Healthy Volunteer Studies in the Development of Anticancer Drugs with Genotoxic Findings

Background Recent scientific advances in cancer research have led to the development of immunomodulatory and molecularly targeted drugs with better safety profiles than chemotherapeutics, which makes it possible to include healthy volunteers (HVs) in clinical trials. In this study, we aimed to identify the number of marketing authorization applications (MAAs) that enrolled HVs in a clinical trial and to identify the number of anticancer drugs that were given to HVs despite a positive genotoxic finding. In addition, we evaluated the dose of anticancer drugs administered to HVs and the justification for proceeding with HV studies despite a positive genotoxic finding. Methods Publicly available information from the European Medicines Agency (EMA) website was used for this study. Anticancer drugs were identified using the human medicines highlights published by EMA between January 2010 and December 2019. EPARs were used to collect general information of the anticancer drugs, details on genotoxicity studies, and the enrollment of HVs in clinical trials. Results We identified 71 MAAs for small molecule anticancer drugs with a positive or negative CHMP opinion in the EU. Forty-eight anticancer drugs were studied in HVs, of which 12 anticancer drugs were administered to HVs despite positive genotoxic findings in the standard battery. Systematic and extensive genetic toxicology screening demonstrated the absence of genotoxic risks to the cell system. Conclusion We showed that despite a positive genotoxic finding, comprehensive genetic toxicology testing demonstrated the absence of risks to the cell system at the human exposure dose. Therefore, these anticancer drugs posed no harm to HVs.

Crystal methamphetamine use in British Columbia, Canada: A cross-sectional study of people who access harm reduction services

Introduction Increased use of crystal methamphetamine (“crystal meth”) has been observed across North America and international jurisdictions, including a notable increase in the presence of methamphetamines in illicit drug toxicity deaths in British Columbia (BC), Canada. We used data from a cross-sectional survey and urine toxicology screening to report the prevalence, correlates, and validity of self-reported crystal meth use among clients of harm reduction sites in BC. Materials and methods Survey data were collected from 1,107 participants across 25 communities in BC, through the 2018 and 2019 Harm Reduction Client Survey. We described reported substance use and used a multivariate logistic regression model to characterize crystal meth use. Urine samples provided by a subset of participants were used to derive validity of self-reported three-day crystal meth use compared to urine toxicology screening. Results Excluding tobacco, crystal meth was the most frequently reported substance used in the past three days in 2018 and 2019 (59.7% and 71.7%, respectively). Smoking was the dominant route of administration for crystal meth, crack, heroin, and fentanyl. Multivariate analysis determined significantly higher odds of crystal meth use among those who used opioids (Adjusted Odds Ratio [AOR] = 3.13), cannabis (AOR = 2.10), and alcohol (1.41), and among those who were not regularly housed (AOR = 2.08) and unemployed (AOR = 1.75). Age ≥50 was inversely associated with crystal meth use (AOR = 0.63). Sensitivity of self-reported crystal meth use was 86%, specificity was 86%, positive predictive value was 96%, and negative predictive value was 65%. Conclusions Crystal meth was the most commonly used substance among clients of harm reduction sites in BC in 2018 and 2019, and was frequently used concurrently with opioids. Comparison to urine samples demonstrated high validity of self-reported crystal meth use. Understanding evolving patterns of substance use will be imperative in tailoring harm reduction and substance use services for individuals that use crystal meth.

Marijuana: An Underappreciated Risk Factor for Acute Type A Aortic Dissection?

Background: Stimulants such as cocaine and amphetamines are well-established risk factors for acute aortic dissection. Despite the fact that marijuana is the most commonly used illicit drug in the United States, its relationship to acute aortic syndromes has not been well studied. Methods: A comprehensive retrospective review was undertaken of all consecutive patients who presented with acute Stanford type A aortic dissection from January 2017 to December 2019. Of 152 patients identified, 51 (33.6%) underwent comprehensive urine toxicology screening at clinical presentation. The characteristics and outcomes of the patients with urine results positive for tetrahydrocannabinol (THC) (n = 9, 17.6%) were compared with the 42 patients who had no evidence of recent marijuana consumption. Results: Of the 51 dissection patients who underwent broad-spectrum urine toxicology screening upon presentation, 9 (17.6%) returned positive results for THC, a proportion higher than would be expected for the general population. All THC patients were male; 3 concurrently tested positive for cocaine, and 3 others had evidence of recent amphetamine use. The THC patients were significantly younger than the non-THC patients (mean ± standard deviation age 48 ± 11.3 versus 61.4 ± 12.3 years, respectively, P = .004). A greater proportion of the THC cohort had a known diagnosis of aortic aneurysm before the dissection (44.4% versus 4.8%, P = .006). All patients underwent expeditious surgical repair. Thirty-day mortality for the entire cohort of 51 patients was 19.6% (10 deaths); for the THC group, it was 11.1% (1 death). There was no difference in the incidence of major postoperative complications between the 2 groups. Conclusion: Marijuana is the third most commonly used substance in the United States, after alcohol and tobacco. Although marijuana use is understudied, our results suggest that marijuana may be a contributing risk factor for acute type A aortic dissection, particularly in patients with other predisposing risk factors. Given the recent national trend to legalize marijuana, with the concomitant potential for exponential increases in its consumption, we suggest that the diagnosis of aortic dissection be considered earlier in any younger patient who presents with suggestive symptoms, especially if there is a history of recent marijuana use.

Substance use disorder in anaesthetists: A personal perspective

In this article, I present a firsthand account as an anaesthetist with substance use disorder who has been through rehabilitation and returned to clinical anaesthesia, followed by an overview of substance use disorder in anaesthesia. Substance use disorder is prevalent within the anaesthesia community and can result in tragic consequences, including death in many cases. The incidence is around one to two per 1000 anaesthetist years and this appears to be rising, perhaps mirroring the population-wide increase in substance use disorder as a result of the opioid epidemic. Recognising substance use disorder in a colleague and intervening to try and help them and protect patients can be immensely challenging. Carrying out a successful intervention requires careful planning and coordination in order to protect the affected individual, their colleagues and patients. Returning to clinical anaesthesia following a diagnosis of substance use disorder is also contentious, with the high abstinence rate (relative to the wider substance use disorder population) having to be balanced against the risk of death following relapse. Any return to practice must be well planned and supported, and include appropriate toxicology screening. With such measures, rehabilitation and a return to clinical anaesthesia is possible in certain cases. For the affected individual regaining, then maintaining, their professional identity can be a powerful motivator to remain abstinent. Drug diversion and substance use disorder in anaesthesia is unlikely ever to be fully preventable, but strategies such as biometric dispensing, analysis of unused drugs, random toxicology and ongoing education may help to keep it to a minimum.

Diminished Consciousness in a Woman Following an Unsuspected Scopolamine Overdose

Scopolamine is used clinically, but it is also used as a recreational drug and as an incapacitating drug, in sexual crimes and robberies. In this paper, the authors report the case of a woman with a diminished consciousness following an unsuspected overdose with scopolamine and review published articles on scopolamine poisoning that included concentrations in biological samples. Scopolamine was identified in the patient’s serum and urine samples collected 1 h post-admission to intensive care unit at concentrations of 8.4 ng/mL and 62,560 ng/mL (169,539 ng/mg creatinine), respectively. In non-fatal cases, the median [interquartile range] of serum scopolamine levels was 1.9 [2.1] ng/mL. The serum concentration found in our case would explain the abrupt clinical presentation suffered by the patient. Scopolamine in urine could be detected up to 48 h after admission. This report illustrates that broad toxicology screening, including scopolamine, should be considered when patients with diminished consciousness are attended after ruling out infection or cerebrovascular disease. This can play an important role in identifying this potentially life-threatening etiology.