Rheumatology (Oxford). 2022 Sep 21:keac522. doi: 10.1093/rheumatology/keac522. Online ahead of print.

ABSTRACT

OBJECTIVE: To evaluate the long-term efficacy and safety of brodalumab, a fully human anti-interleukin-17 receptor A monoclonal antibody, in patients with axial spondyloarthritis (axSpA).

METHODS: Patients receiving subcutaneous brodalumab 210 mg during the 16-week double-blind period of this multicentre, phase 3 study conducted across Japan, Korea and Taiwan continued the same during the 52-week open-label extension, whereas patients receiving placebo switched to brodalumab 210 mg at week 16. Efficacy (Assessment of SpondyloArthritis International Society [ASAS] 40 and ASAS 20 response rates; change from baseline in Ankylosing Spondylitis Disease Activity Score using C-reactive protein [ASDAS-CRP]) and safety were evaluated.

RESULTS: Overall, 145 patients (brodalumab, n = 77; placebo, n = 68) received brodalumab during the open-label extension. ASAS 40 response rates (95% confidence interval [CI]) of 56.3% (44.7%, 67.3%) and 57.4% (44.1%, 70.0%) were achieved in the brodalumab and placebo groups, respectively, at week 68. ASAS 20 response rates (95% CI) achieved at week 68 in both treatment groups were similar (brodalumab, 71.3% [60.0%, 80.8%]; placebo, 78.7% [66.3%, 88.1%]). The least squares mean change (95% CI) in ASDAS-CRP at week 68 suggested a clinically important improvement (change, ≥1.1) in both treatment groups (brodalumab, -1.528 [-1.737, -1.319]; placebo, -1.586 [-1.815, -1.357]). The exposure-adjusted event rates (per 100 patient-years) for treatment-emergent adverse events (TEAEs) and drug-related TEAEs were 255.9 and 147.9, respectively; nasopharyngitis (35.6) and upper respiratory tract infection (14.7) were the most common TEAEs.

CONCLUSION: Brodalumab demonstrated sustained efficacy and a consistent safety profile in patients with axSpA over 68 weeks.

CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02985983.

PMID:36130275 | DOI:10.1093/rheumatology/keac522

Eur J Endocrinol. 2022 Sep 1:EJE-22-0449. doi: 10.1530/EJE-22-0449. Online ahead of print.

ABSTRACT

OBJECTIVE: To evaluate the safety and efficacy of weekly PEG-rhGH in children with idiopathic short stature (ISS) in China.

DESIGN AND METHODS: A multicenter, phase II study randomized subjects 1:1:1 to weekly subcutaneous injections of PEG-rhGH 0.1 (low dose [LD]) or 0.2 mg/kg/week (high dose [HD]) or control for 52 weeks. The primary endpoint was change in HT-SDS from baseline to week 52. Secondary endpoints were height velocity (HV), bone maturity, IGF-1 SDS, and IGF-1/IGFBP-3 ratio.

RESULTS: A total of 360 children with ISS were recruited in the study (n=120 in each group). At week 52, the mean change from baseline in HT-SDS was 0.56 ± 0.26, 0.98 ± 0.35, and 0.20 ± 0.26 in the LD, HD, and control groups, respectively (within-group P<0.0001; inter-group P<0.0001). Statistically significant changes in HV, IGF-1, IGF-1/IGFBP-3 ratio, and IGF-1 SDS at week 52 from baseline were observed in both treatment groups (P<0.0001). There were clear dose-dependent responses for all auxological variables. PEG-rhGH was well tolerated throughout the treatment period with treatment-emergent adverse events (TEAEs) reported in 86.5%, 84.6%, and 91.3% of children in the HD, LD, and control groups, respectively. The incidence of TEAEs was similar in all treatment groups despite the difference in doses. A total of 27 (8.7%) children experienced drug-related TEAEs.

CONCLUSION: Fifty-two-week treatment with PEG-rhGH 0.1 or 0.2 mg/kg/week achieved significant improvement in HT-SDS and other growth-related variables, including HV, IGF-1 SDS, and IGF-1/IGFBP-3 ratio, in a dose-dependent manner. Both doses were well tolerated with similar safety profiles.

PMID:36130048 | DOI:10.1530/EJE-22-0449

Clin Transl Sci. 2022 Sep 20. doi: 10.1111/cts.13419. Online ahead of print.

ABSTRACT

Interstitial lung disease (ILD), as an adverse effect of certain drugs, leads to inflammation and damage in the walls of alveoli, making it difficult for the alveoli to take up oxygen. Interstitial pneumonia with no identifiable cause is called idiopathic interstitial pneumonia (IIP), and among the major IIPs, idiopathic pulmonary fibrosis (IPF) is diagnosed in about half of patients. Current treatment options are limited, among which the antifibrotic drugs nintedanib (Ofev®) and pirfenidone (Pirespa®) are the first-line drugs. In this study, we investigated the incidence of ILD possibly caused by antifibrotic agents using data from the Japanese Adverse Drug Event Report (JADER) database, a database of spontaneous adverse event reports published by the Pharmaceuticals and Medical Devices Agency (PMDA), and the FDA Adverse Event Reporting System (FAERS) published by the U.S. Food and Drug Administration. We used the FAERS and JADER to detect the signals of adverse events on the basis of reporting odds ratios. The relationship between indications and adverse events was clarified by separating indications and adverse events using the spontaneous adverse event reporting database with novel drug involvement. Regarding the involvement of nintedanib and pirfenidone in the development of ILD, JADER and FAERS showed signals for both nintedanib and pirfenidone as suspect drugs, and no signals for nintedanib or pirfenidone as concomitant drug interactions were detected. We highlight this because there are only a few effective drugs for IPF, and effective and safe drug therapies should be implemented by taking into consideration drug-induced ILD.

PMID:36128688 | DOI:10.1111/cts.13419

Methods Mol Biol. 2022;2544:119-127. doi: 10.1007/978-1-0716-2557-6_8.

ABSTRACT

Inhibition of bile acid excretion by drugs is a significant factor in the development of drug-induced cholestatic liver injury. We constructed a new in vitro assay system to detect bile acid-dependent cytotoxicity in hepatocytes. This cell-based system can assess the toxicity of the parent compound, as well as the contribution of metabolite(s). In addition, this system can utilize several types of hepatocytes (primary hepatocytes, hepatoma cell line, and induced pluripotent stem cell-induced hepatocytes). In this chapter, a method to detect drug-induced bile acid-dependent toxicity in hepatocytes is described.

PMID:36125714 | DOI:10.1007/978-1-0716-2557-6_8

Pharmacol Res Perspect. 2022 Oct;10(5):e01008. doi: 10.1002/prp2.1008.

ABSTRACT

The misattribution of an adverse drug reaction (ADR) as a symptom or illness can lead to the prescribing of additional medication, referred to as a prescribing cascade. The aim of this systematic review is to identify published prescribing cascades in community-dwelling adults. A systematic review was reported in line with the PRISMA guidelines and pre-registered with PROSPERO. Electronic databases (Medline [Ovid], EMBASE, PsycINFO, CINAHL, Cochrane Library) and grey literature sources were searched. Inclusion criteria: community-dwelling adults; risk-prescription medication; outcomes-initiation of new medicine to "treat" or reduce ADR risk; study type-cohort, cross-sectional, case-control, and case-series studies. Title/abstract screening, full-text screening, data extraction, and methodological quality assessment were conducted independently in duplicate. A narrative synthesis was conducted. A total of 101 studies (reported in 103 publications) were included. Study sample sizes ranged from 126 to 11 593 989 participants and 15 studies examined older adults specifically (≥60 years). Seventy-eight of 101 studies reported a potential prescribing cascade including calcium channel blockers to loop diuretic (n = 5), amiodarone to levothyroxine (n = 5), inhaled corticosteroid to topical antifungal (n = 4), antipsychotic to anti-Parkinson drug (n = 4), and acetylcholinesterase inhibitor to urinary incontinence drugs (n = 4). Identified prescribing cascades occurred within three months to one year following initial medication. Methodological quality varied across included studies. Prescribing cascades occur for a broad range of medications. ADRs should be included in the differential diagnosis for patients presenting with new symptoms, particularly older adults and those who started a new medication in the preceding 12 months.

PMID:36123967 | DOI:10.1002/prp2.1008

Cochrane Database Syst Rev. 2022 Sep 20;9:CD014804. doi: 10.1002/14651858.CD014804.pub2.

ABSTRACT

BACKGROUND: Solid organ transplantation has seen improvements in both surgical techniques and immunosuppression, achieving prolonged survival. Essential to graft acceptance and post-transplant recovery, immunosuppressive medications are often accompanied by a high prevalence of gastrointestinal (GI) symptoms and side effects. Apart from GI side effects, long-term exposure to immunosuppressive medications has seen an increase in drug-related morbidities such as diabetes mellitus, hyperlipidaemia, hypertension, and malignancy. Non-adherence to immunosuppression can lead to an increased risk of graft failure. Recent research has indicated that any microbial imbalances (otherwise known as gut dysbiosis or leaky gut) may be associated with cardiometabolic diseases in the long term. Current evidence suggests a link between the gut microbiome and the production of putative uraemic toxins, increased gut permeability, and transmural movement of bacteria and endotoxins and inflammation. Early observational and intervention studies have been investigating food-intake patterns, various synbiotic interventions (antibiotics, prebiotics, or probiotics), and faecal transplants to measure their effects on microbiota in treating cardiometabolic diseases. It is believed high doses of synbiotics, prebiotics and probiotics are able to modify and improve dysbiosis of gut micro-organisms by altering the population of the micro-organisms. With the right balance in the gut flora, a primary benefit is believed to be the suppression of pathogens through immunostimulation and gut barrier enhancement (less permeability of the gut).

OBJECTIVES: To assess the benefits and harms of synbiotics, prebiotics, and probiotics for recipients of solid organ transplantation.

SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register up to 9 March 2022 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

SELECTION CRITERIA: We included randomised controlled trials measuring and reporting the effects of synbiotics, prebiotics, or probiotics, in any combination and any formulation given to solid organ transplant recipients (any age and setting). Two authors independently assessed the retrieved titles and abstracts and, where necessary, the full text to determine which satisfied the inclusion criteria.

DATA COLLECTION AND ANALYSIS: Data extraction was independently carried out by two authors using a standard data extraction form. The methodological quality of included studies was assessed using the Cochrane risk of bias tool. Data entry was carried out by one author and cross-checked by another. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

MAIN RESULTS: Five studies (250 participants) were included in this review. Study participants were adults with a kidney (one study) or liver (four studies) transplant. One study compared a synbiotic to placebo, two studies compared a probiotic to placebo, and two studies compared a synbiotic to a prebiotic. Overall, the quality of the evidence is poor. Most studies were judged to have unclear (or high) risk of bias across most domains. Of the available evidence, meta-analyses undertaken were of limited data from small studies. Across all comparisons, GRADE evaluations for all outcomes were judged to be very low certainty evidence. Very low certainty evidence implies that we are very uncertain about results (not estimable due to lack of data or poor quality). Synbiotics had uncertain effects on the change in microbiota composition (total plasma p-cresol), faecal characteristics, adverse events, kidney function or albumin concentration (1 study, 34 participants) compared to placebo. Probiotics had uncertain effects on GI side effects, infection rates immediately post-transplant, liver function, blood pressure, change in fatty liver, and lipids (1 study, 30 participants) compared to placebo. Synbiotics had uncertain effects on graft health (acute liver rejection) (2 studies, 129 participants: RR 0.73, 95% CI 0.43 to 1.25; 2 studies, 129 participants; I² = 0%), the use of immunosuppression, infection (2 studies, 129 participants: RR 0.18, 95% CI 0.03 to 1.17; I² = 66%), GI function (time to first bowel movement), adverse events (2 studies, 129 participants: RR 0.79, 95% CI 0.40 to 1.59; I² = 20%), serious adverse events (2 studies, 129 participants: RR 1.49, 95% CI 0.42 to 5.36; I² = 81%), death (2 studies, 129 participants), and organ function measures (2 studies; 129 participants) compared to prebiotics.

AUTHORS' CONCLUSIONS: This review highlights the severe lack of high-quality RCTs testing the efficacy of synbiotics, prebiotics or probiotics in solid organ transplant recipients. We have identified significant gaps in the evidence. Despite GI symptoms and postoperative infection being the most common reasons for high antibiotic use in this patient population, along with increased morbidity and the growing antimicrobial resistance, we found very few studies that adequately tested these as alternative treatments. There is currently no evidence to support or refute the use of synbiotics, prebiotics, or probiotics in solid organ transplant recipients, and findings should be viewed with caution. We have identified an area of significant uncertainty about the efficacy of synbiotics, prebiotics, or probiotics in solid organ transplant recipients. Future research in this field requires adequately powered RCTs comparing synbiotics, prebiotics, and probiotics separately and with placebo measuring a standard set of core transplant outcomes. Six studies are currently ongoing (822 proposed participants); therefore, it is possible that findings may change with their inclusion in future updates.

PMID:36126902 | DOI:10.1002/14651858.CD014804.pub2

MMW Fortschr Med. 2022 Sep;164(16):31. doi: 10.1007/s15006-022-1932-6.

NO ABSTRACT

PMID:36123474 | DOI:10.1007/s15006-022-1932-6

PLoS One. 2022 Sep 19;17(9):e0272743. doi: 10.1371/journal.pone.0272743. eCollection 2022.

ABSTRACT

Adverse drug events are significant causes of emergency department visits. Systematic evaluation of adverse drug events leading to emergency department visits by age is lacking. This multicenter retrospective observational study evaluated the prevalence and features of adverse drug event-related emergency department visits across ages. We reviewed emergency department medical records obtained from three university hospitals between July 2014 and December 2014. The proportion of adverse drug events among total emergency department visits was calculated. The cause, severity, preventability, and causative drug(s) of each adverse drug event were analyzed and compared between age groups (children/adolescents [<18 years], adults [18-64 years], and the elderly [≥65 years]). Of 59,428 emergency department visits, 2,104 (3.5%) were adverse drug event-related. Adverse drug event-related emergency department visits were more likely to be female and older. Multivariate logistic regression analysis revealed that compared to non- adverse drug event-related cases, adverse drug event-related emergency department visitors were more likely to be female (60.6% vs. 53.6%, p<0.001, OR 1.285, 95% CI 1.025-1.603) and older (50.8 ± 24.6 years vs. 37.7 ± 24.4 years, p<0.001, OR 1.892, 95% CI: 1.397-2.297). Comorbidities such as diabetes, chronic kidney disease, chronic liver disease, and malignancies were also significantly associated with adverse drug event-related emergency department visits. Side effects were the most common type of adverse drug events across age groups, although main types differed substantially depending on age. Serious adverse drug events, hospitalizations, and adverse drug event-related deaths occurred more frequently in the elderly than in adults or children/adolescents. The proportion of adverse drug event-related emergency department visits that were preventable was 15.3%. Causative drugs of adverse drug events varied considerably depending on age group. Adverse drug event features differ substantially according to age group. The findings suggest that an age-specific approach should be adopted in the preventive strategies to reduce adverse drug events.

PMID:36121802 | PMC:PMC9484687 | DOI:10.1371/journal.pone.0272743

Front Immunol. 2022 Sep 2;13:919958. doi: 10.3389/fimmu.2022.919958. eCollection 2022.

ABSTRACT

BACKGROUND: Androgen sensitivity, which was established as the leading etiology of androgenetic alopecia (AGA) and benign prostatic hyperplasia (BPH), plays an important role in SARS-CoV-2 infection. Vaccination is essential for AGA and BPH patients in view of the high risk from SARS-CoV-2 infection.

PURPOSE: We aimed to investigate the associated factors for SARS-CoV-2 vaccination and its side effects in populations with AGA and BPH.

METHOD: We collected the data on SARS-CoV-2 vaccination and adverse reactions of male AGA and BPH patients visited the outpatient of Xiangya hospital by telephone and web-based questionnaires. Vaccination rate and adverse reactions were compared by different vaccine types and use of anti-androgen therapy.

RESULT: A total of 457 AGA patients and 397 BPH patients were recruited in this study. Among which, 92.8% AGA patients and 61.0% BPH patients had at least the first dose of SARS-CoV-2 vaccination (p < 0.001). Having comorbidities and use of anti-androgen therapy increased the risk of un-vaccination among AGA by 2.875 and 3.729 times, respectively (p < 0.001). Around 31.1% AGA patients and 9.5% BPH patients presented adverse reactions, which were mostly mild. Anti-androgen therapy increased the inclination of injection site pain after vaccination (18.7% vs 11.9%; OR: 1.708, 95% CI: 1.088-2.683, p = 0.019).

CONCLUSION: Co-existence of other systemic diseases and anti-androgen therapy were the limiting factors for SARS-CoV-2 unvaccination, especially in AGA patients. The importance of SARS-CoV-2 vaccines should be strengthened and popularized in androgen sensitive phenotypes.

PMID:36119091 | PMC:PMC9478654 | DOI:10.3389/fimmu.2022.919958

Front Immunol. 2022 Sep 2;13:1001823. doi: 10.3389/fimmu.2022.1001823. eCollection 2022.

ABSTRACT

The use of immune checkpoint inhibitors (ICIs) can improve survival of patients with malignant tumors, however, the ICI treatment is associated with unpredictable toxicity as immune-related adverse effects (irAEs). Here we report two cases of metastatic malignant gastrointestinal tumors where severe immune-mediated hepatotoxicity (IMH) developed, characterized by liver failure, after the ICI therapy. Through a strong immunosuppressive treatment and a non-biological artificial liver and supportive treatment, the liver function was restored in both cases, and the anti-tumor treatment effect was guaranteed. These results showed that the non-biological artificial liver could be capable of improve prognosis during the ICI therapy.

PMID:36119055 | PMC:PMC9478575 | DOI:10.3389/fimmu.2022.1001823

Acta Med Port. 2022 Sep 19. doi: 10.20344/amp.16971. Online ahead of print.

ABSTRACT

Inflammatory reactions in the Bacillus Calmette-Guérin (BCG) inoculation scar site have been previously described, in association with viral infections. The inflammation of the scar in association with other vaccines has been described with the flu vaccine and, more recently, after the second dose of mRNA anti-SARS-CoV-2 vaccines (mRNA-1273 e BNT162b2), in two healthcare workers. We present the case of a 27-year-old female, without a relevant past medical history, including no previous SARS-CoV-2 infection, and with inflammation of the BCG scar eight days after the first dose of the mRNA anti-SARS-CoV-2 vaccine. Pharmacovigilance and the notification of adverse events should be encouraged, as a way of warding off hesitation in this process.

PMID:36121099 | DOI:10.20344/amp.16971

Infect Prev Pract. 2022 Aug 28;4(4):100242. doi: 10.1016/j.infpip.2022.100242. eCollection 2022 Dec.

ABSTRACT

BACKGROUND: Varicella-zoster virus (VZV) infection can cause life-threatening events in immunocompromised patients. Post-exposure prophylaxis (PEP) is required to prevent secondary VZV infection. Limited evidence is available for the use of acyclovir (ACV)/valacyclovir (VCV) as PEP.

METHODS: Herein, we retrospectively analyzed immunocompromised paediatric patients with significant exposure to VZV. Patients administered PEP were categorized into four groups: 1) ACV/VCV group; 2) intravenous immunoglobulin (IVIG) group; 3) ACV/VCV/IVIG group; 4) vaccine group.

RESULTS: Among 69 exposure events, 107 patients were administered PEP (91, ACV/VCV; 16, ACV/VCV/IVIG) and 10 patients did not receive PEP (non-PEP group). The index case was diagnosed based on clinical symptoms in 55 cases (79.7%). Fourteen cases (20.3%) were confirmed using direct virological diagnostic procedures. In the PEP group, only 2 patients (2.2%) developed secondary VZV infections. Additionally, 2 patients in the non-PEP group (20.0%) developed secondary VZV infection. The incidence of secondary VZV infection was significantly lower in the PEP group than in the non-PEP group (P=0.036). Among patients administered PEP, no antiviral drug-induced side effects were detected.

CONCLUSIONS: Antiviral agents administered as PEP are effective and safe for preventing VZV infections in immunocompromised patients. Rapid virological diagnosis of index cases might allow efficient administration of PEP after significant exposure to VZV infection.

PMID:36120112 | PMC:PMC9471438 | DOI:10.1016/j.infpip.2022.100242

Dis Markers. 2022 Sep 9;2022:4829750. doi: 10.1155/2022/4829750. eCollection 2022.

ABSTRACT

OBJECTIVE: To investigate the efficacy of dapagliflozin for diabetes mellitus complicated by coronary artery diseases and its impact on vascular endothelial function.

METHODS: Between August 2020 and August 2021, 80 patients with coronary heart disease complicated by type 2 diabetes mellitus were recruited and randomly assigned to receive either dapagliflozin (5 mg daily) plus original oral hypoglycemic agents (dapagliflozin group) or original oral hypoglycemic agents alone (control group). Outcome measures included blood pressure, blood glucose, cholesterol levels, vascular endothelial function, cardiovascular events, and drug-related adverse events.

RESULTS: The two groups had similar outcome indices upon admission (P > 0.05). After 20 weeks of medication, the two groups of patients showed similar blood pressure, hemoglobin A1c (HbA1c), and low-density lipoprotein (LDL-C) levels versus those before treatment (P > 0.05), and no significant differences were found in intergroup comparison neither (P > 0.05). Dapagliflozin plus conventional hypoglycemic agents resulted in a significantly higher reactive hyperemia index (RHI) value, fewer cases with abnormal vascular endothelial function, and fewer major cardiovascular events during treatment versus the sole use of conventional hypoglycemic agents (P < 0.05). There was no significant difference in drug-related adverse events between the two groups (P > 0.05).

CONCLUSION: Dapagliflozin improves the vascular endothelial functions of patients with diabetes mellitus complicated by coronary artery disease with a high safety profile and favorable efficacy.

PMID:36118673 | PMC:PMC9481371 | DOI:10.1155/2022/4829750

Adv Ther. 2022 Sep 17. doi: 10.1007/s12325-022-02291-2. Online ahead of print.

ABSTRACT

INTRODUCTION: Lasmiditan is the first 5-HT1F receptor agonist with potential to address the huge unmet medical needs for the treatment of migraine in China. The CENTURION study was the first phase 3 study of lasmiditan in Caucasian and Chinese patients with migraine. This post hoc analysis further demonstrates the safety profile of lasmiditan in the Chinese population and was urgently needed.

METHODS: Patients were randomized 1:1:1 to lasmiditan 200 mg lasmiditan 100 mg, or a control group. The incidence of treatment-emergent adverse events (TEAEs), their severity, and incidence by treated attacks for frequently reported TEAEs (≥ 5%) were evaluated. The duration, onset, and relationship of efficacy with very common TEAEs (≥ 10%) was analyzed.

RESULTS: A total of 281 Chinese patients were included in this post hoc analysis. No deaths and no study drug-related treatment emergent serious adverse events (TESAEs) were reported. The incidence of at least one TEAE was higher in patients receiving lasmiditan 200 mg (73.9%) and 100 mg (66.3%) versus placebo (26.6%). TEAEs were generally mild or moderate in severity, and the incidence of frequently reported TEAEs was generally highest during the first attack. Very common TEAEs with lasmiditan included dizziness, asthenia, somnolence, muscular weakness, fatigue, and nausea. The duration of dizziness was longest during the first attack. There were no cardio-cerebrovascular ischemic events and serotonin syndrome. The presence of very common TEAEs (except nausea), and severe dizziness, did not appear to have a negative influence on the efficacy.

CONCLUSION: In the Chinese population of the CENTURION study, most of the TEAEs were neurologic, of mild or moderate severity, and self-limiting. The distribution of frequently reported TEAEs at the first attack differed from the primary cohort, while the overall safety profile of lasmiditan in the Chinese population was generally consistent with the CENTURION primary cohort. No new safety concerns were observed in the Chinese population.

TRIAL REGISTRATION: NCT03670810.

PMID:36114949 | DOI:10.1007/s12325-022-02291-2

Sci Rep. 2022 Sep 16;12(1):15619. doi: 10.1038/s41598-022-19887-x.

ABSTRACT

This study was undertaken to determine the risk of bevacizumab-induced lung toxicity, time to onset, and post hoc outcomes using the Japanese Adverse Drug Event Report database. We analysed data for the period between April 2004 and March 2021. Data on lung toxicities were extracted, and relative risk of adverse events (AEs) was estimated using the reporting odds ratio. We analysed 5,273,115 reports and identified 20,399 reports of AEs caused by bevacizumab. Of these, 1679 lung toxicities were reportedly associated with bevacizumab. Signals were detected for nine lung toxicities. A histogram of times to onset showed occurrence from 35 to 238 days, but some cases occurred even more than one year after the start of administration. Approximately 20% of AEs were thromboembolic events. Among these, pulmonary embolism was the most frequently reported and fatal cases were also reported. The AEs showing the highest fatality rates were pulmonary haemorrhage, pulmonary infarction, and pulmonary thrombosis. In conclusion, we focused on lung toxicities caused by bevacizumab as post-marketing AEs. Some cases could potentially result in serious outcomes, patients should be monitored for signs of onset of AEs not only at the start of administration, but also over a longer period of time.

PMID:36114412 | PMC:PMC9481601 | DOI:10.1038/s41598-022-19887-x

Int J STD AIDS. 2022 Sep 16:9564624221116533. doi: 10.1177/09564624221116533. Online ahead of print.

ABSTRACT

Dolutegravir and doravirine are individually safe and effective antiretroviral therapy (ART) components, but their combined use has not been studied in clinical trials and is not recommended in HIV treatment guidelines. We noted persons with HIV (PWH) receiving dolutegravir with doravirine at our Washington, DC, infectious disease clinic and undertook a service evaluation to understand why providers selected this ART, whether HIV virologic suppression was achieved and identify adverse effects of concomitant use. Case registry and prescriptions data identified 21 PWH receiving concomitant dolutegravir and doravirine with mean follow-up 576.1 days (range 413-751); frequent reasons for switching were multiple ART resistance (57.1%), proton pump inhibitor usage (28.6%) and renal failure (28.6%), with 52.4% switched from protease inhibitor or cobicistat-boosted regimens. Dolutegravir with doravirine alone was prescribed for 60%, and additional ART in 40%. During 12 months follow-up mean CD4 was 585.9 (baseline 570.7) with undetectable viral load in 77.8% (baseline 66.7%). No discontinuations for drug-related adverse events or virologic failure occurred. Dolutegravir with doravirine was well tolerated in small numbers of highly treatment experienced PWH at our clinic, achieving virologic suppression in most. Establishing the efficacy and safety of dolutegravir with doravirine for HIV treatment in randomized trials remains important.

PMID:36113042 | DOI:10.1177/09564624221116533

J Clin Pharmacol. 2022 Sep;62 Suppl 1:S6-S8. doi: 10.1002/jcph.2100.

NO ABSTRACT

PMID:36106786 | DOI:10.1002/jcph.2100

Clin Exp Rheumatol. 2022 Sep;40(8):1543-1553. doi: 10.55563/clinexprheumatol/pjs6eh. Epub 2022 Sep 14.

ABSTRACT

OBJECTIVES: A post-marketing all-patient surveillance program was conducted to evaluate the safety and effectiveness of canakinumab, a monoclonal anti-interleukin-1β antibody, in patients in Japan with cryopyrin-associated periodic fever syndrome (CAPS), including familial cold auto-inflammatory syndrome, Muckle-Wells syndrome, and neonatal onset multisystem inflammatory disease.

METHODS: All patients with CAPS who received canakinumab treatment after drug approval in Japan were registered in this non-interventional, observational study. The observation period per patient was two years. Patients newly treated with canakinumab (New patients; NP) and those continuously treated with canakinumab following clinical trials (Roll-over patients; RP) were included. Data collection of clinical symptoms affecting physical function and prognosis was not mandated but assessed where available. Here, the interim results are reported.

RESULTS: Of 87 patients in the safety set, the proportion of patients with any adverse drug reactions (ADRs) and any serious ADRs was 31.03% and 3.45%, respectively. The most common ADRs reported under system organ class were infections and infestations (20.69%). Of 84 patients in the effectiveness set, 75.76% and 83.33% of NP and RP, respectively, were responders at Week 24, achieving complete response without relapse. Responder rates were maintained up to Week 104. Clinical symptoms affecting physical function and prognosis remained unchanged in over half of those patients.

CONCLUSIONS: Interim results provided the safety profile of canakinumab in a real-world setting, and identified no new safety concerns. Treatment with canakinumab has suggested sustained remission in the majority of patients in the real-world setting.

PMID:36106540 | DOI:10.55563/clinexprheumatol/pjs6eh

Pharmacol Res Perspect. 2022 Oct;10(5):e01005. doi: 10.1002/prp2.1005.

ABSTRACT

Tyrosine kinase inhibitors (TKI) have revolutionized the treatment of chronic myeloid leukemia (CML), but patients still experience treatment-limiting toxicities or therapeutic failure. To investigate the real-world use and outcomes of imatinib in patients with CML in Australia, a retrospective cohort study of patients with CML commencing imatinib (2001-2018) was conducted across two sites. Prescribing patterns, tolerability outcomes, and survival and molecular response were evaluated. 86 patients received 89 imatinib treatments. Dose modifications were frequently observed (12-month rate of 58%). At last follow-up, 62 patients (5-year rate of 55%) had permanently discontinued imatinib treatment, of which 44 switched to another TKI (5-year rate of 46%). Within 3 months of starting imatinib, 43% (95% CI, 32%-53%) of patients experienced imatinib-related grade ≥3 adverse drug reactions (ADRs). Higher comorbidity score, lower body weight, higher imatinib starting dose, and Middle Eastern or North African ancestry were associated with a higher risk of grade ≥3 ADR occurrence on multivariable analysis (MVA). Estimated overall survival and event-free survival rates at 3 years were 97% (95% CI, 92%-100%) and 81% (95% CI, 72%-92%), respectively. Cumulative incidence of major molecular response (MMR) at 3 years was 63% (95% CI, 50%-73%). On MVA, imatinib starting dose, ELTS score, BCR-ABL1 transcript type, pre-existing pulmonary disease, and potential drug-drug interactions were predictive of MMR. In conclusion, imatinib induced deep molecular responses that translated to good survival outcomes in a real-world setting, but was associated with a higher incidence of ADRs, dose modifications and treatment discontinuations than in clinical trials.

PMID:36106342 | DOI:10.1002/prp2.1005

Pediatr Endocrinol Diabetes Metab. 2022 Sep 15:47569. doi: 10.5114/pedm.2022.118398. Online ahead of print.

ABSTRACT

INTRODUCTION: Drug-induced diabetes mellitus (DIDM) could be defined as a heterogenic group of diabetes caused by pharmacotherapy. The DIDM is considered to be reversible after discontinuation of diabetogenic treatment, but there is a risk of persistence, which is related to the duration of treatment, prescribed medication, and body mass index.

CASE PRESENTATION: A 13-year-old boy treated for nephrotic syndrome with the use of tacrolimus and prednisone was diagnosed with diabetes during a check-up visit. On admission, he showed a cushingoid appearance and complained of dry mouth, which was not accompanied by polyuria or polydipsia. Blood tests showed elevated levels of glucose, and glycated A1c fraction of haemoglobin (HbA1c = 10.2%). Pancreatic islet autoantibodies were negative. The fasting and postprandial C-peptide levels were within the normal range. Diabetic ketoacidosis was excluded. Intensive insulin therapy was initially introduced; the daily dose of insulin per kilogram was low (TDD/kg = 0.31 U/kg). Those findings prompted us to consider diabetes mellitus type 2 or DIDM. Moreover, the TDD/kg and HbA1c additionally decreased after the steroid withdrawal. Because he was constantly on diabetogenic therapy and experienced periodical hyperglycaemia, DIDM could not be excluded. Therefore, our patient remained on insulin treatment.

CONCLUSIONS: DIDM in children is challenging for all specialists. Diabetologists need to remember about this rare subtype of diabetes, and other specialist should perform screening on their patients who are at risk of DIDM. There is a great need for guidelines that would provide a standardized approach for diagnosing and treating DIDM in the paediatric population.

PMID:36106423 | DOI:10.5114/pedm.2022.118398