Pharmacoepidemiol Drug Saf. 2024 Aug;33(8):e5874. doi: 10.1002/pds.5874.

ABSTRACT

PURPOSE: The European Medicines Agency's (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) launched a strategy to examine the public health impact of major regulatory interventions aimed at minimising risks of medicinal products. We conducted a lessons learnt analysis of impact studies completed between 2015 and 2023.

METHODS: We surveyed PRAC Sponsors and (Co-)Rapporteurs involved in the evaluation of 12 impact studies (10 commissioned by EMA and 2 conducted collaboratively by Member States) to explore how these support regulatory decision-making. Questions covered achievement of study objectives, risk minimisation effectiveness, added value for regulatory decision-making, and recommendations for future impact studies. Themes were generated using thematic content analysis.

RESULTS: Survey responses from 15 PRAC Sponsors and (Co-)Rapporteurs from 10 European Union Member States were included in the analysis. Among four cross-sectional surveys and eight drug utilisation studies, 50% achieved all objectives, the other studies partially due to limitations. Two studies concluded that risk minimisation measures were overall effective, two were effective with variation across countries, two were partially effective and four studies showed limited effectiveness. Two studies were deemed inconclusive due to limitations. The reasons for the limited effectiveness of risk minimisation may be explored using mixed-method approaches. Assessment of study feasibility and a priori discussion of effectiveness measurements is important.

CONCLUSION: Despite limitations, impact research adds value to regulatory decision-making by addressing knowledge gaps and providing additional information on unintended consequences of regulatory interventions. Our recommendations will help to improve planning, conducting and interpretating future impact studies.

PMID:39092454 | DOI:10.1002/pds.5874

JTO Clin Res Rep. 2024 May 16;5(7):100689. doi: 10.1016/j.jtocrr.2024.100689. eCollection 2024 Jul.

ABSTRACT

Neurocognitive adverse events (NAEs) have been reported in up to 60% of patients on lorlatinib, a potent central nervous system-active ALK inhibitor. Manifestations may include psychotic, mood, speech, and cognitive symptoms. Current guidance recommends permanent discontinuation of lorlatinib in cases of grade IV NAEs. Here, we report a case of successful rechallenge of dose-reduced lorlatinib after recovery of grade IV psychosis in a patient with ALK-positive NSCLC.

PMID:39091593 | PMC:PMC11293564 | DOI:10.1016/j.jtocrr.2024.100689

Chem Res Toxicol. 2024 Aug 19;37(8):1231-1245. doi: 10.1021/acs.chemrestox.4c00205. Epub 2024 Aug 1.

ABSTRACT

Reactive metabolite (RM) formation is widely accepted as playing a crucial role in causing idiosyncratic adverse drug reactions (IADRs), where the liver is most affected. An important goal of drug design is to avoid selection of drug candidates giving rise to RMs and therefore risk causing problems later on involving IADRs. The simplest, initial approach is to avoid test structures that have substructures known or strongly suspected to be associated with IADRs. However, as is evident from the many case reports of IADRs, in most cases a clear association with any (bio)chemical mechanism is lacking, which makes it hard to establish any structure-toxicity relationship. Separate studies of RM formation, in vitro and in vivo, have led to likely evidence and to establishing many structural alerts (SAs) that can be used for fast selection/deselection of planned test compounds. As a background to a discussion of the concept, 25 kinase inhibitor drugs with known problems of hepatotoxicity were probed against a set of SAs contained in the application SpotRM. A clear majority of the probed drugs show liabilities as evident by being flagged by more than one of the fairly established types of SAs. At the same time, no clear SAs were found in three drugs, which is discussed in the broader context of usefulness and selection tactics of SAs in drug design.

PMID:39088358 | DOI:10.1021/acs.chemrestox.4c00205

Orphanet J Rare Dis. 2024 Aug 1;19(1):286. doi: 10.1186/s13023-024-03294-8.

ABSTRACT

BACKGROUND: The potentially fatal attacks experienced by porphyria carriers are triggered by various porphyrinogenic drugs. However, determining the safety of particular drugs is challenging.

METHODS: We retrospectively used the U.S. Food and Drug Administration's Adverse Event Reporting System (FAERS) to identify drugs associated with porphyria as an adverse event (AE) extracted from data from January 2004 to March 2022. The associated search terms included "Porphyria," "Porphyria screen," "Porphyria non-acute," "Porphyria acute," "Acquired porphyria," and "Pseudoporphyria." Signal mining analysis was performed to identify the association between drugs and AEs by four algorithms, namely the reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker.

RESULTS: FAERS reported 1470 cases of porphyria-related AEs, and 406 drugs were screened after combining trade and generic names. All four algorithms identified 52 drugs with signals. The characteristics of all the reports and signaling drugs were analyzed.

CONCLUSIONS: This is the first report of drug-associated porphyria that provides critical information on drug porphyrogenicity, facilitating rational and evidence-based drug prescription and improving the accuracy of porphyrogenicity prediction based on model algorithms. Moreover, this study serves a reference for clinicians to ensure that porphyrinogenic drugs are not prescribed to carriers of porphyria genetic mutations.

PMID:39090656 | DOI:10.1186/s13023-024-03294-8

Insights Imaging. 2024 Aug 1;15(1):191. doi: 10.1186/s13244-024-01771-z.

ABSTRACT

Systemic anticancer therapies (SACTs) are the leading cause of drug-induced interstitial lung disease (ILD). As more novel SACTs become approved, the incidence of this potentially life-threatening adverse event (AE) may increase. Early detection of SACT-related ILD allows for prompt implementation of drug-specific management recommendations, improving the likelihood of AE resolution and, in some instances, widening the patient's eligibility for future cancer treatment options. ILD requires a diagnosis of exclusion through collaboration with the patient's multidisciplinary team to rule out other possible etiologies of new or worsening respiratory signs and symptoms. At Grade 1, ILD is asymptomatic, and thus the radiologist is key to detecting the AE prior to the disease severity worsening. Planned computed tomography scans should be reviewed for the presence of ILD in addition to being assessed for tumor response to treatment, and when ILD is suspected, a high-resolution computed tomography (HRCT) scan should be requested immediately. An HRCT scan, with < 2-mm slice thickness, is the most appropriate method for detecting ILD. Multiple patterns of ILD exist, which can impact patient prognosis. The four main patterns include acute interstitial pneumonia / acute respiratory distress syndrome, organizing pneumonia, hypersensitivity pneumonitis, and non-specific interstitial pneumonia; their distinct radiological features, along with rarer patterns, are discussed here. Furthermore, HRCT is essential for following the course of ILD and might help to determine the intensity of AE management and the appropriateness of re-challenging with SACT, where indicated by drug-specific prescribing information. ILD events should be monitored closely until complete resolution. CRITICAL RELEVANCE STATEMENT: The incidence of potentially treatment-limiting and life-threatening systemic anticancer therapy-related interstitial lung disease (SACT-related ILD) events is likely increasing as more novel regimens become approved. This review provides best-practice recommendations for the early detection of SACT-related ILD by radiologists. KEY POINTS: Radiologists are crucial in detecting asymptomatic (Grade 1) ILD before severity/prognosis worsens. High-resolution computed tomography is the most appropriate method for detecting ILD. Drug-induced ILD is a diagnosis of exclusion, involving a multidisciplinary team. Familiarity with common HRCT patterns, described here, is key for prompt detection. Physicians should highlight systemic anticancer therapies (SACTs) with a known risk for interstitial lung diseases (ILD) on scan requisitions.

PMID:39090512 | DOI:10.1186/s13244-024-01771-z

ESMO Open. 2024 Jul 31;9(8):103643. doi: 10.1016/j.esmoop.2024.103643. Online ahead of print.

ABSTRACT

BACKGROUND: LHC165 is a Toll-like receptor (TLR)-7 agonist that generates an effective tumor antigen-specific T-cell adaptive immune response as well as durable antitumor responses. We aimed to evaluate the safety, tolerability, efficacy, dose-limiting toxicities, and pharmacokinetics (PK) of LHC165 single agent (SA) ± spartalizumab [PDR001; anti-programmed cell death protein 1 (PD-1)] in adult patients with advanced solid tumors.

MATERIALS AND METHODS: In this phase I/Ib, open-label, dose-escalation/expansion study, patients received LHC165 SA 100-600 μg biweekly through intratumoral (IT) injection and LHC165 600 μg biweekly + spartalizumab 400 mg Q4W through intravenous (IV) infusion.

RESULTS: Forty-five patients were enrolled: 21 patients received LHC165 SA, and 24 patients received LHC165 + spartalizumab. The median duration of exposure was 8 weeks (range 2-129 weeks). No maximum tolerated dose was reached. Recommended dose expansion was established as LHC165 600 μg biweekly as SA and in combination with spartalizumab 400 mg Q4W. The most common drug-related adverse events (AEs) were pyrexia (22.2%), pruritus (13.3%), chills (11.1%), and asthenia (4.4%). The only serious AE (SAE) suspected to be related to the study drug was grade 3 pancreatitis (n = 1). Across all tumor types, overall response rate and disease control were 6.7% and 17.8%, respectively. Overall median progression-free survival (PFS) and immune-related PFS was 1.7 months. LHC165 serum PK demonstrated an initial rapid release followed by a slower release due to continued release of LHC165 from the injection site.

CONCLUSIONS: LHC165 demonstrated acceptable safety and tolerability both as SA and in combination with spartalizumab, and evidence of limited antitumor activity was seen in adult patients with relapsed/refractory or metastatic solid tumors.

PMID:39088985 | DOI:10.1016/j.esmoop.2024.103643

Front Pharmacol. 2024 Jul 17;15:1419369. doi: 10.3389/fphar.2024.1419369. eCollection 2024.

ABSTRACT

BACKGROUND: High-intensity chemotherapy can cause life-threatening complications in pediatric patients. Therefore, this study investigated safety and efficacy of long-acting pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF; Jinyouli®) in children undergoing high-intensity chemotherapy.

METHODS: Treatment-naive patients received post-chemotherapy PEG-rhG-CSF as primary prophylaxis for two cycles. The primary endpoints were drug-related adverse events (AEs) and bone pain scores. Secondary endpoints included grade 3-4 neutropenia, duration of neutropenia recovery, absolute neutrophil count changes, febrile neutropenia (FN), reduced chemotherapy intensity, antibiotic usage, and AE severity. The cost-effectiveness of PEG-rhG-CSF was compared with that of rhG-CSF (Ruibai®).

RESULTS: Here, 307 and 288 patients underwent one and two PEG-rhG-CSF cycles, respectively. Ninety-one patients experienced drug-related AEs, primarily bone pain (12.7%). Moreover, Grade 3-4 neutropenia and FN were observed. Median FN durations were 3.0 days in both cycles. No drug-related delays were observed during chemotherapy. One patient experienced grade 4 neutropenia-induced reduction in chemotherapy intensity during cycle 2. In total, 138 patients received antibiotics. PEG-rhG-CSF exhibited superior cost-effectiveness compared to rhG-CSF.

CONCLUSION: Our findings indicate that PEG-rhG-CSF is safe, efficient, and cost-effective in pediatric patients undergoing high-intensity chemotherapy, providing preliminary evidence warranting further randomized controlled trials.

PMID:39086394 | PMC:PMC11288831 | DOI:10.3389/fphar.2024.1419369

J Psychopharmacol. 2024 Aug;38(8):690-700. doi: 10.1177/02698811241265756. Epub 2024 Jul 31.

ABSTRACT

OBJECTIVE: Despite considerable research examining the efficacy of psychedelic-assisted therapies (PATs) for treating psychiatric disorders, assessment of adverse events (AEs) in PAT research has lagged. Current AE reporting standards in PAT trials are poorly calibrated to features of PAT that distinguish it from other treatments, leaving many potential AEs unassessed.

METHODS: A multidisciplinary working group of experts involved in PAT pooled formally and informally documented AEs observed through research experience and published literature. This information was integrated with (a) current standards and practices for AE reporting in pharmacotherapy and psychotherapy trials and (b) published findings documenting post-acute dosing impacts of psychedelics on subjective states, meaning, and psychosocial health variables, to produce a set of AE constructs important to evaluate in PAT as well as recommended methods and time frames for their assessment and monitoring. Correspondence between identified potential AEs and current standards for AE assessment was examined, including the extent of coverage of identified AE constructs by 25 existing measures used in relevant research.

RESULTS: Fifty-four potential AE terms warranting systematized assessment in PAT were identified, defined, and categorized. Existing measures demonstrated substantial gaps in their coverage of identified AE constructs. Recommendations were developed for how to assess PAT AEs (including patient, clinician, and informant reports), and when to assess over preparation, dosing session, integration, and follow-up. Application of this framework is demonstrated in a preliminary assessment protocol (available in the supplement).

CONCLUSIONS: This assessment framework addresses the need to capture post-acute dosing AEs in PAT, accounting for its pharmacotherapy and psychotherapy components, as well as documented impacts of psychedelics on worldviews and spirituality.

PMID:39082259 | DOI:10.1177/02698811241265756

Cardiovasc Toxicol. 2024 Jul 31. doi: 10.1007/s12012-024-09906-w. Online ahead of print.

ABSTRACT

Cardiac toxicity is an adverse event of several classes of anti-cancer drugs. Herein, we present the case of a 52-year-old woman with metastatic renal cell carcinoma (RCC), previously treated with debulking surgery, pembrolizumab (immune checkpoint inhibitor) in combination with axitinib (tyrosine kinase inhibitor (TKI)), followed by lenvatinib (TKI) and belzutifan (HIF-2α inhibitor), who developed myocarditis proven by cardiac magnetic resonance and endomyocardial biopsy. The case was notable for reporting a not-yet described adverse event during treatment with belzutifan plus lenvatinib, the etiology of which was of unobvious determination given the pre-exposure to pembrolizumab, a known cause of drug-related myocarditis. We surmise that myocarditis was a delayed adverse event related to pembrolizumab (8 months after treatment interruption), although we emphasize that only attentive monitoring of cardiac adverse events of patients exposed to belzutifan and lenvatinib in the context of large clinical trials may rule out any causal implication of these drugs.

PMID:39085529 | DOI:10.1007/s12012-024-09906-w

Zhonghua Yan Ke Za Zhi. 2024 Aug 11;60(8):704-712. doi: 10.3760/cma.j.cn112142-20231227-00312.

ABSTRACT

With the extensive application of targeted drugs, the survival rate of cancer patients has been significantly improved. However, adverse reactions to the drugs have also become apparent, especially those affecting the ocular surface, which can severely impact patients' vision and quality of life. The article systematically analyzes a variety of targeted drugs, including epidermal growth factor receptor inhibitors, human epidermal growth factor receptor 2 inhibitors, fibroblast growth factor receptor inhibitors, selective estrogen receptor modulators, vascular endothelial growth factor receptor inhibitors, aromatase inhibitors, proteasome inhibitors, antibody-drug conjugates, Bruton's tyrosine kinase inhibitors, FMS-like tyrosine kinase 3 inhibitors, and cyclin-dependent kinase inhibitors, and discusses their adverse reactions on the ocular surface. The review emphasizes the role of clinicians in monitoring and managing patients' ocular surface health and the importance of early diagnosis and intervention to ensure that patients receive optimal visual protection while undergoing antitumor treatment.

PMID:39085162 | DOI:10.3760/cma.j.cn112142-20231227-00312

J Microbiol Immunol Infect. 2024 Jul 14:S1684-1182(24)00114-2. doi: 10.1016/j.jmii.2024.07.003. Online ahead of print.

ABSTRACT

BACKGROUND: The ongoing, observational BICSTaR (BICtegravir Single Tablet Regimen) cohort study is evaluating real-world effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in people with HIV across 14 countries over 24 months. We present 12-month data from the BICSTaR Asia cohort.

METHODS: Data were pooled from retrospective and prospective cohorts of antiretroviral therapy (ART)-naïve (hereafter, TN) and ART-experienced (hereafter, TE) people with HIV (aged ≥21 years) receiving B/F/TAF in routine clinical care in the Republic of Korea, Singapore, and Taiwan. Analyses included effectiveness (primary endpoint: HIV-1 RNA <50 copies/ml, missing = excluded analysis), CD4 count, CD4/CD8 ratio, safety, treatment persistence, and patient-reported outcomes (prospective group).

RESULTS: The analysis population included 328 participants (80 retrospective, 248 prospective; 65 TN, 263 TE). Participants were predominantly male (96.9% TN, 93.2% TE) with ≥1 comorbidity (52.3% TN, 57.8% TE); median age (years) was 31 (TN) and 42 (TE). Following 12 months of B/F/TAF, HIV-1 RNA was <50 copies/ml in 98.2% (54/55) of TN and 97.0% (227/234) of TE participants. Median (Q1, Q3) CD4 cell count increased by +187 (119, 291) cells/μl in the TN group (p < 0.001) and remained stable (+8 [-91, 110] cells/μl) in the TE group. B/F/TAF persistence was high in the prospective group, with 1/34 (2.9%) TN and 5/214 (2.3%) TE participants discontinuing treatment within 12 months. Drug-related adverse events occurred in 5.8% (19/328) of participants, leading to treatment discontinuation in 0.6% (2/328).

CONCLUSIONS: Real-world evidence from BICSTaR supports the effectiveness, safety and tolerability of B/F/TAF in people with HIV in Asia.

PMID:39079772 | DOI:10.1016/j.jmii.2024.07.003

Cureus. 2024 Jun 28;16(6):e63353. doi: 10.7759/cureus.63353. eCollection 2024 Jun.

ABSTRACT

Stevens-Johnson Syndrome (SJS) constitutes a rather uncommon, and rarely fatal hypersensitivity reaction that primarily impacts the skin and mucous membranes and in certain cases may be attributed to drug administration. The aim of this article is to present a case of etoricoxib-induced SJS in a 46-year-old, female patient. The patient presented herself, as a medical emergency, to the Department of Oral Medicine/Pathology, School of Dentistry, Aristotle University of Thessaloniki, Greece, reporting pain, especially acute pain while eating certain foods, discomfort, dysphagia, and a wound in the left half of the hard palate. The clinical examination revealed a broad ulcer, in the left half of the hard palate as well as multiple ulcerations and erosions in the upper and lower lip. Her medical history was clear; however, the patient mentioned to have received etoricoxib, due to severe back pain, one day prior to our clinical examination. The patient received methylprednisolone 16 mg, twice per day, for two days, followed by methylprednisolone 8 mg, twice per day, for two more days. Her symptoms resigned and since the connection between etoricoxib and SJS was established, the patient was advised to avoid etoricoxib and be wary of adverse effects, when taking drugs especially non-steroidal anti-inflammatory medication. This is one of the first case reports in the literature, linking etoricoxib administration with the emergence of SJS, highlighting the importance of pharmacovigilance. The up-to-date registration of drug-induced adverse effects is of immense importance to protect future patients. SJS does not have a defined treatment strategy. Therefore, most patients are given supportive care and symptomatic treatment, which most commonly involves corticosteroids and antivirals such as acyclovir.

PMID:39077250 | PMC:PMC11283930 | DOI:10.7759/cureus.63353

Rev Cardiovasc Med. 2024 Feb 27;25(3):74. doi: 10.31083/j.rcm2503074. eCollection 2024 Mar.

ABSTRACT

The development of anti-tumor drugs has notably enhanced the survival rates and quality of life for patients with malignant tumors. However, the side effects of these drugs, especially cardiotoxicity, significantly limit their clinical application. The cardiotoxicity associated with anti-tumor drugs has been a subject of extensive attention and research. Traditional to mitigate these side effects have included reducing drug dosages, shortening treatment duration, modifying administration methods, and opting for drugs with lower toxicity. However, either approach may potentially compromise the anti-tumor efficacy of the medications. Therefore, exploring other effective methods for anti-cardiotoxicity will be the focus of future research. The potential of traditional Chinese medicine (TCM) in managing cardiovascular diseases and cancer treatment has gained widespread recognition. TCM is valued for its minimal side effects, affordability, and accessibility, offering promising avenues in the prevention and treatment of cardiotoxicity caused by anti-tumor drugs. Among its constituents, flavonoids, which are present in many TCMs, are particularly notable. These monomeric compounds with distinct structural components have been shown to possess both cardiovascular protective properties and anti-tumor capabilities. In this discussion, we will delve into the classification of anti-tumor drugs and explore the underlying mechanisms of their associated cardiotoxicity. Additionally, we will examine flavonoids found in TCM and investigate their mechanisms of cardiovascular protection. This will include an analysis of how these natural compounds can mitigate the cardiac side effects of anti-tumor therapies while potentially enhancing overall patient health and treatment outcomes.

PMID:39076949 | PMC:PMC11263839 | DOI:10.31083/j.rcm2503074

Rev Cardiovasc Med. 2022 Nov 9;23(11):380. doi: 10.31083/j.rcm2311380. eCollection 2022 Nov.

ABSTRACT

Lipid-lowering therapy is of great importance in reducing the burden of atherosclerotic cardiovascular disease. Statins act as first-line therapy in the current lipid management guidelines. However, statin use is limited in (1) statin-induced adverse events, including statin-associated muscle symptoms, new-onset diabetes mellitus, drug-induced liver injuries, acute kidney injuries, cognitive effects, hemorrhagic strokes, and cataracts; (2) special populations, including pregnant and lactating patients, patients with decompensated cirrhosis, and patients on dialysis; (3) coadministration with statin-interactive drugs, such as anti-human immunodeficiency virus drugs, anti-hepatitis C virus drugs, and immunosuppressive drugs. These considerable statin-limited groups are in urgent need of safer alternative lipid-lowering options. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are attracting widespread attention for their documented safety in general populations and superior lipid-lowering properties. Therefore, questions have been raised whether PCSK9 inhibitors could be a safe alternative in patients who are intolerant to statin therapy. In this review, we discuss the safety of PCSK9 inhibitors in statin-limited conditions. We conclude that PCSK9 inhibitors are a safe alternative lipid-lowering therapy in various statin-limited conditions. Furthermore, we identify several limitations in the current literature and suggest future directions, for the refinement of lipid management regimens.

PMID:39076187 | PMC:PMC11269069 | DOI:10.31083/j.rcm2311380

Reg Anesth Pain Med. 2024 Jul 29:rapm-2024-105835. doi: 10.1136/rapm-2024-105835. Online ahead of print.

NO ABSTRACT

PMID:39074953 | DOI:10.1136/rapm-2024-105835

Clin Transl Gastroenterol. 2024 Jul 29. doi: 10.14309/ctg.0000000000000754. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: Peptic ulcer disease (PUD) and post-procedural artificial ulcers are common ulcer disease. For them, Proton pump inhibitor (PPI) and potassium-competitive acid blocker (P-CAB) are commonly used in clinical practice. PPI requires acid, time, and multiple doses, but P-CAB has fewer limitations. We compared the efficacy, safety and prevention of PPI and P-CAB in PUD and artificial ulcer.

METHODS: We searched PubMed, ClinicalTrials.gov, Embase, Cochrane Library, and Web of Science databases for all studies. All eligible randomized controlled trials up to August 5, 2023 were included. Healing rates, shrinking rates, treatment-emergent adverse events rates and recurrence rates were measured. Risk of bias, sensitivity analyses, and heterogeneity were also performed.

RESULT: 20 researches which were selected from 926 screening studies and in total 6567 participants were included. The risk ratio (RR) of healing rate with P-CABs versus PPIs of PUD at 4-week was RR 1.01 (95% CI 0.98-1.04). In addition, the healing rate distinction of artificial peptic ulcer was RR 1.04 (0.89-1.22), and the shrinking rate was MD 0.10 (-1.30-1.51). The result of TEAEs rate of PUD was RR 1.11 (0.91-1.35) and the delayed bleeding rate of artificial ulcer was RR 0.35 (0.16-0.80). The RR for recurrence rate of drug-related ulcers was 0.45 (0.25-0.81).

CONCLUSION: P-CAB is non-inferior in healing artificial ulcer and conventional PUD, also the incidence of TEAEs. But there may be a statistical advantage in holding back delayed bleeding and preventing drug-induced ulcers. More standardized experiments are needed for further applications and more precise conclusions.

PMID:39072507 | DOI:10.14309/ctg.0000000000000754

J Pain Res. 2024 Jul 22;17:2431-2441. doi: 10.2147/JPR.S453806. eCollection 2024.

ABSTRACT

PURPOSE: This study compared the efficacy, tolerability, and safety of rimegepant 75 mg oral tablet - a small molecule calcitonin-gene receptor peptide (CGRP) receptor antagonist - with placebo in the acute treatment of migraine.

METHODS: This double-blind, randomized, placebo-controlled trial enrolled adults aged ≥18 years with at least a 1-year history of migraine. Participants randomized to rimegepant 75 mg oral tablet or placebo treated a single migraine attack of moderate or severe pain intensity. The coprimary endpoints, pain freedom and freedom from the most bothersome symptom ([MBS] nausea, photophobia, or phonophobia) at 2 hours postdose, were evaluated using Mantel-Haenszel risk estimation.

RESULTS: Of the 1485 participants enrolled, 1162 (78.2%) were randomized to rimegepant (n = 582) or placebo (n = 580). Most participants (85.5%) were female; the population had a mean (SD) age of 41.6 (12.2) years and a history of 4.7 (1.8) migraine attacks per month. At 2 hours postdose, rimegepant-treated participants had higher pain freedom rates (19.2% [104/543] vs 14.2% [77/541]; risk difference 4.9; 95% confidence interval [CI] 0.5 to 9.3; P=0.0298) and MBS freedom rates (36.6% [199/543] vs 27.7% [150/541]; risk difference 8.9; 95% CI 3.4 to 14.4; P=0.0016) than placebo-treated participants. Rimegepant-treated participants also had higher rates of pain relief (56.0% [304/543] vs 45.7% [247/541]; risk difference 10.3; 95% CI 4.4 to 16.2, P=0.0006) at 2 hours postdose. The most common adverse events were nausea (0.9% [5/546] vs 1.1% [6/549]) and dizziness (0.7% [4/546] vs 0.4% [2/549]). No signal of drug-induced liver injury due to rimegepant was identified.

CONCLUSION: Rimegepant 75 mg oral tablet was effective in the acute treatment of migraine. Tolerability and safety were similar to placebo, with no evidence of hepatotoxicity.

TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT03235479.

PMID:39070853 | PMC:PMC11277999 | DOI:10.2147/JPR.S453806

Clinics (Sao Paulo). 2024 Jul 27;79:100449. doi: 10.1016/j.clinsp.2024.100449. eCollection 2024.

ABSTRACT

BACKGROUND: There is no gold-standard trigger for detecting drug-induced respiratory disorders, a type of Adverse Drug Event (ADE) with high morbimortality, particularly in older people.

OBJECTIVE: To propose and evaluate the performance of triggers for detecting hospitalizations related to drug-induced respiratory disorders in older people.

METHODS: A pilot cross-sectional study was conducted with older people (age ≥ 60) admitted to a Brazilian hospital. Electronic chart documentation was screened using ICD-10 codes; Global Trigger Tool (GTT); and drugs potentially associated with respiratory disorders. A chart and medication review were conducted to perform the causality assessment using the instrument developed by the World Health Organization. The performance of triggers was evaluated by the Positive Predictive Value (PPV), with values ≥ 0.20 indicating good performance.

RESULTS: Among 221 older people, 72 were eligible. Potential drug-induced dyspnea and/or cough were detected in six older people (6/72), corresponding to a prevalence of 8.3 %. The overall PPV of the triggers was 0.14, with abrupt medication stop (PPV = 1.00), codeine (PPV = 1.00), captopril (PPV = 0.33), and carvedilol (PPV = 0.33) showing good performance. Two triggers were proposed for detecting therapeutic ineffectiveness associated with respiratory disorders: furosemide (PPV = 0.23) and prednisone (PPV = 0.20).

CONCLUSION: The triggers enabled the identification that one in 12 hospitalizations was related to drug-induced respiratory. Although good performance was observed in the application of triggers, additional investigations are needed to assess the feasibility of incorporating them into clinical practice for the screening, detection, management, and reporting of these ADEs, which are considered to be underreported and difficult to detect.

PMID:39068723 | DOI:10.1016/j.clinsp.2024.100449

Asian Pac J Cancer Prev. 2024 Jul 1;25(7):2291-2295. doi: 10.31557/APJCP.2024.25.7.2291.

ABSTRACT

BACKGROUND: Fatigue is an immune-related adverse event (irAE) associated with immune checkpoint inhibitors (ICIs) used for cancer treatment. Chinese herbal medicines (Ho-zai) are used to treat cancer-related fatigue. However, no interactions between ICIs and Ho-zai have been reported. Herein, we investigated the risk of irAEs associated with the concomitant use of ICIs and Ho-zai.

METHODS: We extracted data of patients who used ICI and Ho-zai from the Japanese Adverse Event Reporting Database. The proportional reporting ratio (PRR) was calculated for patients using ICI, Ho-zai, or both. We focused on cases of interstitial lung disease (ILD) and colitis, which were among the most severe cases of irAEs among these patients. The shrinkage method used by the World Health Organization-Uppsala Monitoring Center was used to detect the interactions.

RESULTS: Of the 799,670 patients in the database, 77,219, 2060, and 92 were using ICIs, Ho-zai, and combination treatment, respectively. The ILD and colitis groups included 39,388 and 17,522 patients, respectively. ILD signals were detected for both ICIs and Ho-zai. There were 24 cases of patients treated with concomitant ICIs and Ho-zai who developed ILD. For all combinations of all ICIs and all Ho-zai, Ω025 was negative, which suggested no ILD-related interactions. Colitis signals were detected for ICIs except for atezolizumab, avelumab, and durvalumab. There were eight patients treated with concomitant ICI and Ho-zai who developed colitis. For all combinations of all ICIs and all Ho-zai, Ω025 was negative, which suggested no colitis-related interactions.

CONCLUSION: To our knowledge, this is the first study to investigate interactions between ICIs and Ho-zai. Signals were detected for ILD in both ICI and Ho-zai groups, and colitis in the ICI group. However, the combined use of these treatments did not increase the risk of irAEs.

PMID:39068560 | DOI:10.31557/APJCP.2024.25.7.2291

J Hematol Oncol. 2024 Jul 27;17(1):54. doi: 10.1186/s13045-024-01581-2.

ABSTRACT

Cancer immunotherapies, represented by immune checkpoint inhibitors (ICIs), have reshaped the treatment paradigm for both advanced non-small cell lung cancer and small cell lung cancer. Programmed death receptor-1/programmed death receptor ligand-1 (PD-1/PD-L1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) are some of the most common and promising targets in ICIs. Compared to ICI monotherapy, which occasionally demonstrates treatment resistance and limited efficacy, the dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 operates at different stages of T cell activation with synergistically enhancing immune responses against cancer cells. This emerging dual therapy heralds a new direction for cancer immunotherapy, which, however, may increase the risk of drug-related adverse reactions while improving efficacy. Previous clinical trials have explored combination therapy strategy of anti-PD-1/PD-L1 and anti-CTLA-4 agents in lung cancer, yet its efficacy remains to be unclear with the inevitable incidence of immune-related adverse events. The recent advent of bispecific antibodies has made this sort of dual targeting more feasible, aiming to alleviate toxicity without compromising efficacy. Thus, this review highlights the role of dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 in treating lung cancer, and further elucidates its pre-clinical mechanisms and current advancements in clinical trials. Besides, we also provide novel insights into the potential combinations of dual blockade therapies with other strategies to optimize the future treatment mode for lung cancer.

PMID:39068460 | DOI:10.1186/s13045-024-01581-2