PURPOSE.This article reviews the pharmacology, clinical utility, adverse effects, and abuse potential of kratom.
SUMMARY.The leaves of Mitragyna speciosa contain the biologically active alkaloids of ...kratom. Kratom exerts opioid and α-2 receptor agonistic effects as well as antiinflammatory and parasympathetic-impeding effects. There are no published human pharmacologic, pharmacokinetic, or drug interaction studies on kratom or mitragynine, making it virtually impossible to fully understand kratomʼs therapeutic potential and risks and the populations most likely to benefit or experience harm from its use. Kratom has been used to ameliorate opioid withdrawal symptoms but also induces withdrawal. Human pharmacologic, pharmacokinetic, and clinical data are of low quality, precluding any firm conclusions regarding safety and efficacy. Respiratory depression has not been commonly reported, but kratom does cause a host of adverse effects without clear guidance for how they should be treated. There are numerous assessments where people have been unable to stop using kratom therapy, and withdrawal signs and symptoms are problematic. Kratom does not appear in normal drug screens and, when taken with other substances of abuse, may not be recognized. Thirty-six deaths have been attributed to kratom, and the Food and Drug Administration issued a public health warning about the substance in November 2017.
CONCLUSION.Kratom exerts opioid and α-2 receptor agonistic effects as well as antiinflammatory and parasympathetic-impeding effects. Human pharmacologic, pharmacokinetic, and clinical data are of low quality, precluding any firm conclusions regarding safety and efficacy.
N-nitrosodimethylamine (NDMA) is a hepatotoxic agent and carcinogen contaminant in commonly used medications such as valsartan, losartan, irbesartan, and ranitidine. NDMA can be produced during ...manufacture, introduced from contaminated ingredients procured elsewhere, or introduced from contaminated solvents and catalysts. The Food and Drug Administration has established a maximum dose of NDMA that is permissible per tablet and guidance for manufacturers. However, many unanswered questions about NDMA contamination need rigorous investigation.
The Dietary Supplement Health and Education Act led to a flood of poor-quality dietary supplements. The Food and Drug Administration’s (FDA’s) jurisdiction is limited to removing products proven ...unsafe, rather than prospectively assessing them for quality manufacturing. With so many products available, there is very little FDA oversight until reports of patient harm occur. Microbial and heavy metal contamination, adulteration with synthetic drugs (including drugs banned from the United States), substituting herbs, and fraudulently specifying ingredients on the label have all occurred. Clinicians should collectively advocate for legislative change, only recommend products tested by outside laboratories for quality, and educate consumers about the risks of using unverified products.
Effect of statins on skeletal muscle function Parker, Beth A; Capizzi, Jeffrey A; Grimaldi, Adam S ...
Circulation (New York, N.Y.),
01/2013, Letnik:
127, Številka:
1
Journal Article
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Many clinicians believe that statins cause muscle pain, but this has not been observed in clinical trials, and the effect of statins on muscle performance has not been carefully studied.
The Effect ...of Statins on Skeletal Muscle Function and Performance (STOMP) study assessed symptoms and measured creatine kinase, exercise capacity, and muscle strength before and after atorvastatin 80 mg or placebo was administered for 6 months to 420 healthy, statin-naive subjects. No individual creatine kinase value exceeded 10 times normal, but average creatine kinase increased 20.8±141.1 U/L (P<0.0001) with atorvastatin. There were no significant changes in several measures of muscle strength or exercise capacity with atorvastatin, but more atorvastatin than placebo subjects developed myalgia (19 versus 10; P=0.05). Myalgic subjects on atorvastatin or placebo had decreased muscle strength in 5 of 14 and 4 of 14 variables, respectively (P=0.69).
These results indicate that high-dose atorvastatin for 6 months does not decrease average muscle strength or exercise performance in healthy, previously untreated subjects. Nevertheless, this blinded, controlled trial confirms the undocumented impression that statins increase muscle complaints. Atorvastatin also increased average creatine kinase, suggesting that statins produce mild muscle injury even among asymptomatic subjects. This increase in creatine kinase should prompt studies examining the effects of more prolonged, high-dose statin treatment on muscular performance.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00609063.
Objective:
To assess the impact of inflammation on cytochrome P450 (CYP) drug metabolism in human subjects.
Data Sources:
A PubMed search was done from 1980 to July 2021 limited to human subjects and ...English language using a search strategy of (((phase I metabolism) OR (CYP) OR (cytochrome P450)) AND (inflammatory OR inflammation)).
Study Selection and Data Extraction:
Narrative review of human studies assessing the impact of inflammation or inflammatory suppression with biologic drugs on CYP drug metabolism were used.
Data Synthesis:
Patients with inflammatory conditions ranging from fungal, viral, or bacterial infections to noninfectious causes (critical illness, surgical procedure, cancer, or transplantation of stem cells or organs) have suppressed drug metabolism. Markers of inflammation such as C-reactive protein or α-1-acid glycoprotein are correlated with reduced clearance through CYP3A4, CYP1A2, and CYP2C19. Elevated interleukin-6 concentrations are also associated or correlated with reduced clearance for CYP3A4 and CYP2C-19 isoenzymes. There was insufficient information to properly assess CYP2D6.
Relevance to Patient Care and Clinical Practice:
Health professionals should appreciate that patients with acute or chronic inflammation from infectious or noninfectious causes could have suppressed drug metabolism through CYP3A4, CYP1A2, and CYP2C19. For narrow therapeutic index drugs, such as many of the drugs assessed in this review, that means more judicious drug monitoring to prevent adverse events.
Conclusions:
Like other types of drug-drug or drug-disease interactions, inflammation can alter the steady-state concentration of CYP metabolized drugs.
Combined use of inhaled corticosteroids and long-acting β-agonists (LABAs) as the controller and the quick relief therapy termed single maintenance and reliever therapy (SMART) is a potential ...therapeutic regimen for the management of persistent asthma.
To conduct a systematic review and meta-analysis of the effects of SMART in patients with persistent asthma.
The databases of MEDLINE via OVID, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews were searched from database inception through August 2016 and updated through November 28, 2017. Two reviewers selected randomized clinical trials or observational studies evaluating SMART vs inhaled corticosteroids with or without a LABA used as the controller therapy and short-acting β-agonists as the relief therapy for patients aged 5 years or older with persistent asthma and reporting on an outcome of interest.
Meta-analyses were conducted using a random-effects model to calculate risk ratios (RRs), risk differences (RDs), and mean differences with corresponding 95% CIs. Citation screening, data abstraction, risk assessment, and strength of evidence grading were completed by 2 independent reviewers.
Asthma exacerbations.
The analyses included 16 randomized clinical trials (N = 22 748 patients), 15 of which evaluated SMART as a combination therapy with budesonide and formoterol in a dry-powder inhaler. Among patients aged 12 years or older (n = 22 524; mean age, 42 years; 14 634 65% were female), SMART was associated with a reduced risk of asthma exacerbations compared with the same dose of inhaled corticosteroids and LABA as the controller therapy (RR, 0.68 95% CI, 0.58 to 0.80; RD, -6.4% 95% CI, -10.2% to -2.6%) and a higher dose of inhaled corticosteroids and LABA as the controller therapy (RR, 0.77 95% CI, 0.60 to 0.98; RD, -2.8% 95% CI, -5.2% to -0.3%). Similar results were seen when SMART was compared with inhaled corticosteroids alone as the controller therapy. Among patients aged 4 to 11 years (n = 341; median age, 8 range, 4-11 years; 69 31% were female), SMART was associated with a reduced risk of asthma exacerbations compared with a higher dose of inhaled corticosteroids as the controller therapy (RR, 0.55 95% CI, 0.32 to 0.94; RD, -12.0% 95% CI, -22.5% to -1.5%) or the same dose of inhaled corticosteroids and LABA as the controller therapy (RR, 0.38 95% CI, 0.23 to 0.63; RD, -23.2% 95% CI, -33.6% to -12.1%).
In this meta-analysis of patients with persistent asthma, the use of single maintenance and reliever therapy compared with inhaled corticosteroids as the controller therapy (with or without a long-acting β-agonist) and short-acting β-agonists as the relief therapy was associated with a lower risk of asthma exacerbations. Evidence for patients aged 4 to 11 years was limited.
In this month’s Annals of Pharmacotherapy, the largest observational study assessing the early versus later use of vasopressin has been published. When this new study is combined with the other ...available observational studies, there are 2 important outcomes to focus on. When all the observational studies are pooled together, no reduction in new onset arrhythmias is seen (odds ratio OR = 0.91, 95% confidence interval CI = 0.41-1.95) with early versus late vasopressin use while the reduction in renal replacement therapy just missed statistical significance (OR = 0.56, 95% CI = 0.32-1.00). Early vasopressin likely does not reduce new onset arrhythmias versus later use but might reduce the need for renal replacement therapy.
Iterative near-term ecological forecasting Dietze, Michael C.; Fox, Andrew; Beck-Johnson, Lindsay M. ...
Proceedings of the National Academy of Sciences - PNAS,
02/2018, Letnik:
115, Številka:
7
Journal Article
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Two foundational questions about sustainability are “How are ecosystems and the services they provide going to change in the future?” and “How do human decisions affect these trajectories?” Answering ...these questions requires an ability to forecast ecological processes. Unfortunately, most ecological forecasts focus on centennial-scale climate responses, therefore neither meeting the needs of near-term (daily to decadal) environmental decision-making nor allowing comparison of specific, quantitative predictions to new observational data, one of the strongest tests of scientific theory. Near-term forecasts provide the opportunity to iteratively cycle between performing analyses and updating predictions in light of new evidence. This iterative process of gaining feedback, building experience, and correcting models and methods is critical for improving forecasts. Iterative, near-term forecasting will accelerate ecological research, make it more relevant to society, and inform sustainable decision-making under high uncertainty and adaptive management. Here, we identify the immediate scientific and societal needs, opportunities, and challenges for iterative near-term ecological forecasting. Over the past decade, data volume, variety, and accessibility have greatly increased, but challenges remain in interoperability, latency, and uncertainty quantification. Similarly, ecologists have made considerable advances in applying computational, informatic, and statistical methods, but opportunities exist for improving forecast-specific theory, methods, and cyberinfra-structure. Effective forecasting will also require changes in scientific training, culture, and institutions. The need to start forecasting is now; the time for making ecology more predictive is here, and learning by doing is the fastest route to drive the science forward.
Efficacy and safety of treatments for hospitalized COVID-19 are uncertain. We systematically reviewed efficacy and safety of remdesivir for the treatment of COVID-19.
Studies evaluating remdesivir in ...adults with hospitalized COVID-19 were searched in several engines until August 21, 2020. Primary outcomes included all-cause mortality, clinical improvement or recovery, need for invasive ventilation, and serious adverse events (SAEs). Inverse variance random effects meta-analyses were performed.
We included four randomized controlled trials (RCTs) (n = 2296) two vs. placebo (n = 1299) and two comparing 5-day vs. 10-day regimens (n = 997), and two case series (n = 88). Studies used intravenous remdesivir 200mg the first day and 100mg for four or nine more days. One RCT (n = 236) was stopped early due to AEs; the other three RCTs reported outcomes between 11 and 15 days. Time to recovery was decreased by 4 days with remdesivir vs. placebo in one RCT (n = 1063), and by 0.8 days with 5-days vs. 10-days of therapy in another RCT (n = 397). Clinical improvement was better for 5-days regimen vs. standard of care in one RCT (n = 600). Remdesivir did not decrease all-cause mortality (RR 0.71, 95%CI 0.39 to 1.28, I2 = 43%) and need for invasive ventilation (RR 0.57, 95%CI 0.23 to 1.42, I2 = 60%) vs. placebo at 14 days but had fewer SAEs; 5-day decreased need for invasive ventilation and SAEs vs. 10-day in one RCT (n = 397). No differences in all-cause mortality or SAEs were seen among 5-day, 10-day and standard of care. There were some concerns of bias to high risk of bias in RCTs. Heterogeneity between studies could be due to different severities of disease, days of therapy before outcome determination, and how ordinal data was analyzed.
There is paucity of adequately powered and fully reported RCTs evaluating effects of remdesivir in hospitalized COVID-19 patients. Until stronger evidence emerges, we cannot conclude that remdesivir is efficacious for treating COVID-19.
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