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Delirium is a common and serious postoperative complication. Subanaesthetic ketamine is often administered intraoperatively for postoperative analgesia, and some evidence suggests that ketamine prevents delirium. The primary purpose of this trial was to assess the effectiveness of ketamine for prevention of postoperative delirium in older adults. The Prevention of Delirium and Complications Associated with Surgical Treatments [PODCAST] study is a multicentre, international randomised trial that enrolled adults older than 60 years undergoing major cardiac and non-cardiac surgery under general anaesthesia. Using a computer-generated randomisation sequence we randomly assigned patients to one of three groups in blocks of 15 to receive placebo (normal saline), low-dose ketamine (0·5 mg/kg), or high dose ketamine (1·0 mg/kg) after induction of anaesthesia, before surgical incision. Participants, clinicians, and investigators were blinded to group assignment. Delirium was assessed twice daily in the first 3 postoperative days using the Confusion Assessment Method. We did analyses by intention-to-treat and assessed adverse events. This trial is registered with clinicaltrials.gov, number NCT01690988. Between Feb 6, 2014, and June 26, 2016, 1360 patients were assessed, and 672 were randomly assigned, with 222 in the placebo group, 227 in the 0·5 mg/kg ketamine group, and 223 in the 1·0 mg/kg ketamine group. There was no difference in delirium incidence between patients in the combined ketamine groups and the placebo group (19·45% vs 19·82%, respectively; absolute difference 0·36%, 95% CI −6·07 to 7·38, p=0·92). There were more postoperative hallucinations (p=0·01) and nightmares (p=0·03) with increasing ketamine doses compared with placebo. Adverse events (cardiovascular, renal, infectious, gastrointestinal, and bleeding), whether viewed individually (p value for each >0·40) or collectively (36·9% in placebo, 39·6% in 0·5 mg/kg ketamine, and 40·8% in 1·0 mg/kg ketamine groups, p=0·69), did not differ significantly across groups. A single subanaesthetic dose of ketamine did not decrease delirium in older adults after major surgery, and might cause harm by inducing negative experiences. National Institutes of Health and Cancer Center Support.

In Niemann–Pick disease type C, a rare lysosomal storage disorder, treatment with N -acetyl- l -leucine, which may ameliorate lysosomal and metabolic dysfunction, resulted in better neurologic status than placebo.

This book provides a broad reference covering important drugs of abuse including amphetamines, opiates, and steroids. It also covers psychoactive plants such as caffeine, peyote, and psilocybin. It provides chemical structures, analytical methods, clinical features, and treatments of these drugs of abuse, serving as a highly useful, in-depth supplement to a general medical toxicology book. The style allows for the easy application of the contents to searchable databases and other electronic products, making this an essential resource for practitioners in medical toxicology, industrial hygiene, occupational medicine, pharmaceuticals, environmental organizations, pathology, and related fields.

Drug–drug interactions (DDIs) occur commonly and may lead to severe adverse drug reactions if not handled appropriately. Considerable information to support clinical decision making regarding potential DDIs is available in the literature and through various systems providing electronic decision support for healthcare providers. The challenge for the prescribing physician lies in sorting out the evidence and identifying those drugs for which potential interactions are likely to become clinically manifest. P-glycoprotein (P-gp) is a drug transporting protein that is found in the plasma membranes in cells of barrier and elimination organs, and plays a role in drug absorption and excretion. Increasingly, P-gp has been acknowledged as an important player in potential DDIs and a growing body of information on the role of this transporter in DDIs has become available from research and from the drug approval process. This has led to a clear need for a comprehensive review of P-gp-mediated DDIs with a focus on highlighting the drugs that are likely to lead to clinically relevant DDIs. The objective of this review is to provide information for identifying and interpreting evidence of P-gp-mediated DDIs and to suggest a classification for individual drugs based on both in vitro and in vivo evidence (substrates, inhibitors and inducers). Further, various ways of handling potential DDIs in clinical practice are described and exemplified in relation to drugs interfering with P-gp.

Impairments in social cognition are common in schizophrenia and predict poor functional outcome. The purpose of this proof-of-concept randomized, parallel group clinical trial was to assess whether intranasal oxytocin (OT), given before social cognitive training, enhances learning of social cognitive skills. Twenty seven male outpatients with schizophrenia participated in a 6-week (12 session) training on social cognitive skills. Training focused on three domains: facial affect recognition, social perception, and empathy. Subjects were randomly assigned (double blind) to receive either intranasal OTor placebo 30 min before each session. Participants did not receive OT between sessions or on the day of assessments. We evaluated scores on social-cognition measures, as well as clinical symptoms and neurocognition, at baseline, 1 week following the final training session, and 1 month later. Our prespecified primary outcome measure was a social-cognition composite score comprised of five individual measures. There were main effects of time (indicating improvement across the combined-treatment groups) on the social-cognition composite score at both 1 week and 1 month following completion of training. Subjects receiving OT demonstrated significantly greater improvements in empathic accuracy than those receiving placebo at both posttreatment and 1 month follow up. There were no OT-related effects for the other social cognitive tests, clinical symptoms, or neurocognition. This study provides initial support for the idea that OT enhances the effectiveness of training when administered shortly before social cognitive training sessions. The effects were most pronounced on empathic accuracy, a high-level social cognitive process that is not easily improved in current social cognitive remediation programs.

ObjectiveTo examine the efficacy and safety of the therapeutic regimen using oral and intravenous l-arginine for pediatric and adult patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS).MethodsIn the presence and absence of an ictus of stroke-like episodes within 6 h prior to efficacy assessment, we correspondingly conducted the systematic administration of oral and intravenous l-arginine to 15 and 10 patients with MELAS in two, 2-year, prospective, multicenter clinical trials at 10 medical institutions in Japan. Subsequently, patients were followed up for 7 years. The primary endpoint in the clinical trial of oral l-arginine was the MELAS scale, while that for intravenous l-arginine was the improvement rates of headache and nausea/vomiting at 2 h after completion of the initial intravenous administration. The relationships between the ictuses of stroke-like episodes and plasma arginine concentrations were examined.ResultsOral l-arginine extended the interictal phase (p = 0.0625) and decreased the incidence and severity of ictuses. Intravenous l-arginine improved the rates of four major symptoms—headache, nausea/vomiting, impaired consciousness, and visual disturbance. The maximal plasma arginine concentration was 167 μmol/L when an ictus developed. Neither death nor bedriddenness occurred during the 2-year clinical trials, and the latter did not develop during the 7-year follow-up despite the progressively neurodegenerative and eventually life-threatening nature of MELAS. No treatment-related adverse events occurred, and the formulations of l-arginine were well tolerated.ConclusionsThe systematic administration of oral and intravenous l-arginine may be therapeutically beneficial and clinically useful for patients with MELAS.

Central nervous system (CNS)-active medications pose serious health risks for older adults with dementia but are nonetheless commonly used. Few deprescribing interventions have focused on people with dementia. We conducted a one-arm pilot study in six primary care practices of an integrated healthcare system between February and August 2023. The deprescribing intervention consisted of patient/care partner education and self-management materials and provider decision support. Participants were aged 60+ with diagnosed dementia and prescribed at least one CNS-active medication for three or more months of the six-month period prior to study start. We assessed feasibility and acceptability of the intervention and feasibility of ascertaining medication discontinuation and medically treated falls. The intervention was delivered to all (N = 114) eligible participants; their mean age was 80 ± 9 years; 72% were female and 13% non-White. Intervention acceptability, assessed by Weiner’s Acceptability of Intervention measure, was rated 3.5/5 (range 1–5; higher scores indicate higher acceptability). Among baseline antipsychotic users (N = 89), 39 (43.8%) had discontinued at follow-up. Among baseline tricyclic antidepressant users (N = 11), 6 (54.5%) had discontinued at follow-up. Among baseline skeletal muscle relaxant users (N = 3), 2 (66.7%) had discontinued at follow-up. Among baseline benzodiazepine users (N = 3), 1 (33.3%) had discontinued at follow-up. Among baseline opioid users (N = 13), 1 (7.7%) had discontinued at follow-up. Medically treated falls occurred among 22% at baseline vs. 21% at follow-up. The intervention is feasible and acceptable and may achieve meaningful reduction in CNS-active medication prescriptions. Findings support a controlled trial with sufficient power to assess effects on relevant clinical outcomes.

Central nervous system (CNS)-active polypharmacy (defined as concurrent exposure to three or more antidepressant, antipsychotic, antiseizure, benzodiazepine, opioid, or nonbenzodiazepine benzodiazepine receptor agonists) is associated with significant potential harms in persons living with dementia (PLWD).We conducted a pilot trial to assess a patient nudge intervention's implementation feasibility and preliminary effectiveness to prompt deprescribing conversations between PLWD experiencing CNS-active polypharmacy and their primary care clinicians (\"clinicians\"). We used the electronic health record to identify PLWD prescribed CNS-active polypharmacy in primary care clinics from two health systems. Clinics were assigned to intervention (n = 10) or control (n = 12), with PLWD in intervention clinics mailed an educational brochure to prompt discussion with clinicians about the appropriateness of their CNS-active regimen. We conducted chart reviews for evidence of documentation related to these medications and used the electronic health record (EHR) to assess preliminary effectiveness 120 days after sending the brochure (e.g., number of CNS-active medications prescribed, change in total standardized daily dose [TSDD] of CNS-active medications, and change in prevalence of CNS-active polypharmacy). We interviewed 10 clinicians from intervention clinics to assess their perceptions about the acceptability of the intervention. PLWD in the intervention group (n = 61) and control group (n = 68) had an average age of 72.4 years (standard deviation [SD] 9.7), 62.8% were female, and 84.5% were white. We did not find any documented evidence of conversations related to CNS-active medications between PLWD who received the brochure and their primary care clinicians. After 120 days, there was no significant between-group difference in the mean number of CNS-active medications prescribed (- 1.0 [SD 1.3] versus - 1.0 [SD 1.3]), mean TSDD (- 1.6 [SD 6.0] versus - 1.3 [SD 5.8]), or the percentage of patients with CNS-active polypharmacy (52.6% versus 50.4%). Interviews with clinicians suggested they were aware that combinations of CNS-active medications were not ideal; however, they reported inheriting patients who were already on these medications, and they did not have sufficient clinic time or access to safer alternatives to overcome patient hesitation to deprescribe. A direct-to-patient mailed educational brochure did not demonstrate feasibility in provoking deprescribing conversations between PLWD and clinicians or preliminary effectiveness in decreasing CNS-active polypharmacy.

Achieving sufficient delivery across the blood–brain barrier is a key challenge in the development of drugs to treat central nervous system (CNS) disorders. This is particularly the case for biopharmaceuticals such as monoclonal antibodies and enzyme replacement therapies, which are largely excluded from the brain following systemic administration. In recent years, increasing research efforts by pharmaceutical and biotechnology companies, academic institutions and public–private consortia have resulted in the evaluation of various technologies developed to deliver therapeutics to the CNS, some of which have entered clinical testing. Here we review recent developments and challenges related to selected blood–brain barrier-crossing strategies — with a focus on non-invasive approaches such as receptor-mediated transcytosis and the use of neurotropic viruses, nanoparticles and exosomes — and analyse their potential in the treatment of CNS disorders.The blood–brain barrier is a perennial challenge for the delivery of therapeutics to the central nervous system. In their Review, Terstappen and colleagues discuss non-invasive approaches to brain delivery, particularly for biopharmaceuticals, some of which are now in clinical testing.

Rationale There has been an explosion of research on the potential benefits of the social neuropeptide oxytocin for a number of mental disorders including substance use disorders. Recent evidence suggests that intranasal oxytocin has both direct anti-addiction effects and pro-social effects that may facilitate engagement in psychosocial treatment for substance use disorders. Objectives We aimed to assess the tolerability of intranasal oxytocin and its effects on heroin craving, implicit association with heroin and social perceptual ability in opioid-dependent patients receiving opioid replacement therapy (ORT) and healthy control participants. Methods We performed a randomized, double-blind, placebo-controlled, within- and between-subjects, crossover, proof-of-concept trial to examine the effects of oxytocin (40 international units) on a cue-induced craving task (ORT patients only), an Implicit Association Task (IAT), and two social perception tasks: the Reading the Mind in the Eyes Task (RMET) and The Awareness of Social Inference Test (TASIT). Results Oxytocin was well tolerated by patients receiving ORT but had no significant effects on craving or IAT scores. There was a significant reduction in RMET performance after oxytocin administration versus placebo in the patient group only, and a significant reduction in TASIT performance after oxytocin in both the patient and healthy control groups. Conclusions A single dose of intranasal oxytocin is well tolerated by patients receiving ORT, paving the way for future investigations. Despite no significant improvement in craving or IAT scores after a single dose of oxytocin and some evidence that social perception was worsened, further investigation is required to determine the role oxytocin may play in the treatment of opioid use disorder. Clinical Trial Registration Methadone Oxytocin Option. ClinicalTrials.gov identifier: NCT01728909