The intervention was clinical management in a dedicated unit. We measured baseline venous lactate, electrolytes, biochemical variables, admission arterial blood pH, and gas tensions for calculation of the strong anion gap. MEASUREMENTS AND MAIN RESULTS The mean (95% confidence interval) admission strong anion gap was 11.1 (10.4-11.9) mEq/L, compared with lactate (geometric mean, 95% confidence interval) at 2.9 (2.7-3.2) mmol/L. Strong anion gap had a high predictive value for mortality (area under the receiver operating characteristic curve 0.73 (95% confidence interval, 0.65-0.82), which was independent of plasma lactate and creatinine concentrations. Renal failure and hepatic dysfunction were both associated with, but were not the sole determinants of, high levels of strong anion gap. CONCLUSIONS In severe malaria, unidentified anions other than lactate are the most important contributors to metabolic acidosis, a major cause of death. The strong anion gap is a powerful prognostic indicator in patients with severe malaria.
-
10.
Magnesium-creatine supplementation effects on body water.
Brilla, LR, Giroux, MS, Taylor, A, Knutzen, KM
Metabolism: clinical and experimental. 2003;(9):1136-40
Abstract
This study evaluated magnesium-creatine (MgCre) supplementation on body water and quadriceps torque. Maltodextran (Placebo), Mg oxide plus Cre (MgO-Cre), and Mg-creatine chelate (MgC-Cre) at 800 mg Mg and 5 g Cre per day were used for 2 weeks in 35 subjects in a random assignment, blinded study. Pre-post measures were completed with bioimpedance to determine total body water (TBW), extracellular water (ECF), and intracellular water (ICF), and an isokinetic device at 180 degrees per second for knee extension peak torque (T), total work (W), and power (PWR). Body weights increased for both treatment groups, MgO-Cre Delta 0.75 kg (P <.05) and MgC-Cre Delta 0.4 kg (P =.07). Significant pre-post differences (P <.05) were noted only for MgC-Cre in ICW (26.29 v 28.01 L) and ECW (15.75 v 14.88 L). MgC-Cre had significant peak T (Nm) increase (124.5 v135.8, P <.05), while MgO-Cre (116.4 v 124.9, P =.06) and placebo (119.8 v 123.7, P =.343) did not. Both treatment groups had increased PWR (P <.05). MgC-Cre affects cellular fluid compartments. The peak torque changes were significant only in the MgC-Cre group, which had increases in ICW that may infer more muscular creatine due to its osmotic effect, and with increased cellular hydration, perhaps increased protein synthesis.