A Double Blind, Placebo-Controlled, Randomized Crossover Study of the Acute Metabolic Effects of Olanzapine in Healthy Volunteers

Atypical antipsychotics exhibit metabolic side effects including diabetes mellitus and obesity. The adverse events are preceded by acute worsening of oral glucose tolerance (oGTT) along with reduced plasma free fatty acids (FFA) and leptin in animal models. It is unclear whether the same acute effects occur in humans.A double blind, randomized, placebo-controlled crossover trial was conducted to examine the potential metabolic effects of olanzapine in healthy volunteers. Participants included male (8) and female (7) subjects [18-30 years old, BMI 18.5-25]. Subjects received placebo or olanzapine (10 mg/day) for three days prior to oGTT testing. Primary endpoints included measurement of plasma leptin, oral glucose tolerance, and plasma free fatty acids (FFA). Secondary metabolic endpoints included: triglycerides, total cholesterol, high- and low-density lipoprotein cholesterol, heart rate, blood pressure, body weight and BMI. Olanzapine increased glucose Area Under the Curve (AUC) by 42% (2808±474 vs. 3984±444 mg/dl·min; P = 0.0105) during an oGTT. Fasting plasma leptin and triglycerides were elevated 24% (Leptin: 6.8±1.3 vs. 8.4±1.7 ng/ml; P = 0.0203) and 22% (Triglycerides: 88.9±10.1 vs. 108.2±11.6 mg/dl; P = 0.0170), whereas FFA and HDL declined by 32% (FFA: 0.38±0.06 vs. 0.26±0.04 mM; P = 0.0166) and 11% (54.2±4.7 vs. 48.9±4.3 mg/dl; P = 0.0184), respectively after olanzapine. Other measures were unchanged.Olanzapine exerts some but not all of the early endocrine/metabolic changes observed in rodent models of the metabolic side effects, and this suggest that antipsychotic effects are not limited to perturbations in glucose metabolism alone. Future prospective clinical studies should focus on identifying which reliable metabolic alterations might be useful as potential screening tools in assessing patient susceptibility to weight gain and diabetes caused by atypical antipsychotics.ClinicalTrials.gov NCT00741026

Prediction of overuse injuries in professional U18-U21 footballers using metrics of training distance and intensity

The most common injury in professional football is an overuse injury to the lower limb. A significant external risk factor of this injury is the mismanagement of training and match loads. The aim of the current study was to examine the predictability of overuse injuries in professional youth soccer players using volume and intensity variables derived from Global Positioning Systems (GPS). A total of 41 players (Age - 17.8 yrs±1.1 yrs) training and match loads were assessed. These external loads were measured over two competitive seasons for every training session and match for each individual. A linear regression was used to test the predictability of the injury based on load, which were grouped using loading groups calculated from squad weekly averages. The load groupings assigned were: Low load = 1 SD below the squad mean score; Normal load = ±1 SD from the squad mean; High load = 1 SD above squad mean. The analysis demonstrated that total distance significantly predicted overuse injury incidence rates (F(1, 39) = 6.482, p = 0.015), whereas high speed running meters could not (F(1, 39) = 1.003, p = 0.323). This study demonstrated that distance covered in training and matches can impact on the incidence of overuse injury in youth soccer players. Coaches should seek to monitor player training loads and incorporate this metric into their decision making for protecting players from overuse injury

Test-retest reliability of a 30-minute fixed perceived effort cycling exercise

Purpose: Using exercise protocols at a fixed rating of perceived effort (RPE) is a useful method for exploring the psychophysical influences on exercise performance. However, studies that have employed this protocol have arbitrarily selected RPE values without considering how these values correspond to exercise intensity thresholds and domains. Therefore, aligning RPE intensities with established physiological thresholds seems more appropriate, although the reliability of this method has not been assessed. Methods: Eight recreationally active cyclists completed two identical ramped incremental trials on a cycle ergometer to identify gas exchange threshold (GET). A linear regression model plotted RPE responses during this test alongside gas parameters to establish an RPE corresponding to GET (RPEGET) and 15% above GET (RPE+15%GET). Participants then completed three trials at each intensity, in which performance, physiological, and psychological measures were averaged into five-minute time zone (TZ) intervals and 30-minute ‘overall’ averages. Data were assessed for reliability using intraclass correlation coefficients (ICC) and accompanying standard error measurements (SEM), 95% confidence intervals, and coefficient of variations (CoV). Results: All performance and gas parameters showed excellent levels of test-retest reliability (ICCs = >.900) across both intensities. Performance, gas-related measures, and heart rate averaged over the entire 30-minute exercise demonstrated good intra-individual reliability (CoV = <5%). Conclusion: Recreationally active cyclists can reliably replicate fixed perceived effort exercise across multiple visits when RPE is aligned to physiological thresholds. Some evidence suggests that exercise at RPE+15%GET is more reliable than RPEGET

Tramadol is a performance enhancing drug in highly trained cyclists. A randomised controlled trial

Tramadol is a potent narcotic analgesic reportedly used in multiple sports to reduce exertional pain and confer a performance advantage. This study sought to identify whether tramadol enhances performance in time trial cycling. Twenty-seven highly trained cyclists were screened for tramadol sensitivity and then attended the laboratory across three visits. Visit 1 identified maximal oxygen uptake, peak power output and gas exchange threshold through a ramp incremental test. Participants returned to the laboratory on two further occasions to undertake cycling performance tests following the ingestion of either 100 mg of soluble tramadol or a taste-matched placebo control in a double-blind, randomised, and crossover design. In the performance tests participants completed a 30 min non-exhaustive fixed intensity cycling task at a Heavy exercise intensity (272 ± 42 W), immediately followed by a competitive self-paced 25-mile time trial (TT). Following removal of two outlier data sets, analysis was completed on n=25. Participants completed the TT significantly faster (d = 0.54, p=0.012) in the tramadol condition (3758 s ± 232 s) compared to the placebo condition (3808 s ± 248 s) and maintained a significantly higher mean power output (+9 W) throughout the TT (ƞp2 = 0.262, p=0.009). Tramadol reduced perception of effort during the fixed intensity trial (p=0.026). The 1.3% faster time in the tramadol condition would be sufficient to change the outcomes of a race and is highly meaningful and pervasive in this cohort of highly trained cyclists. The data from this study suggests that tramadol is a performance enhancing drug

Pharmacological hypotheses: Is acetaminophen selective in its cyclooxygenase inhibition?

The precise mechanistic action of acetaminophen (ACT; paracetamol) remains debated. ACT’s analgesic and antipyretic actions are attributed to cyclooxygenase (COX) inhibition preventing prostaglandin (PG) synthesis. Two COX isoforms (COX1/2) share 60% sequence structure, yet their functions vary. COX variants have been sequenced among various mammalian species including humans. A COX1 splice variant (often termed COX3) is purported by some as the elusive target of ACT’s mechanism of action. Yet a physiologically functional COX3 isoform has not been sequenced in humans, refuting these claims. ACT may selectively inhibit COX2, with evidence of a 4.4‐fold greater COX2 inhibition than COX1. However, this is markedly lower than other available selective COX2 inhibitors (up to 433‐fold) and tempered by proof of potent COX1 inhibition within intact cells when peroxide tone is low. COX isoform inhibition by ACT may depend on subtle in vivo physiological variations specific to ACT. In vivo ACT efficacy is reliant on intact cells and low peroxide tone while the arachidonic acid concentration state can dictate the COX isoform preferred for PG synthesis. ACT is an effective antipyretic (COX2 preference for PG synthesis) and can reduce afebrile core temperature (likely COX1 preference for PG synthesis). Thus, we suggest with specificity to human in vivo physiology that ACT: (i) does not act on a third COX isoform; (ii) is not selective in its COX inhibition; and (iii) inhibition of COX isoforms are determined by subtle and nuanced physiological variations. Robust research designs are required in humans to objectively confirm these hypotheses

Therapy with the Opioid Antagonist Naltrexone Promotes Mucosal Healing in Active Crohn&apos;s Disease: A Randomized Placebo-Controlled Trial

Abstract Background Endogenous opioid peptides have been shown to play a role in the development and/or perpetuation of inflammation. We hypothesize that the endogenous opioid system is involved in inflammatory bowel disease, and antagonism of the opioid-opioid receptor will lead to reversal of inflammation. Aims A randomized double-blind placebo-controlled study was designed to test the efficacy and safety of an opioid antagonist for 12 weeks in adults with active Crohn&apos;s disease. Methods Forty subjects with active Crohn&apos;s disease were enrolled in the study. Randomized patients received daily oral administration of 4.5-mg naltrexone or placebo. Providers and patients were masked to treatment assignment. The primary outcome was the proportion of subjects in each arm with a 70-point decline in Crohn&apos;s Disease Activity Index score (CDAI). The secondary outcome included mucosal healing based upon colonoscopy appearance and histology. Results Eighty-eight percent of those treated with naltrexone had at least a 70-point decline in CDAI scores compared to 40% of placebo-treated patients (p = 0.009). After 12 weeks, 78% of subjects treated with naltrexone exhibited an endoscopic response as indicated by a 5-point decline in the Crohn&apos;s disease endoscopy index severity score (CDEIS) from baseline compared to 28% response in placebo-treated controls (p = 0.008), and 33% achieved remission with a CDEIS score \6, whereas only 8% of those on placebo showed the same change. Fatigue was the only side effect reported that was significantly greater in subjects receiving placebo. Conclusions Naltrexone improves clinical and inflammatory activity of subjects with moderate to severe Crohn&apos;s disease compared to placebo-treated controls. Strategies to alter the endogenous opioid system provide promise for the treatment of Crohn&apos;s disease