Therapie. 2021 Dec 24:S0040-5957(21)00266-3. doi: 10.1016/j.therap.2021.12.014. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: The EREMI project was set up to collect data on adverse drug reactions (ADRs) occurring due to off-label and/or unlicensed drugs prescribed to hospitalised children in France. These events were evaluated by a regional pharmacovigilance centre (RPC) and an adjudication committee (AC). The aim of this study was to assess the agreement between these two different entities on their evaluation of ADRs.

EXPERIMENTAL APPROACH: The RPC first validated the ADRs and assessed their causality using the Naranjo scale. The AC assessed then ADRs using all available information, including the RPC evaluation. The agreement on severity and nature of ADRs, role of treatment (suspect or concomitant) and drug causality was calculated using Cohen's nonparametric kappa coefficient (k).

KEY RESULTS: Three hundred and eighty-six events were reported in 219 children. The RPC excluded 65 events and validated 321 ADRs. Agreement was very good on nature of ADRs (k=0.85) and role of treatment (k=0.81), moderate on severity of ADRs (k=0.60) and very poor on drug causality (k=0.05).

CONCLUSION AND IMPLICATIONS: Agreement between the RPC and the AC was not constant throughout this evaluation. They troubled to agree on severe ADRs and on drug causality.

PMID:34998623 | DOI:10.1016/j.therap.2021.12.014

Circulation. 2022 Jan 25;145(4):299-308. doi: 10.1161/CIRCULATIONAHA.121.054883. Epub 2022 Jan 7.

ABSTRACT

BACKGROUND: Multiple reports associate the cardiac sodium channel gene (SCN5A) variants S1103Y and R1193Q with type 3 congenital long QT syndrome and drug-induced long QT syndrome. These variants are too common in ancestral populations to be highly arrhythmogenic at baseline, however: S1103Y allele frequency is 8.1% in African Americans and R1193Q 6.1% in East Asians. R1193Q is known to increase late sodium current (INa-L) in cardiomyocytes derived from induced pluripotent stem cells but the role of these variants in modulating repolarization remains poorly understood.

METHODS: We determined the effect of S1103Y on QT intervals among African-American participants in a large electronic health record. Using cardiomyocytes derived from induced pluripotent stem cells carrying naturally occurring or genome-edited variants, we studied action potential durations (APDs) at baseline and after challenge with the repolarizing potassium current (IKr) blocker dofetilide and INa-L and IKr at baseline.

RESULTS: In 1479 African-American participants with no confounding medications or diagnoses of heart disease, QT intervals in S1103Y carriers was no different from that in noncarriers. Baseline APD was no different in cells expressing the Y allele (SY, YY cells) compared with isogenic cells with the reference allele (SS cells). However, INa-L was increased in SY and YY cells and the INa-L blocker GS967 shortened APD in SY/YY but not SS cells (P<0.001). IKr was increased almost 2-fold in SY/YY cells compared with SS cells (tail current: 0.66±0.1 versus 1.2±0.1 pA/pF; P<0.001). Dofetilide challenge prolonged APD at much lower concentrations in SY (4.1 nmol/L [interquartile range, 1.5-9.3]; n=11) and YY (4.2 nmol/L [1.7-5.0]; n=5) than in SS cells (249 nmol/L [22.3-2905]; n=14; P<0.001 and P<0.01, respectively) and elicited afterdepolarizations in 8/16 SY/YY cells but only in 1/14 SS cells. R1193Q cells similarly displayed no difference in baseline APD but increased IKr and increased dofetilide sensitivity.

CONCLUSIONS: These common ancestry-specific variants do not affect baseline repolarization, despite generating increased INa-L. We propose that increased IKr serves to maintain normal repolarization but increases the risk of manifest QT prolongation with IKr block in variant carriers. Our findings emphasize the need for inclusion of diverse populations in the study of adverse drug reactions.

PMID:34994586 | DOI:10.1161/CIRCULATIONAHA.121.054883

Andrology. 2022 Jan 7. doi: 10.1111/andr.13153. Online ahead of print.

ABSTRACT

BACKGROUND: Male hypogonadism (testosterone level < 300 ng/dl) is a clinical syndrome that results from failure of the testis to produce physiological levels of testosterone. Most marketed testosterone replacement therapy products often require multiple dose adjustment clinic visits to achieve the desired, eugonadal testosterone levels.

OBJECTIVE: To evaluate the efficacy and safety of a novel oral testosterone undecanoate therapy for the treatment of hypogonadism.

MATERIAL AND METHODS: Ninety-five (N = 95) hypogonadal men were enrolled in this open-label, single-arm, multicenter study in the United States (NCT03242590). Subjects received 225 mg of oral testosterone undecanoate (TLANDO) twice a day for 24 days without dose adjustment. Primary efficacy was percentages of subjects who achieved mean 24-h testosterone levels within the eugonadal range and secondary efficacies were evaluated based on the upper limit of lab normal range of testosterone concentration.

RESULTS: Subjects enrolled were on average age of 56 years, with about 17% of subjects older than 65 years. The mean body mass index was 32.8 kg/m2 . The baseline mean total testosterone values were below the normal range (202 ± 74 ng/dl). Post-treatment with 450 mg testosterone undecanoate daily dose without dose adjustment, 80% of subjects (95% confidence interval of 72%-88%) achieved a testosterone Cavg in the normal range and restored testosterone levels to mean testosterone Cavg of 476 ± 184 ng/dl at steady state. Testosterone restoration was comparable to other approved testosterone replacement therapy products. TLANDO was well tolerated with no deaths, no drug-related serious adverse events, and no hepatic adverse events.

DISCUSSION AND CONCLUSIONS: TLANDO restored testosterone levels to the normal range in the majority of hypogonadal males. This new oral testosterone replacement therapy can provide an option for no-titration oral testosterone replacement therapy. This therapy has the potential to improve patient compliance in testosterone replacement therapy.

PMID:34994093 | DOI:10.1111/andr.13153

Clin Infect Dis. 2022 Jan 6:ciab1065. doi: 10.1093/cid/ciab1065. Online ahead of print.

ABSTRACT

BACKGROUND: GSK3640254 (GSK'254) is a next-generation HIV-1 maturation inhibitor with pharmacokinetics (PK) supporting once-daily therapy.

METHODS: This phase IIa double-blind (sponsor-unblinded), randomized, placebo-controlled, adaptive study evaluated antiviral effect, safety, tolerability, and PK of once-daily GSK'254 monotherapy administered with food (moderate-fat meal) in HIV-1-positive, treatment-naive adults. In part 1, participants received GSK'254 10 or 200 mg for 10 days. In part 2, participants received GSK'254 40, 80, or 140 mg for 7 days, modified from 10 days by a protocol amendment to decrease potential for resistance-associated mutations (RAMs). The primary endpoint was maximum change from baseline in HIV-1 RNA.

RESULTS: Maximum changes in HIV-1 RNA of -0.4, -1.2, -1.0, -1.5, and -2.0 log10 occurred with GSK'254 10, 40, 80, 140, and 200 mg, respectively. Regardless of dosing duration, doses ≥40 mg resulted in ≥1-log10 declines in HIV-1 RNA. Plasma PK was generally dose proportional to 140 mg but non-proportional between 140 and 200 mg. Four participants in the 200-mg group developed RAMs on Day 11 in part 1, one with phenotypic resistance. No RAMs occurred in part 2. Adverse events (AEs) were reported by 22 (65%) participants; headache was the most common (n=4). Two non-drug-related serious AEs occurred. All AEs were of mild-to-moderate intensity, except for 2 grade 3 non-drug-related AEs in 1 participant.

CONCLUSIONS: This monotherapy study established a dose-antiviral response relationship for GSK'254. No safety or tolerability concerns were noted. These results supported dose selection for the ongoing phase IIb study (ClinicalTrials.gov: NCT04493216).

PMID:34996113 | DOI:10.1093/cid/ciab1065

Anticancer Agents Med Chem. 2022 Jan 6. doi: 10.2174/1871520622666220106103336. Online ahead of print.

ABSTRACT

Microbial L-asparaginase is the most effective first-line therapeutic used in the treatment protocols of paediatric and adult leukemia. Leukemic cell's auxotrophy for L-asparagine is exploited as a therapeutic strategy to mediate cell death through metabolic blockade of L-asparagine using L-asparaginase. Escherichia coli and Erwinia chrysanthemi serve as the major enzyme deriving sources accepted in clinical practise and the enzyme has bestowed improvements in patient outcomes over the last 40 years. However, an array of side effects generated by the native enzymes due to glutamine co-catalysis and short serum stays augmenting frequent dosages, intended a therapeutic switch towards the development of biobetter alternatives for the enzyme including the formulations resulting in sustained local depletion of L-asparagine. In addition, the treatment with L-asparaginase in few cancer types has proven to elicit drug-induced cytoprotective autophagy mechanisms and therefore warrants concern. Although the off-target glutamine hydrolysis has been viewed in contributing the drug-induced secondary responses in cells deficient with asparagine synthetase machinery, the beneficial role of glutaminase-asparaginase in proliferative regulation of asparagine prototrophic cells has been looked forward. The current review provides an overview on the enzyme's clinical applications in leukemia and possible therapeutic implications in other solid tumours, recent advancements in drug formulations, and discusses the aspects of two-sided roles of glutaminase-asparaginases and drug-induced cytoprotective autophagy mechanisms.

PMID:34994334 | DOI:10.2174/1871520622666220106103336

Health Serv Res Manag Epidemiol. 2021 Dec 21;8:23333928211068919. doi: 10.1177/23333928211068919. eCollection 2021 Jan-Dec.

ABSTRACT

BACKGROUND: As part of the accelerated approval of mifepristone as an abortifacient in 2000, the Food and Drug Administration (FDA) required prescribers to report all serious adverse events (AEs) to the manufacturer who was required to report them to the FDA. This information is included in the FDA Adverse Event Reporting System (FAERS) and is available to the public online. The actual Adverse Event Reports (AERs) can be obtained through the Freedom of Information Act (FOIA).

METHODS: We compared the number of specific AEs and total AERs for mifepristone abortions from January 1, 2009 to December 31, 2010 from 1. Planned Parenthood abortion data published by Cleland et al. 2. FAERS online dashboard, and 3. AERs provided through FOIA and analyzed by Aultman et al.

RESULTS: Cleland identified 1530 Planned Parenthood mifepristone cases with specific AEs for 2009 and 2010. For this period, FAERS online dashboard includes a total (from all providers) of only 664, and the FDA released only 330 AERs through FOIA. Cleland identified 1158 ongoing pregnancies in 2009 and 2010. FAERs dashboard contains only 95, and only 39 were released via FOIA.

CONCLUSIONS: There are significant discrepancies in the total number of AERs and specific AEs for 2009 and 2010 mifepristone abortions reported in 1. Cleland's documentation of Planned Parenthood AEs, 2. FAERS dashboard, and 3. AERs provided through FOIA. These discrepancies render the FAERS inadequate to evaluate the safety of mifepristone abortions.

PMID:34993274 | PMC:PMC8724996 | DOI:10.1177/23333928211068919

Psychiatriki. 2021 Dec;32(Supplement I):70-81. doi: 10.22365/jpsych.2021.052.

ABSTRACT

Treatment-Resistant Depression (TRD) calls for the development of effective interventions for mood elevation and stabilization. Recently, both ketamine and its S-enantiomer (esketamine) have been investigated with successful clinical trials demonstrating effectiveness in TRD. More specifically, in 2019, intranasally administered esketamine, as opposed to the more effective intravenous ketamine, has been approved by the FDA as a treatment option for TRD. Treatment with esketamine, however, potentially comes with major adverse effects, including risk of psychosis, the possibility of abuse and dependence after repeated use, transient but non-negligible change in blood pressure and the heart rate, and potential toxicity on the urothelium and the liver. These risks are minimized when treatment is kept within the recommended dose range and the drug is administered by experienced medical personnel. Nevertheless, these risks appear to be offset by the effectiveness of esketamine in a wide range of depressive symptoms, such as anhedonia, anxiety, cognitive impairment, suicidality, and general dysfunction. This review highlights the need for more phase 4 clinical studies to evaluate esketamine's performance in real life, including long-term effectiveness and risk studies.

PMID:34990382 | DOI:10.22365/jpsych.2021.052

Clin J Gastroenterol. 2022 Jan 5. doi: 10.1007/s12328-021-01582-5. Online ahead of print.

ABSTRACT

A 71-year-old Japanese man was treated with 200 mg of pembrolizumab for lung adenocarcinoma with multiple bone metastases at the Department of Respiratory Medicine of Kameda General Hospital. After 19 treatment courses, he complained of epigastric pain before meals. Upper gastrointestinal endoscopy showed multiple erosions in the gastric antrum, and antacids were administered at follow-up. After 27 treatment courses, the patient underwent another endoscopy because of anorexia. The erosions were enlarged and had increased from the gastric antrum to the greater curvature of the body. Histological biopsy showed lymphocytic infiltration with a predominance of CD8-positive T cells. The patient had previously been treated for Helicobacter pylori infection, and we suspected drug-induced gastritis due to the administration of immune checkpoint inhibitors in the course of the disease. Pembrolizumab was discontinued, and the patient's symptoms gradually improved. Endoscopic examinations were performed 2, 5, and 9 months after discontinuation of pembrolizumab, and improvement in mucosal findings and decreased lymphocyte infiltration were confirmed each time. The patient has remained without any relapse of symptoms for more than 1 year after discontinuing treatment.

PMID:34985687 | DOI:10.1007/s12328-021-01582-5

AIDS Rev. 2021;23(4):214-225. doi: 10.24875/AIDSRev.M21000044.

ABSTRACT

Neuropsychiatric disorders and central nervous system-related symptoms are very common in people with HIV and can have a very negative impact on their quality of life and worsen the prognosis of the disease. These disorders are multifactorial in origin, but may be triggered or worsened by the use of certain antiretroviral treatments. This paper reviews the epidemiology of neuropsychiatric disorders and symptoms in people with HIV, the recommendations and tools available for their early assessment, as well as the neurotoxicity of the main families of antiretroviral (ARV) drugs. It is important to focus on improvement towards the detection of these disorders during the first evaluation or patient follow-up, aimed at improving quality of life. Because of the central nervous system neurotoxicity profile of different antiretroviral drugs, proactive assessment of neuropsychiatric disorders and symptoms prior to treatment start and during follow-up is necessary.

PMID:34980928 | DOI:10.24875/AIDSRev.M21000044

J Asthma. 2022 Jan 3:1-7. doi: 10.1080/02770903.2021.2018705. Online ahead of print.

ABSTRACT

OBJECTIVES: Neuropsychiatric events (NEs) reported with montelukast during post-marketing surveillance by the US Food & Drug Administration resulted in a 2008 safety alert and a black box warning in 2020. Our objective was to evaluate montelukast exposure and NEs risk using sequence symmetry analysis.

METHODS: National Veterans Health Administration (VHA) administrative data were used to identify 11 840 patients prescribed incident montelukast during fiscal year 2014. Incident prescribing of neuropsychiatric medication was used as a proxy marker for incident NEs and included antidepressants, benzodiazepines, hypnotics, antipsychotics, mood stabilizers, and buspirone. Symmetry ratios were calculated as the ratio of patients with an incident neuropsychiatric event in the year following montelukast initiation to the year preceding initiation. Exposure counterfactual analyses were used to examine the relationship between potential therapeutic alternatives to montelukast and risk for NEs.

RESULTS: Incident NEs were observed in 2305 patients following montelukast initiation and 2734 patients preceding montelukast initiation (SR 0.84, 95% CI 0.80-0.89). Sensitivity analyses examining each of the 6 sub-types of psychiatric medications also failed to show increased risk of NEs following montelukast initiation. Therapeutic alternatives to montelukast, such as inhaled corticosteroids, were also not associated increased NE risk.

CONCLUSIONS: Initiation of montelukast was not associated with increased risk of a variety of NEs in this sequence symmetry analysis involving adult patients in the VHA. Our findings do not support the hypothesis that NEs are associated with montelukast initiation.

PMID:34979844 | DOI:10.1080/02770903.2021.2018705

Neurol India. 2021 Nov-Dec;69(6):1524-1538. doi: 10.4103/0028-3886.333440.

ABSTRACT

BACKGROUND: Lamotrigine (LMT) is a phenyltriazine derivative that was originally described as an antiepileptic drug.

OBJECTIVE: This literature review aims to evaluate the clinical epidemiological profile, pathological mechanisms, and management of lamotrigine-associated movement disorders.

METHODS: Relevant reports in six databases were identified and assessed by two reviewers without language restriction. Reports that the individuals only developed tremor or ataxia after LMT use were not included.

RESULTS: In total 48 reports of 108 cases from 19 countries were assessed. The movement disorders associated with LMT found were 29 tics, 21 dyskinesias, 14 myoclonus, 13 parkinsonism, 10 dystonia, and 1 stuttering. The not clearly defined cases included 10 akathisia, 4 myoclonus, 4 cerebellar syndromes, 1 hypertonia, 1 dyskinesia, and an unknown number of dystonia cases. The mean reported age was 33.34 years (range: 1.574 years). The male was the predominant sex and the most common LMT indication was epilepsy. The mean LMT-dose at the movement disorder onset was 228 mg. The time from LMT start to the onset of movement disorder was within 6 months in 81%. The time from LMT withdrawal to complete recovery was within 1 month in 83%. The most common management was LMT withdrawal.

CONCLUSIONS: In the literature, the majority of the cases did not give a clear picture of the individual, and the times of movement disorder onset and recovery are not described. We believe that before withdrawal LMT, a dose adjustment based on the benefits and adverse events with careful evaluation case-by-case can be done.

PMID:34979637 | DOI:10.4103/0028-3886.333440

ACS Biomater Sci Eng. 2022 Jan 3. doi: 10.1021/acsbiomaterials.1c00994. Online ahead of print.

ABSTRACT

In vitro drug-induced liver injury (DILI) models are promising tools for drug development to predict adverse events during clinical usage. However, the currently available DILI models are not specific or not able to predict the injury accurately. This is believed to be mainly because of failure to conserve the hepatocyte phenotype, lack of longevity, and difficulty in maintaining the tissue-specific microenvironment. In this study, we have assessed the potential of decellularized liver extracellular matrix (DLM) in retaining the hepatic cellular phenotype and functionality in the presence of a tissue-specific microenvironment along with its role in influencing the effect of the drug on hepatic cells. We show that DLM helps maintain the phenotype of the hepatic cell line HepG2, a well-known cell line for secretion of human proteins that is easily available. Also, the DLM enhanced the expression of a metabolic marker carbamoyl phosphate synthetase I (CPS1), a regulator of urea cycle, and bile salt export pump (BSEP), a marker of hepatocyte polarity. We further validated the DLM for its influence on the sensitivity of cells toward different classes of drugs. Interestingly, the coculture model, in the presence of endothelial cells and stellate cells, exhibited a higher sensitivity for both acetaminophen and trovafloxacin, a toxic compound that does not show any toxicity on preclinical screening. Thus, our results demonstrate for the first time that a multicellular combination along with DLM can be a potential and reliable DILI model to screen multiple drugs.

PMID:34978414 | DOI:10.1021/acsbiomaterials.1c00994

J Pak Med Assoc. 2021 Oct;71(10):2481-2482. doi: 10.47391/JPMA.01-131.

NO ABSTRACT

PMID:34974602 | DOI:10.47391/JPMA.01-131

J Pak Med Assoc. 2021 Oct;71(10):2373-2377. doi: 10.47391/JPMA.796.

ABSTRACT

OBJECTIVE: To determine the proportion of treatment-related mortality among mortalities of paediatric acute lymphoblastic leukaemia and to identify probable causes and risk factors.

METHODS: The observational retrospective study was conducted in February-March 2019 at the Department of Paediatric Haematology-Oncology and Bone Marrow Transplant, the Children's Hospital and the Institute of Child Health, Lahore, Pakistan, and comprised data of all paediatric patients of acute lymphoblastic leukaemia who expired during treatment from January 2017 till September 2018. Death due to relapse and deaths before treatment were excluded. Data was analysed using SPSS 16.

RESULTS: Of the 247 deaths during the study period, 144(58.3%) were treatment-related mortality cases; 81(56.2%) males and 63(43.8%) females with an overall mean age of 5.0±3.83 years. The commonest cause was sepsis 126(87.5%), followed by haemorrhagic complications 11(7.6%), drug toxicity 4(2.8%), tumour lysis syndrome 2(1.4%) and thromboembolism 1(0.7%). Significant factors associated with treatment-related mortality were weight-for-age, immunophenotype, the reason for admission, and absolute neutrophil count (p<0.05).

CONCLUSIONS: Treatment-related mortality, though potentially avoidable, was found to be a major cause of death among paediatric patients of acute lymphoblastic leukaemia, and sepsis was the most common cause.

PMID:34974574 | DOI:10.47391/JPMA.796

Adv Exp Med Biol. 2021;1342:357-375. doi: 10.1007/978-3-030-79308-1_14.

ABSTRACT

Immune checkpoint inhibitors are a form of immunotherapy that are increasingly being used in a wide variety of cancers. Immune-related adverse events (irAEs) pose a major challenge in the treatment of cancer patients. Pneumonitis, the most common lung irAE, can cause significant disruptions in the treatment of cancer and may be life-threatening. The goal of this chapter is to instruct readers on the incidence and clinical manifestations of pneumonitis and to offer guidance in the evaluation and treatment of patients with pneumonitis.

PMID:34972974 | DOI:10.1007/978-3-030-79308-1_14

Emerg Med Australas. 2022 Jan 1. doi: 10.1111/1742-6723.13929. Online ahead of print.

ABSTRACT

OBJECTIVE: To determine the burden, on the ED, of harm from unintentional adverse drug events (ADEs) in the community.

METHODS: A retrospective, observational study of 936 randomly selected presentations to a level 6 ED at a principal referral hospital in Brisbane, Australia, in November 2017. Clinical records were screened by a pharmacist, who identified suspected ADEs. All suspected ADEs and a random selection of presentations without ADEs were reviewed by an expert panel, which classified, by consensus: occurrence and type of ADE, contribution of ADE to presentation, severity of harm and preventability of presentation. Medication-related ED presentations (ADE-Ps) and potential ADEs were, respectively, defined as presentations directly attributable to an ADE, and medication events that occurred but did not cause the ED presentation. Descriptive data analysis was performed.

RESULTS: The median (interquartile range) age of patients was 40 (27-58) years, with 49.7% (95% confidence interval [CI] 46.5-52.9) being male. The prevalences of ADE-Ps and potential ADEs were 9.2% (95% CI 7.5-11.3) and 5.0% (95% CI 3.8-6.6), respectively. The severity of harm was classified as 'death or likely permanent harm' in 4.7% (95% CI 0.2-9.1) of ADE-Ps, 'temporary harm' (89.5%, 95% CI 83.1-96.0) and 'minimal or no harm' (5.8%, 95% CI 0.9-10.8). Most (79.1%, 95% CI 70.5-87.7) ADE-Ps were preventable.

CONCLUSIONS: There is a high burden on emergency care because of unintended medication harm in the community. Interventions to reduce such harm are likely to require a co-ordinated primary, acute and public healthcare response. The high proportion of presentations with potential ADEs indicates opportunity for harm mitigation in the ED.

PMID:34973155 | DOI:10.1111/1742-6723.13929

J Clin Immunol. 2022 Jan 1. doi: 10.1007/s10875-021-01181-6. Online ahead of print.

ABSTRACT

PURPOSE: The purpose of this phase 3 study was to evaluate the efficacy, pharmacokinetics (PK), and safety of Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (IGSC 20%) in patients with primary immunodeficiency (PI).

METHODS: Immunoglobulin treatment-experienced subjects with PI received 52 weeks of IGSC 20% given weekly at the same dose as the subject's previous IgG regimen (DAF 1:1); the minimum dose was 100 mg/kg/week. The primary endpoint was serious bacterial infections (SBIs [null vs alternative hypothesis: SBI rate per person per year ≥ 1 vs < 1]). IgG subclasses and specific pathogen antibody levels were also measured.

RESULTS: Sixty-one subjects (19 children [≤ 12 years], 10 adolescents [> 12-16 years], and 32 adults) were enrolled. The rate of SBIs per person per year was 0.017. The 1-sided 99% upper confidence limit was 0.036 (< 1), and the null hypothesis was rejected. The rate of hospitalization due to infection per person per year was 0.017 (2-sided 95% confidence interval: 0.008-0.033) overall. The mean trough total IgG concentrations were comparable to the previous IgG replacement regimen. The average of the individual mean trough ratios (IGSC 20%:previous regimen) was 1.078 (range: 0.83-1.54). The average steady-state mean trough IgG concentrations were 947.64 and 891.37 mg/dL, respectively. Seven subjects had serious treatment-emergent adverse events (TEAEs); none was drug-related. The rate of all TEAEs, including local infusion site reactions, during 3045 IGSC 20% infusions was 0.135. Most TEAEs were mild or moderate.

CONCLUSIONS: IGSC 20% demonstrated efficacy and good safety and tolerability in subjects with PI.

PMID:34973143 | DOI:10.1007/s10875-021-01181-6

Adv Exp Med Biol. 2021;1342:339-355. doi: 10.1007/978-3-030-79308-1_13.

ABSTRACT

The expanded approval of immune checkpoint inhibitors (ICIs) for the treatment of multiple cancer types has offered patients more opportunities in treatment selection and survival.Hepatotoxicity is a well-recognized immune-related adverse event (irAE) associated with treatment with ICI. It is considered a type of drug-induced liver injury (DILI). Depending on the specific ICI and whether the patient receives single- or dual-drug therapy, the incidence of hepatotoxicity in general could be as high as 30%. As more patients receive treatment with ICI, more cases of hepatotoxicity are expected to occur. Clinicians must exercise close pharmacovigilance to recognize liver-related irAEs early.ICI-mediated hepatobiliary toxicity (or "IMH") generally presents as asymptomatic elevations of alanine transaminase and aspartate transaminase, with or without alkaline phosphatase elevation. Some patients may present with jaundice, fever, or malaise. Rarely, it may cause liver failure and death. The diagnosis of IMH is made after careful exclusion of other causes of acute hepatitis based on medical history, laboratory evaluation, imaging, and liver histological findings. In clinically significant cases of IMH, the management involves discontinuation of ICI followed by close monitoring and the initiation of immunosuppression. Current society guidelines, which are not based on robust evidence, specify treatment recommendations depending on the grade of liver injury, according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. However, our clinical experience suggests possible alternatives, including lower corticosteroid dosing with adjunct therapies. Whereas current guidelines endorse permanent cessation of future ICI treatment in patients diagnosed with grades 3-4 IMH, published clinical experience suggests potential for flexibility when assessing for candidacy of resuming ICI.Because histologic bile duct injury has been observed in cases ascribed to IMH, ICI-mediated cholangiopathic disease probably exists on a spectrum within IMH. Even extrahepatic bile duct involvement has been observed. This phenotype warrants special considerations in treatment and surveillance.ICI-related cholecystitis has been rarely reported in the literature. Management follows current standards of care for typical cases of cholecystitis. No relationship with ICI-mediated cholangiopathic disease has been observed.Assessing for and managing ICI-associated pancreatic injury remain challenging to the clinician. Many cases of asymptomatic serum lipase elevation are detected on routine labs without clinical signs or symptoms of typical acute pancreatitis. However, symptomatic patients should be initially managed like traditional cases of acute pancreatitis requiring hospitalization for evaluation and inpatient management.

PMID:34972973 | DOI:10.1007/978-3-030-79308-1_13

Pan Afr Med J. 2021 Nov 17;40:165. doi: 10.11604/pamj.2021.40.165.28574. eCollection 2021.

ABSTRACT

INTRODUCTION: timely adverse drug reactions (ADRs) reporting has contributed immensely towards public health safety. Community health extension workers (CHEWs) provides basic medical care in rural areas. This study assessed the knowledge, attitude, practice, and determinants of ADRs reporting among CHEWs in public health institutions, Southwest, Nigeria.

METHODS: a cross-sectional survey of 333 CHEWs randomly selected from public health facilities using self-administered questionnaires. The questionnaire sought information on the knowledge, attitude and practice of CHEWs towards ADRs reporting. The knowledge and attitude questions were scored and categorized. The association between dependent and independent variables assessed with bivariate and multivariate logistic regressions, and p < 0.05 considered statistically significant.

RESULTS: among 333 respondents, 205 (61.6%) had encountered patients with ADRs but only 26 (12.6%) had reported it with yellow forms. About half, 169 (50.8%), and 191 (57.4%) respondents had a positive attitude and inadequate knowledge of ADRs reporting respectively. Sex (aOR: 2.84, 95% CI: 2.10-7.10; p < 0.0001), working in Ogbomoso area (aOR: 3.3, 95% CI: 1.34-8.21; p=0.01), and training (aOR: 2.01, 95% CI: 1.20-3.42; p = 0.01) were factors associated with adequate knowledge. The determinant of ADRs reporting was training (aOR: 3.63, 95% CI: 1.13-11.63; p = 0.03).

CONCLUSION: though CHEWs had a slightly positive attitude, they had inadequate knowledge and poor ADRs reporting. The determinant of inadequate ADRs reporting knowledge and under reporting was lack of training. There is an urgent need for educational intervention programmes towards improving knowledge and practices of ADRs reporting among CHEWs.

PMID:34970407 | PMC:PMC8683451 | DOI:10.11604/pamj.2021.40.165.28574

Clin Immunol. 2021 Dec 28:108916. doi: 10.1016/j.clim.2021.108916. Online ahead of print.

ABSTRACT

In recent years, therapeutic agents affecting the immune system have been largely implemented in the treatment of various hematological, rheumatological and dermatological disorders. Their clinical use has offered important benefits for affected patients and has also ameliorated clinical outcome and prognosis in many cases. Nonetheless, as any treatment, the use of these drugs may be associated with side effects. One of the target organs in such cases is the gastrointestinal tract. In particular, the exacerbation or the onset of inflammatory bowel disease (IBD) in treated patients is not infrequent, although the mechanism of action of these agents may be different. In this review we will focus on the use of therapeutic agents affecting the immune system and the development or exacerbation of IBD, with a mention on the possible underlying pathogenetic mechanisms.

PMID:34971840 | DOI:10.1016/j.clim.2021.108916