Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Pharmacokinetics and pharmacokinetic variability of heroin and its metabolites: review of the literature

This article reviews the pharmacokinetics of heroin after intravenous, oral, intranasal, intramuscular and rectal application and after inhalation in humans, with a special focus on heroin maintenance therapy in heroin dependent patients. In heroin maintenance therapy high doses pharmaceutically prepared heroin (up to 1000 mg/day) are prescribed to chronic heroin dependents, who do not respond to conventional interventions such as methadone maintenance treatment. Possible drug-drug interactions with the hydrolysis of heroin into 6-monoacetylmorphine and morphine, the glucuronidation of morphine and interactions with drug transporting proteins are described. Since renal and hepatic impairment is common in the special population of heroin dependent patients, specific attention was paid on the impact of renal and hepatic impairment. Hepatic impairment did not seem to have a clinically relevant effect on the pharmacokinetics of heroin and its metabolites. However, some modest effects of renal impairment have been noted, and therefore control of the creatinine clearance during heroin-assisted treatment seems recommendabl

Population pharmacokinetics of heroin and its major metabolites

BACKGROUND: In several European countries and in Canada, clinical trials are being conducted in which heroin-addicted patients are treated with pharmaceutically prepared heroin in order to reduce the destructive behaviour that is so often associated with this drug. OBJECTIVE: To develop an integrated population pharmacokinetic model for heroin (diamorphine) and its pharmacodynamically active metabolites 6-acetylmorphine, morphine, morphine-3-glucuronide and morphine-6-glucuronide. Additionally, the influence on heroin pharmacokinetics of several covariates that are typical for this population was determined. METHOD: Plasma concentration data from 106 heroin-dependent patients in The Netherlands (74 heroin inhalers and 32 injectors) were obtained. The 'chasing the dragon' technique was used for inhalation, in which the fumes of heroin base, heated on aluminum foil, were inhaled. Heroin doses varied between 66 and 450 mg. Heroin, 6-acetylmorphine and morphine data were fitted simultaneously using sequential two-compartment models. Morphine-3-glucuronide and morphine-6-glucuronide data were fitted separately to one-compartment models. All data analysis was performed using nonlinear mixed-effect modelling. RESULTS: The bioavailability of inhaled heroin was estimated to be 53% (95% CI 43.7, 62.3). The terminal half-lives of heroin and 6-acetylmorphine were estimated to be 7.6 and 21.8 minutes, respectively. The clearances of morphine and the morphine-glucuronides were estimated to be 73.6 L/h (95% CI 62.8, 84.4) and between 6 and 10 L/h, respectively. The terminal half-life of 6-acetylmorphine was 13% lower in cocaine users (p 60 mL/min) do not need to be taken into account in the medical prescription of pharmaceutically prepared heroin for the treatment of heroin dependenc

Use of Opioids Increases With Age in Older Adults: An Observational Study (2005-2017)

Aim: Pain is increasingly treated with opioids. Potential harms of opioid therapy disproportionally affect older patients. This study aims to provide information on trends, nature and duration of opioid prescribing to older adults, in primary care and to explore differences between older patients from different ages. Methods: Primary care data (2005-2017) were derived from routine electronic medical records of patients in Nivel Primary Care Database. All opioid prescriptions with Anatomical Therapeutic Chemical Classification (ATC) code N02A were selected (except for codeine). Diagnoses were recorded using the International Classification of Primary Care (ICPC). Patients were categorized in three age groups (65-74, 75-84, and ≥85 years). Descriptive analyses were used to describe the trend of opioid prescriptions for specific opioids, the duration of use and underlying diagnoses. Results: 283,600 patients were included of which 32,287 had at least one opioid prescription in 2017. An increase in the number of older adults who received at least one opioid was seen between 2005 and 2017. The oldest patients were more likely to be prescribed an opioid, especially when it comes to strong opioids, the increase in the volume of prescribing was highest in this group. Moreover, over 40% of the oldest patients used strong opioids chronically. Strong opioids were mostly prescribed for musculoskeletal diagnoses. Cancer was the second most common diagnosis for strong opioids in the younger subgroups, whereas less specified diagnoses were as second in the oldest subgroup. Conclusion: Opioid prescription changes with increasing age in frequency, nature, and duration, despite higher harm risks among older patients. Because of the high prevalence of chronic use, it is important to monitor the patient throughout the treatment and to critically evaluate the initiation and continuation of opioid prescriptions

Pharmacokinetics and pharmacodynamics of high doses of pharmaceutically prepared heroin, by intravenous or by inhalation route in opioid-dependent patients

A pharmacokinetic-pharmacodynamic study was performed in opioid-dependent patients in the Netherlands, who were currently treated with high doses of pharmaceutically prepared heroin on medical prescription. Besides intravenous heroin, heroin was prescribed for inhalation by "chasing the dragon" method. In this technique, heroin base is heated on aluminium foil, and heroin vapours are inhaled into the lungs. Not much is known about the pharmacokinetics profile and bioavailability of this specific administration method. Therefore, a study was performed on pharmacokinetics and pharmacodynamics of heroin inhalation and intravenous use. Eleven patients who injected heroin and 9 patients who inhaled heroin entered the study. They were on steady-state heroin treatment for at least 12 months. For safety reasons, there was no crossing-over between heroin injection or inhalation. In a double-blind randomised study, 67-100-150% of the regular heroin maintenance dose was administered to each patient. Maximal single heroin dose was 450 mg. Plasma concentrations of heroin and its metabolites 6-monoacetylmorphine, morphine and morphine-glucuronides were analysed using LC-MS-MS. Blood pressure, heart rate, skin temperature and reaction time were assessed. Furthermore, visual analogue scales regarding craving and appreciation of heroin effect were scored by the subjects. Both in inhaling and injecting patients, the areas under curve of heroin and all measured metabolites were linearly related to heroin dose. Mean C(max) of heroin and its metabolites were 2-6 times lower after inhalation, than after intravenous injection. Bioavailability (F) of heroin inhalation was estimated as 52% (95% CI 44-61%). Heroin was rapidly cleared from plasma. Cl/F was 930 l/hr (95% CI 799-1061 l/hr) after intravenous administration, and 1939 l/hr (95% CI 1661-2217 l/hr) after inhalation. Heroin Cl and Vd were correlated to body weight (R(2) 15-19%). Morphine-glucuronides levels were inversely related to creatinine clearance. After heroin administration, the reaction time was significantly prolonged with 28+/-5.3 msec. in injecting and 13+/-4.9 msec. in inhaling patients. Cardiovascular changes were only mild after heroin administration. Craving-scores declined immediately after heroin administration in both administration groups. Subjective heroin effect was rated more positively in heroin inhaling than in injecting patients, despite the lower C(max) levels following heroin inhalation. In both groups, in this blinded study heroin dose increments were more appreciated than dose reductions. Increments of 50% of the regular heroin dose did not cause any serious side effec

Pharmacokinetic comparison of two methods of heroin smoking: 'chasing the dragon' versus the use of a heating device

In preparation for a trial on co-prescription of inhalable heroin and methadone, two methods for inhalation of heroin/caffeine tablets were compared: the commonly used method of 'chasing the dragon' and a standardised procedure for inhalation of volatilised heroin, using a heating device. Five male addicts inhaled a tablet of smokable heroin daily for 5 days, alternating the inhalation method. Plasma concentrations of heroin, 6-acetylmorphine, morphine and morphine-3- and -6-glucuronide were determined using a liquid chromatography method with tandem mass spectrometric detection. The exposure to heroin and its metabolites (expressed as areas under the concentrationtime curve) was significantly lower after smoking via the heating device than after 'chasing the dragon': heroin 80% and 6-acetylmorphine 73% lower (p <0.05). Maximal concentrations of heroin and 6-acetylmorphine were also 80% and 70% lower (p <0.05) after using the heating device. 'Chasing the dragon' is a more efficient inhalation method than inhalation via the heating device. (c) 2004 Published by Elsevier B.V. and ENC

Use of Opioids Increases With Age in Older Adults: An Observational Study (2005-2017)

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Heroin-assisted treatment in the Netherlands: History, findings, and international context

This monograph describes the history, findings and international context of heroin-assisted treatment (HAT) in the Netherlands. The monograph consists of (1) a short introduction and seven paragraphs describing the following aspects of HAT in the Netherlands: (2) history of HAT studies and implementation of routine HAT in the Netherlands; (3) main findings on efficacy, safety and cost-effectiveness from the two randomized controlled HAT trials in the Netherland; (4) new findings from a large cohort study on the effectiveness of HAT in routine clinical practice in the Netherlands; (5) unique data on the patients perspective of HAT; (6) data on the pharmacological and pharmaceutical basis for HAT in the Netherlands; (7) description of the registration process; and (8) account of the international context of HAT. Together, these data show that HAT can now be considered a safe and proven-effective intervention for the treatment of chronic, treatment-resistant heroin dependent patients. (C) 2010 Elsevier B.V. and ECNP. All rights reserve

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