S Afr Med J. 2023 Jun 5;113(6):26-33. doi: 10.7196/SAMJ.2023.v113i5.16522.

ABSTRACT

BACKGROUND: The South African Health Products Regulatory Authority (SAHPRA) monitors the safety of health products by collecting and evaluating adverse drug reaction (ADR) reports submitted by healthcare professionals, patients and pharmaceutical companies. The reports are shared with the World Health Organization (WHO) Programme for International Drug Monitoring. A demographic and clinical profile of ADR reports will improve our understanding of ADR reporting in South Africa to enhance training of reporters at all levels.

OBJECTIVES: This study describes the demographic and clinical profile of spontaneous ADR reports received by the SAHPRA during the year 2017.

METHODS: A retrospective, cross-sectional study was conducted to describe all ADR reports submitted by South Africa to VigiBase®, the WHO global database of Individual Case Safety Reports (ICSRs), during 2017. The demographic profile included patient characteristics (age and sex), type of reporter and the vigiGrade™ completeness score for each ICSR. The clinical profile included characteristics of the case, medicine(s) and reaction(s).

RESULTS: A total of 8 438 reports with a mean completeness score of 0.456 (SD = 0.221) were assessed. Females and males represented 61.96% and 33.05% of cases, respectively (if sex was reported). All age groups were represented; however, 76.28% involved adults (aged 19-64 years). Physicians submitted the most reports (39.66%). Consumers were the reporters in 29.39% of cases. Pharmacists submitted only 4.45% of the reports. Anti-infective medicines were the most reported Anatomical Therapeutic Class (20.08%), while Human Immunodeficiency Virus was the top indication reported (10.27%). The highest number of MedDRA preferred terms used to describe reactions belonged to the System Organ Class, general disorder and administration site conditions. In 55.87% of the reports, the cases were reported as serious and 12.47% fatal. Death was the most reported MedDRA preferred term used to describe a reaction (5.17%).

CONCLUSIONS: This was the first study that described ADR reports received by SAHPRA and improves our understanding of reporting in the country. The core clinical elements that are important in signal detection were often not included in reports. The findings demonstrated that patients were more active contributors to the national pharmacovigilance database than pharmacists. Reporters should be trained in pharmacovigilance and ADR reporting processes to increase the quantity and completeness of reports.

PMID:37278262 | DOI:10.7196/SAMJ.2023.v113i5.16522

Reg Anesth Pain Med. 2023 Jun 6:rapm-2023-104415. doi: 10.1136/rapm-2023-104415. Online ahead of print.

ABSTRACT

BACKGROUND: Dexmedetomidine sedation has advantages, such as low incidence of respiratory depression and prolonged block duration, but also significant disadvantages, such as slow onset, high rate of sedation failure, and a long context-sensitive half-life. Remimazolam provides rapid sedation and recovery, high sedation efficacy and has minimal hemodynamic effects. We hypothesized that patients who received remimazolam would require less rescue midazolam than dexmedetomidine.

METHODS: Patients (n=103) scheduled for surgery under spinal anesthesia were randomized to receive dexmedetomidine (DEX group) or remimazolam (RMZ group) targeting a Modified Observer's Assessment of Alertness/Sedation score of 3 or 4. Rescue midazolam was administered if the patient failed to be sedated after the initial loading dose or despite infusion rate adjustment.

RESULTS: Rescue midazolam administration was significantly higher in the DEX group (0% vs 39.2%; p<0.001). Patients in the RMZ group reached the target sedation level more rapidly. The incidences of bradycardia (0% vs 25.5%; p<0.001) and hypertension (0% vs 21.6%; p<0.001) were higher in the DEX group. Respiratory depression occurred at a higher rate in the RMZ group (21.2% vs 2.0%; p=0.002), but no patients required manual ventilation. Patients in the RMZ group recovered faster, had a shorter PACU stay and higher satisfaction scores. Hypotensive episodes in the PACU were more frequent in the DEX group (1.9% vs 29.4%; p<0.001).

CONCLUSIONS: Remimazolam showed excellent sedation efficacy, minimal hemodynamic effects, and fewer adverse events in the PACU than dexmedetomidine. However, it is important to note that respiratory depression was more frequent with the use of remimazolam.

TRIAL REGISTRATION NUMBER: NCT05447507.

PMID:37280081 | DOI:10.1136/rapm-2023-104415

JAMA. 2023 Jun 6. doi: 10.1001/jama.2023.9106. Online ahead of print.

ABSTRACT

IMPORTANCE: Valganciclovir for 200 days is standard care for cytomegalovirus (CMV) prophylaxis in high-risk CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor, but its use is limited by myelosuppression.

OBJECTIVE: To compare the efficacy and safety of letermovir with valganciclovir for prevention of CMV disease in CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor.

DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-masked, double-dummy, noninferiority, phase 3 trial in adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor at 94 participating sites between May 2018 and April 2021 (final follow-up in April 2022).

INTERVENTIONS: Participants were randomized in a 1:1 ratio (stratified by receipt of lymphocyte-depleting induction immunosuppression) to receive letermovir, 480 mg, orally daily (with acyclovir) or valganciclovir, 900 mg, orally daily (adjusted for kidney function) for up to 200 days after transplant, with matching placebos.

MAIN OUTCOMES AND MEASURES: The primary outcome was CMV disease, confirmed by an independent masked adjudication committee, through posttransplant week 52 (prespecified noninferiority margin, 10%). CMV disease through week 28 and time to onset of CMV disease through week 52 were secondary outcomes. Exploratory outcomes included quantifiable CMV DNAemia and resistance. The rate of leukopenia or neutropenia through week 28 was a prespecified safety outcome.

RESULTS: Among 601 participants randomized, 589 received at least 1 dose of the study drug (mean age, 49.6 years; 422 [71.6%] men). Letermovir (n = 289) was noninferior to valganciclovir (n = 297) for prevention of CMV disease through week 52 (10.4% vs 11.8% of participants with committee-confirmed CMV disease; stratum-adjusted difference -1.4% [95% CI, -6.5% to 3.8%]). No participants who received letermovir vs 5 participants (1.7%) who received valganciclovir developed CMV disease through week 28. Time to onset of CMV disease was comparable between the groups (hazard ratio, 0.90 [95% CI, 0.56-1.47]). Quantifiable CMV DNAemia was detected in 2.1% of participants in the letermovir group vs 8.8% in the valganciclovir group by week 28. Of participants evaluated for suspected CMV disease or CMV DNAemia, none (0/52) who received letermovir and 12.1% (8/66) who received valganciclovir had resistance-associated substitutions. The rate of leukopenia or neutropenia through week 28 was lower with letermovir vs valganciclovir (26% vs 64%; difference, -37.9% [95% CI, -45.1% to -30.3%]; P < .001). Fewer participants in the letermovir group than the valganciclovir group discontinued prophylaxis due to adverse events (4.1% vs 13.5%) or drug-related adverse events (2.7% vs 8.8%).

CONCLUSION AND RELEVANCE: Among adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor, letermovir was noninferior to valganciclovir for prophylaxis of CMV disease over 52 weeks, with lower rates of leukopenia or neutropenia, supporting its use for this indication.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03443869; EudraCT: 2017-001055-30.

PMID:37279999 | DOI:10.1001/jama.2023.9106

J Neurotrauma. 2023 Jun 6. doi: 10.1089/neu.2023.0163. Online ahead of print.

ABSTRACT

Riluzole is sodium-glutamate antagonist which attenuates neurodegeneration in amyotrophic lateral sclerosis (ALS). It has shown favourable results in promoting recovery in preclinical models of traumatic spinal cord injury (tSCI) and in early phase clinical trials. This study aimed to evaluate the efficacy and safety of Riluzole in acute cervical tSCI. An international, multi-center, prospective, randomized, double-blinded, placebo-controlled, adaptive, Phase III trial (NCT01597518) was undertaken. Patients with ASIA Impairment Scale (AIS) A-C, cervical (C4-C8) tSCI, and <12 hours from injury were randomized to receive either Riluzole, at an oral dose of 100mg twice per day (BID) for the first 24 hours followed by 50mg BID for the following 13 days, or placebo. The primary efficacy endpoint was change in Upper Extremity Motor (UEM) scores at 180 days. The primary efficacy analyses were conducted on an intention to treat (ITT) and completed cases (CC) basis. The study was powered at a planned enrolment of 351 patients. The trial began in October 2013 and was halted by the sponsor on May 2020 (and terminated in April 2021) in the face of the global COVID-19 pandemic. One hundred ninety-three patients (54.9% of the preplanned enrolment) were randomized with a follow-up rate of 82.7% at 180 days. At 180 days, in the CC population the Riluzole treated patients compared to placebo had a mean gain of 1.76 UEM scores (95% confidence interval: -2.54-6.06) and 2.86 total motor (TOTM) scores (CI:-6.79-12.52). No drug related serious adverse events were associated with the use of Riluzole. Additional pre-planned sensitivity analyses revealed that in the AIS C population, Riluzole was associated with significant improvement in total motor scores (Estimate: SE 8.0; CI 1.5-14.4) and upper extremity motor scores (SE 13.8; CI 3.1-24.5) at 6 months. AIS B patients had higher reported independence, measured by the SCIM score (45.3 vs. 27.3; d: 18.0 CI: -1.7-38.0) and change in mental health scores, measured by the SF-36 mental health domain (2.01 vs. -11.58; d: 13.2 CI: 1.2-24.8) at 180 days. AIS A patients who received Riluzole had a higher average gain in neurological levels at 6-months compared to placebo (mean 0.50 levels gained vs 0.12 in placebo; d: 0.38, CI: -0.2-0.9). The primary analysis did not achieve the predetermined endpoint of efficacy for riluzole, likely related to insufficient power. However, on pre-planned secondary analyses, all subgroups of cervical SCI subjects (AIS grades A, B and C) treated with Riluzole showed significant gains in functional recovery. The results of this trial may warrant further investigation to extend these findings. Moreover, guideline development groups may wish to assess the possible clinical relevance of the secondary outcome analyses, in light of the fact that SCI is an uncommon orphan disorder without an accepted neuroprotective treatment.

PMID:37279301 | DOI:10.1089/neu.2023.0163

BioDrugs. 2023 Jun 6. doi: 10.1007/s40259-023-00604-7. Online ahead of print.

ABSTRACT

BACKGROUND: GB223 is a novel, fully-humanized monoclonal antibody against the receptor activator of nuclear factor-kappa B ligand (RANKL). In this phase I study, the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of GB223 were investigated.

PATIENTS AND METHODS: This was a randomized, double-blinded, placebo-controlled, single-dose escalation study conducted in 44 healthy Chinese adults. Participants were randomly assigned to receive a single subcutaneous injection dose of 7, 21, 63, 119, or 140 mg of GB223 (n = 34) or placebo (n = 10) and were followed up for 140-252 days.

RESULTS: The results of noncompartmental analysis showed that GB223 was slowly absorbed after dosing, with a time to reach maximum concentration (Tmax) ranging from 5 to 11 days. Serum GB223 concentrations decreased slowly, with a long half-life ranging from 7.91 to 19.60 days. A two-compartment Michaelis-Menten model was found to best describe the pharmacokinetics of GB223, and the absorption rate of GB223 differed between males (0.0146 h-1) and females (0.0081 h-1). Serum C-terminal telopeptide of type I collagen decreased significantly postdose, and the inhibition lasted 42-168 days. No deaths or drug-related serious adverse events occurred. The most frequent adverse events were blood parathyroid hormone increased (94.1%), blood phosphorus decreased (67.6%) and blood calcium decreased (58.8%). In the GB223 group, 44.1% (15/34) of subjects were antidrug antibody positive after dosing.

CONCLUSION: In this study, we demonstrated for the first time that a single subcutaneous injection of GB223, from 7 to 140 mg, is safe and well tolerated in healthy Chinese subjects. GB223 has a nonlinear pharmacokinetic profile, and sex was a potential covariate that may affect the absorption rate of GB223.

CLINICAL TRIAL REGISTRATION: NCT04178044 and ChiCTR1800020338.

PMID:37278972 | DOI:10.1007/s40259-023-00604-7

PLoS One. 2023 Jun 5;18(6):e0286623. doi: 10.1371/journal.pone.0286623. eCollection 2023.

ABSTRACT

OBJECTIVE: To investigate the general characteristics of litigation cases of medical malpractice liability disputes (MMLDs) related to novel antineoplastic drugs (NADs), the drugs involved, as well as the common types of medical errors related to NADs and their damages in the process of diagnosis and treatment, with the aims of improving the level of rational medication use in the clinical application of NADs and actively prevent medical disputes.

METHODS: The China Judgments Online was searched for the cause of action using the key word "MMLDs" along with the name of 77 kinds of NADs. A total of 39 NAD litigation cases meeting the inclusion criteria from 1 January 2009 to 31 December 2021 were analyzed, and each potential adverse drug reaction (ADR) was reviewed to determine a causality assessment using the Naranjo algorithm for non-drug-induced liver injury (DILI) cases and the updated Roussel Uclaf Causality Assessment Method (RUCAM) for the DILI cases. Risk prevention and control strategies were recommended.

RESULTS: Cases that met the inclusion criteria increased substantially each year during the last six years, from three cases in 2009-2015 to 36 cases in 2016-2021. There were more cases in Eastern China than in other geographic regions. Most cases involved tertiary hospitals, patients between 25 and 60 years of age, and patients who were predominately male. There were 18 kinds of NADs involved in medical errors. The most common consequences of NADs were closely related to the death, disability, and increased treatment costs caused by ADRs, inadequate indications, delayed diagnosis and treatment, and misdiagnosis and mistreatment. The most frequent medical errors were medical technology errors, medical ethics errors and medical record writing/safekeeping errors. In two cases involving DILI, one case was unable to undergo further RUCAM scoring because the liver function indicators of the patient before and after treatment were not published.

CONCLUSION: The establishment of mechanisms to reduce the risks associated with the clinical application of NADs is warranted. Healthcare services must maintain strict adherence to the specific requirements of GPCANADs and drug instructions and strictly grasp the indications, contraindications, usage, and dosage of drugs, and strengthen the notification and management of off-label drug use. Monitoring patients for ADRs and preparing rescue and treatment measures for high-risk drugs may serve to reduce damages related to NADs. For DILI cases, medical and appraisal institutions should use RUCAM score to assess causal relationships.

PMID:37276214 | PMC:PMC10241368 | DOI:10.1371/journal.pone.0286623

J Infect Chemother. 2023 Jun 3:S1341-321X(23)00138-1. doi: 10.1016/j.jiac.2023.06.002. Online ahead of print.

ABSTRACT

INTRODUCTION: This single-center study evaluated the efficacy and safety of tazobactam/ceftolozane (TAZ/CTLZ) in combination with metronidazole for intraabdominal infection in a hepato-biliary-pancreatic field in clinical practice.

METHODS: This study included 50 patients, including 35 with intraabdominal abscess or peritonitis, 5 with liver abscess, 4 with cholecystitis, and 6 with cholangitis with sepsis. Of the 50 patients, 29 received TAZ/CTLZ and metronidazole after a prior antibacterial therapy failure, including tazobactam/piperacillin, cefmetazole, and levofloxacin. Source control was performed in 36 patients.

RESULTS: The clinical response could be evaluated in 49 patients. The clinical cure rate at end-of-therapy was 91.8% (45 of 49 patients) and that at test-of-cure was 89.6% (43 of 48 patients). Of 5 patients in whom clinical response at test-of-cure was a failure, 1 developed infectious disease during chemoradiotherapy for recurrent cancer and 4 after liver resection or pancreatoduodenectomy. Three of the 4 patients were associated with pancreatic juice leakage. Isolated pathogens were eradicated or presumably eradicated in 27 of 31 (87.1%) patients in whom microbiological response at test-of-cure could be evaluated. The response rate for AmpC-producing Enterobacteriaceae was 87.5%. Nausea was observed in two patients. Aspartate and alanine aminotransferase activities were increased in 3 of the 50 (6.0%) patients. The activities improved after the antibiotic discontinuation.

CONCLUSIONS: This observational study demonstrated that TAZ/CTLZ in combination with metronidazole has a favorable effect without major drug-related adverse events for intraabdominal infection in the hepato-biliary-pancreatic field in clinical practice although the efficacy of TAZ/CTLZ may decrease in compromised patients.

PMID:37276996 | DOI:10.1016/j.jiac.2023.06.002

Curr Opin Chem Biol. 2023 Jun 3;75:102337. doi: 10.1016/j.cbpa.2023.102337. Online ahead of print.

ABSTRACT

Cellular redox homeostasis is very important for the overall cellular development, function, and oxidative stress often disrupts the process. Small-molecule organoselenium compounds exert key roles in maintaining the redox homeostasis during oxidative stress and cancer owing to their notable antioxidant activities. Among different organoselenium compounds, small-molecule organoselenocyanates have attracted much research attention due to their synthetic utilities and therapeutic potentials. Therefore, the development of convenient synthetic methodologies to different classes of organoselenocyanates from various precursors was explored over the years as useful synthetic building blocks. Additionally, considering their inherent redox and antioxidant properties, the development of biologically relevant organoselenocyanates upon their conjugation with the existing drugs and natural products has been chosen for enhancing the drug potencies and in ameliorating the drug-induced side-effects. In the present report, we have discussed some of the very recent and relevant developments on these aspects in a very concise manner.

PMID:37276751 | DOI:10.1016/j.cbpa.2023.102337

Anaesth Rep. 2023 Jun 1;11(1):e12233. doi: 10.1002/anr3.12233. eCollection 2023 Jan-Jun.

ABSTRACT

A 68-year-old man underwent elective surgical repair of an abdominal wall hernia under general anaesthesia. The operation required muscle relaxation, for which we used rocuronium. Following completion of surgery, 180 mg sugammadex was administered intravenously. Shortly afterwards, the patient became severely bradycardic with hypotension, refractory to treatment with ephedrine. This progressed to a pulseless electrical activity cardiac arrest. After 4 min of cardiopulmonary resuscitation, there was return of spontaneous circulation and, following a period of haemodynamic stability in which general anaesthesia was maintained, the patient emerged from anaesthesia without incident. He remained haemodynamically stable until discharge. Post-resuscitation investigations including the serum tryptase level were unremarkable except for a mild respiratory acidosis and slightly elevated D-dimers. Sugammadex-induced bradycardia has previously been described, but its mechanism remains unknown. We believe that sugammadex was the cause of cardiac arrest in this case because of the timing and sequence of events, the evolution to pulseless electric activity and the relatively uneventful post-arrest clinical course. We hope that our report will help to promote awareness about this potential complication of a now commonly-used drug.

PMID:37273748 | PMC:PMC10234280 | DOI:10.1002/anr3.12233

Cureus. 2023 May 4;15(5):e38525. doi: 10.7759/cureus.38525. eCollection 2023 May.

ABSTRACT

Cocaine is used as an illicit substance responsible for the most common cause of drug-related death. It is a stimulant that acts on the sympathetic nervous system and cardiovascular system leading to exaggerated, prolonged sympathetic activity due to the accumulation of neurotransmitters. Cardiovascular side effects of cocaine are coronary artery spasms, myocarditis, arrhythmias, and congestive heart failure. Takotsubo cardiomyopathy (TCM) is characterized by transient hypokinesis, akinesis, or dyskinesis of the left ventricle (LV) wall with or without apical involvement in the absence of obstructive coronary artery disease. Cocaine-induced TCM is an extremely rare condition emphasizing the need of its prompt diagnosis by the physicians. We present a case report of a 54-year-old male, brought to the emergency department (ED) after an out-of-hospital cardiac arrest (CA), found to have TCM in the setting of cocaine use. Clinicians need to understand the association between cocaine use and the development of TCM as cardiomyopathy of this type can result in complete remission after discontinuing the offending agent.

PMID:37273300 | PMC:PMC10239072 | DOI:10.7759/cureus.38525

Crit Care Med. 2023 Jun 2. doi: 10.1097/CCM.0000000000005920. Online ahead of print.

ABSTRACT

OBJECTIVES: To determine the effectiveness and safety of ciprofol for sedating patients in ICUs who required mechanical ventilation (MV).

DESIGN: A multicenter, single-blind, randomized, noninferiority trial.

SETTING: Twenty-one centers across China from December 2020 to June 2021.

PATIENTS: A total of 135 ICU patients 18 to 80 years old with endotracheal intubation and undergoing MV, who were expected to require sedation for 6-24 hours.

INTERVENTIONS: One hundred thirty-five ICU patients were randomly allocated into ciprofol (n = 90) and propofol (n = 45) groups in a 2:1 ratio. Ciprofol or propofol were IV infused at loading doses of 0.1 mg/kg or 0.5 mg/kg, respectively, over 4 minutes ± 30 seconds depending on the physical condition of each patient. Ciprofol or propofol were then immediately administered at an initial maintenance dose of 0.3 mg/kg/hr or 1.5 mg/kg/hr, to achieve the target sedation range of Richmond Agitation-Sedation Scale (+1 to -2). Besides, continuous IV remifentanil analgesia was administered (loading dose: 0.5-1 μg/kg, maintenance dose: 0.02-0.15 μg/kg/min).

MEASUREMENTS AND MAIN RESULTS: Of the 135 patients enrolled, 129 completed the study. The primary endpoint-sedation success rates of ciprofol and propofol groups were 97.7% versus 97.8% in the full analysis set (FAS) and were both 100% in per-protocol set (PPS). The noninferiority margin was set as 8% and confirmed with a lower limit of two-sided 95% CI for the inter-group difference of -5.98% and -4.32% in the FAS and PPS groups. Patients who received ciprofol had a longer recovery time (p = 0.003), but there were no differences in the remaining secondary endpoints (all p > 0.05). The occurrence rates of treatment-emergent adverse events (TEAEs) or drug-related TEAEs were not significantly different between the groups (all p > 0.05).

CONCLUSIONS: Ciprofol was well tolerated, with a noninferior sedation profile to propofol in Chinese ICU patients undergoing MV for a period of 6-24 hours.

PMID:37272947 | DOI:10.1097/CCM.0000000000005920

J Korean Med Sci. 2023 Jun 5;38(22):e170. doi: 10.3346/jkms.2023.38.e170.

ABSTRACT

BACKGROUND: Although coronavirus disease 2019 (COVID-19) vaccines have been distributed worldwide under emergency use authorization, the real-world safety profiles of mRNA vaccines still need to be clearly defined. We aimed to identify the overall incidence and factors associated with adverse events (AEs) following mRNA COVID-19 vaccination.

METHODS: We conducted web-based survey from December 2 to 10 in 2021 with a 2,849 nationwide sampled panel. Study participants were individuals who had elapsed at least two-weeks after completing two dosing schedules of COVID-19 vaccination aged between 18-49 years. We weighted the participants to represent the Korean population. The outcome was the overall incidence of AEs following mRNA COVID-19 vaccination and associated factors. We estimated the weighted odds ratios (ORs) using multivariable logistic regression models to identify the factors associated with AEs.

RESULTS: Of the 2,849 participants (median [interquartile range] age, 35 [27-42] years; 51.6% male), 90.8% (n = 2,582) for the first dose and 88.7% (n = 2,849) for the second dose reported AEs, and 3.3% and 4.3% reported severe AEs, respectively. Occurrence of AEs was more prevalent in mRNA-1273 (OR, 2.06; 95% confidence interval [CI], 1.59-2.67 vs. BNT162b2), female sex (1.88; 1.52-2.32), and those with dermatologic diseases (2.51; 1.32-4.77). History of serious allergic reactions (1.96; 1.06-3.64) and anticoagulant medication use (4.72; 1.92-11.6) were associated with severe AEs.

CONCLUSION: Approximately 90% of participants reported AEs following mRNA COVID-19 vaccination. Substantial factors, including vaccine type (mRNA-1273), female sex, and dermatologic diseases were associated with AEs. Our findings could aid policymakers in establishing vaccination strategies tailored to those potentially susceptible to AEs.

PMID:37272559 | DOI:10.3346/jkms.2023.38.e170

Int J Surg Pathol. 2023 Jun 4:10668969231177877. doi: 10.1177/10668969231177877. Online ahead of print.

ABSTRACT

Widespread use of vaccinations worldwide in the coronavirus disease (COVID-19) pandemic has resulted in various side effects. Here, we presented a 27-year-old man with autoimmune-like hepatitis after the first dose of the BNT162b2 (mRNA) COVID-19 vaccine and reviewed previous reports. He presented with sweating, febrile sensations, and general weakness. He did not have any medical histories. Although he was treated with biphenyl dimethyl dicarboxylate and ursodeoxycholic acid, the elevated liver enzyme levels persisted for 2 months. Liver biopsy demonstrated portal inflammation with rosette formation, interface hepatitis, and infiltration of lymphocytes, histiocytes, plasma cells, and eosinophils. Especially, centrilobular edema and necrosis were found. The symptoms and liver enzymes improved with prednisolone treatment. If persistently elevated liver enzymes are found after COVID-19 mRNA vaccination, the possibility of autoimmune-like hepatitis induced by the vaccine should be considered and a careful pathologic evaluation is required.

PMID:37272061 | DOI:10.1177/10668969231177877

Br J Haematol. 2023 Jun 4. doi: 10.1111/bjh.18902. Online ahead of print.

ABSTRACT

Appropriate evaluation of heparin-induced thrombocytopaenia (HIT) is imperative because of the potentially life-threatening complications. However, overtesting and overdiagnosis of HIT are common. Our goal was to evaluate the impact of clinical decision support (CDS) based on the HIT computerized-risk (HIT-CR) score, designed to reduce unnecessary diagnostic testing. This retrospective observational study evaluated CDS that presented a platelet count versus time graph and 4Ts score calculator to clinicians who initiated a HIT immunoassay order in patients with predicted low risk (HIT-CR score 0-2). The primary outcome was the proportion of immunoassay orders initiated but cancelled after firing of the CDS advisory. Chart reviews were conducted to assess anticoagulation usage, 4Ts scores and the proportion of patients who had HIT. In a 20-week period, 319 CDS advisories were presented to users who initiated potentially unnecessary HIT diagnostic testing. The diagnostic test order was discontinued in 80 (25%) patients. Heparin products were continued in 139 (44%) patients, and alternative anticoagulation was not given to 264 (83%). The negative predictive value of the advisory was 98.8% (95% CI: 97.2-99.5). HIT-CR score-based CDS can reduce unnecessary diagnostic testing for HIT in patients with a low pretest probability of HIT.

PMID:37271143 | DOI:10.1111/bjh.18902

Sci Rep. 2023 Jun 3;13(1):9036. doi: 10.1038/s41598-023-34961-8.

ABSTRACT

In this single-center observational study with 1,206 participants, we prospectively evaluated SARS-CoV-2-antibodies (anti-S RBD) and vaccine-related adverse drug reactions (ADR) after basic and booster immunization with BNT162b2- and ChAdOx1-S-vaccines in four vaccination protocols: Homologous BNT162b2-schedule with second vaccination at either three or six weeks, homologous ChAdOx1-S-vaccination or heterologous ChAdOx1-S/BNT162b2-schedule, each at 12 weeks. All participants received a BNT162b2 booster. Blood samples for anti-S RBD analysis were obtained multiple times over a period of four weeks to six months after basic vaccination, immediately before, and up to three months after booster vaccination. After basic vaccination, the homologous ChAdOx1-S-group showed the lowest anti-S RBD levels over six months, while the heterologous BNT162b2-ChAdOx1-S-group demonstrated the highest anti-S levels, but failed to reach level of significance compared with the homologous BNT162b2-groups. Antibody levels were higher after an extended vaccination interval with BNT162b2. A BNT162b2 booster increased anti-S-levels 11- to 91-fold in all groups, with the homologous ChAdOx1-S-cohort demonstrated the highest increase in antibody levels. No severe or serious ADR were observed. The findings suggest that a heterologous vaccination schedule or prolonged vaccination interval induces robust humoral immunogenicity with good tolerability. Extending the time to boost-immunization is key to both improving antibody induction and reducing ADR rate.

PMID:37270632 | PMC:PMC10239043 | DOI:10.1038/s41598-023-34961-8

Pharmacol Res Perspect. 2023 Jun;11(3):e01093. doi: 10.1002/prp2.1093.

ABSTRACT

We report the safety and pharmacokinetic properties of the HIV-1 maturation inhibitor GSK3739937 (GSK'937) in healthy participants. This was a phase I, first-in-human, double-blind, randomized, placebo-controlled, single- (part 1) and multiple- (part 2) dose escalation study with an additional open-label relative bioavailability and food effect study (part 3). Participants received oral ascending single doses (10-800 mg) in part 1, up to 18 once-daily 25- to 100-mg or 3 once-weekly 500-mg doses in part 2, and single 100-mg doses as powder-in-bottle or tablet (in fed and fasted states) formulations in part 3. Primary and secondary objectives were safety and pharmacokinetic assessments, respectively. Ninety-one participants were enrolled; 38 reported 81 total adverse events (AEs). All AEs in participants receiving GSK'937 were grade 1 or 2 and resolved during the study. Most drug-related AEs were gastrointestinal (14/17, 82%). The terminal phase half-life of GSK'937 was ~3 days for all doses following single and repeat dosing. Geometric mean maximum concentration and total drug exposures exhibited dose-proportional increases during part 1. Accumulation in exposure following repeat dosing was 6- to 7-fold with daily dosing and ~1.7-fold after weekly treatment, as expected due to the long half-life. Bioavailability of GSK'937 after a meal was 1.35- to 1.40-fold greater as a tablet versus powder-in-bottle and >2-fold higher in fed versus fasted states when provided as a tablet. No unexpected or dose-limiting safety events occurred. Pharmacokinetic parameters of long half-life and accumulation of exposure following repeat dosing suggest the potential for weekly oral dosing. ClinicalTrials.gov identifier: NCT04493684.

PMID:37269076 | DOI:10.1002/prp2.1093

Support Care Cancer. 2023 Jun 2;31(6):371. doi: 10.1007/s00520-023-07836-x.

ABSTRACT

PURPOSE: We aimed to explore patient-reported outcomes (PROs) and patient and physician concordance of side effects perception across lines of therapy (LOT) in multiple myeloma (MM) within the United States of America (USA).

METHODS: Data were drawn from the Adelphi Real World MM III Disease Specific Programme™, a point-in-time survey of hemato-oncologists/hematologists and their patients with MM conducted in the USA between August 2020 and July 2021. Physicians reported patient characteristics and side effects. Patients reported side-effect bother and health-related quality of life (HRQoL) using validated PRO tools (European Organisation for the Research and Treatment of Cancer Quality of Life Core Questionnaire/-MM Module [EORTC QLQ-C30/-MY20], EQ-5D-3L and Functional Assessment of Cancer Therapy-General Population physical item 5). Descriptive, linear regression and concordance analyses were performed.

RESULTS: Records from 63 physicians and 132 patients with MM were analyzed. EORTC QLQ-C30/-MY20 and EQ-5D-3L scores were consistent across LOTs. Scores tended to be worse with higher side-effect bother; patients "very much" bothered by side effects had lower median (interquartile range) global health status scores (33.3 [25.0-50.0]) than those "not at all" bothered (79.2 [66.7-83.3]). Patient and physician concordance on side-effect reporting was poor to fair. Patients frequently reported fatigue and nausea as bothersome side effects.

CONCLUSION: HRQoL of patients with MM was worse with greater side-effect bother. Discordant patient and physician reporting of side effects indicated a need for improved communication during management of MM.

PMID:37268868 | PMC:PMC10238291 | DOI:10.1007/s00520-023-07836-x

Am Soc Clin Oncol Educ Book. 2023 Jun;43:e390428. doi: 10.1200/EDBK_390428.

ABSTRACT

There have been significant advances in the treatment of cancer in the past decade. However, patients continue to suffer from significant side effects of antineoplastic agents that greatly affect their quality of life (QOL), including chemotherapy-induced nausea and vomiting (CINV), chemotherapy-induced peripheral neuropathy (CIPN), and chemotherapy-induced alopecia (CIA). This review aims to provide an updated overview of emerging strategies for the management and prevention of these immediate and long-lasting side effects. The use of integrative medicine including cannabis continues to evolve in the realm of CINV and cancer-related anorexia. Although no pharmaceutical agent has been approved for the prevention of CIPN, cryotherapy, compression therapy and, more recently, cryocompression therapy have shown benefit in small trials, but there are concerns with tolerability especially related to cryotherapy. More data are necessary to determine an effective and tolerable option to prevent CIPN in large, randomized studies. Scalp cooling (SC), which has a similar mechanism to cryotherapy and compression therapy for CIPN prevention, has proven to be an effective and tolerable approach in randomized studies and has significantly limited CIA, an entity that definitively affects the QOL of patients living with cancer. Taken together, cannabis, cryotherapy, compression and cryocompression therapy, and SC all strive to improve the QOL of patients living with cancer by minimizing the side effects of chemotherapeutic agents.

PMID:37267515 | DOI:10.1200/EDBK_390428

Clin J Oncol Nurs. 2023 May 18;27(3):281-288. doi: 10.1188/23.CJON.281-288.

ABSTRACT

BACKGROUND: Patients prescribed oral chemotherapy (OC) may find adherence and management of side effects difficult. Leveraging technology available to patients, such as smartphones, laptops, or at-home computer devices, may help close the loop on crucial information needed for the safe administration of these toxic medications.

OBJECTIVES: The primary aim of this review was to explore the feasibility of standardization of an electronic OC adherence questionnaire to gather patient-reported outcomes. The secondary aim was to determine whether patient-reported outcome measures improve providers' response times to patient-reported concerns.

METHODS: A comprehensive literature review was performed in CINAHL®, Scopus®, Open Access Journal Finder, and SocINDEX. Ten articles, from which four themes were synthesized and discussed, were selected for this review.

FINDINGS: Leveraging eHealth using an OC adherence questionnaire to monitor medication adherence, laboratory testing schedule adherence, and self-management of symptoms and disease, as well as providers' timely response to potential issues, may improve overall health outcomes.

PMID:37267486 | DOI:10.1188/23.CJON.281-288

Drug Deliv. 2023 Dec;30(1):2219419. doi: 10.1080/10717544.2023.2219419.

ABSTRACT

Traditional ophthalmic drugs, such as eye drops, gels and ointments, are accompanied by many problems, including low bioavailability and potential drug side effects. Innovative ophthalmic drug delivery systems have been proposed to overcome the limitations associated with traditional formulations. Recently, contact lens-based drug delivery systems have gained popularity owing to their advantages of sustained drug delivery, prolonged drug retention, improved bioavailability, and few drug side effects. Various methods have been successfully applied to drug-loaded contact lenses and prolonged the drug release time, such as chemical crosslinking, material embedding, molecular imprinting, colloidal nanoparticles, vitamin E modification, drug polymer film/coating, ion ligand polymerization systems, and supercritical fluid technology. Contact lens-based drug delivery systems play an important role in the treatment of multifarious ophthalmic diseases. This review discusses the latest developments in drug-loaded contact lenses for the treatment of ophthalmic diseases, including preparation methods, application in ophthalmic diseases and future prospects.

PMID:37264930 | DOI:10.1080/10717544.2023.2219419