Front Psychiatry. 2024 Jun 18;15:1414622. doi: 10.3389/fpsyt.2024.1414622. eCollection 2024.

ABSTRACT

3,4-Methylenedioxymethamphetamine (MDMA) is being investigated in controlled clinical trials for use as an adjunct medication treatment for post-traumatic stress disorder. MDMA is metabolized by N-demethylation, primarily by CYP2D6, to its main inactive metabolite, 4-hydroxy-3-methoxymethamphetamine. It is also metabolized to a lesser extent by CYP1A2, CYP2B6, and CYP3A4 to its active metabolite, 3,4-methylenedioxyamphetamine. Considering the extensive hepatic metabolism and excretion, MDMA use in psychiatry raises concerns over drug-induced liver injury (DILI), a rare but dangerous event. Majority of the drugs withdrawn from the market for liver injury caused death or transplantation at frequencies under 0.01%. Unfortunately, markers for liver injury were not measured in most published clinical trials. At the same time, no visible DILI-related symptoms and adverse events were observed. Idiosyncratic DILI cases are rarely registered during clinical trials due to their rare nature. In this study, we surveyed a larger, over 1,500, and a more diverse set of reports from the FDA Adverse Event Reporting System and found 23 cases of hepatic injury and hepatic failure, in which MDMA was reported to be taken in addition to one or more substances. Interestingly, 22 out of 23 cases had one or more listed drugs with a known DILI concern based on the FDA's DILIrank dataset. Furthermore, only one report had MDMA listed as the primary suspect. Considering the nearly 20 million doses of MDMA used annually, this single report is insufficient for establishing a significant association with DILI.

PMID:38957734 | PMC:PMC11217510 | DOI:10.3389/fpsyt.2024.1414622

Drugs Aging. 2024 Jul;41(7):583-600. doi: 10.1007/s40266-024-01121-0. Epub 2024 Jul 2.

ABSTRACT

The objective of this review is to summarize and appraise the research methodology, emerging findings, and future directions in pharmacoepidemiologic studies assessing the benefits and harms of pharmacotherapies in older adults with different levels of frailty. Older adults living with frailty are at elevated risk for poor health outcomes and adverse effects from pharmacotherapy. However, current evidence is limited due to the under-enrollment of frail older adults and the lack of validated frailty assessments in clinical trials. Recent advancements in measuring frailty in administrative claims and electronic health records (database-derived frailty scores) have enabled researchers to identify patients with frailty and to evaluate the heterogeneity of treatment effects by patients' frailty levels using routine health care data. When selecting a database-derived frailty score, researchers must consider the type of data (e.g., different coding systems), the length of the predictor assessment period, the extent of validation against clinically validated frailty measures, and the possibility of surveillance bias arising from unequal access to care. We reviewed 13 pharmacoepidemiologic studies published on PubMed from 2013 to 2023 that evaluated the benefits and harms of cardiovascular medications, diabetes medications, anti-neoplastic agents, antipsychotic medications, and vaccines by frailty levels. These studies suggest that, while greater frailty is positively associated with adverse treatment outcomes, older adults with frailty can still benefit from pharmacotherapy. Therefore, we recommend routine frailty subgroup analyses in pharmacoepidemiologic studies. Despite data and design limitations, the findings from such studies may be informative to tailor pharmacotherapy for older adults across the frailty spectrum.

PMID:38954400 | DOI:10.1007/s40266-024-01121-0

Eur J Cancer. 2024 Jun 29;207:114196. doi: 10.1016/j.ejca.2024.114196. Online ahead of print.

ABSTRACT

INTRODUCTION: The prognosis of patients with advanced biliary tract cancer (BTC) is still poor, and new strategies improving patients' outcome are needed. In our trial we investigated safety and activity of nab-paclitaxel in combination with gemcitabine and oxaliplatin as first-line systemic treatment for patients with advanced BTC.

METHODS: In this investigator-initiated, multicenter, dose-escalation, single-arm phase I/II trial, patients were accrued into cohorts of 3 patients and dose escalation was performed following the standard 3 + 3 rule. Primary endpoint was the proportion of patients free from progression at 6 months. Secondary endpoints included safety and tolerability of the combination; progression-free survival (PFS); overall survival (OS); objective response rate (ORR); duration of response.

RESULTS: Between July 2017 and December 2020, 67 patients were treated. Among the 10 patients in the phase I, no dose-limiting toxicity was observed, and dose level 2 was defined as recommended phase II dose for the phase II part. At data cutoff, the 6-month PFS rate was 49.1 % (95 % CI 40.8-57.5 %) with 28 patients out of 57 free from progression or death at 6 months. Median PFS was 6.3 months (95 % CI 3.6-10.1) and median OS was 12.4 months (95 % CI 8-23). ORR was 20.89 %. Most common grade 3 and grade 1-2 drug-related adverse events were neutropenia and peripheral neuropathy, respectively.

CONCLUSION: Triple chemotherapy demonstrated a favorable safety profile. However, the study did not meet its primary endpoint. Future studies will clarify the benefit of chemotherapy combinations in different settings. This trial is registered with ClinicalTrials.gov, NCT03943043.

PMID:38954899 | DOI:10.1016/j.ejca.2024.114196

Zhonghua Jie He He Hu Xi Za Zhi. 2024 Jul 12;47(7):638-646. doi: 10.3760/cma.j.cn112147-20240229-00117.

ABSTRACT

Objective: To explore the characteristics of adverse drug reactions during the 24-week therapy with delamanid-containing regimen for patients with multidrug-resistant and rifampicin-resistant pulmonary tuberculosis (MDR/RR-PTB). Methods: The prospective multicenter study was conducted from June 2020 to June 2023. A total of 608 eligible patients with MDR/RR-PTB were enrolled in 26 tuberculosis medical institutions in China including 364 males and 79 females, aged 39.6(19.0-68.0) years. Patients were treated with chemotherapy regimens containing delamanid. Patients were closely supervised during treatment of medication, and all adverse reactions occurring during treatment were monitored and recorded. The clinical characteristics of adverse reactions were evaluated by descriptive analysis. Chi-square test and multivariate logistic regression were used to analyze the related factors of QTcF interval prolongation (QT corrected with Fridericia's formula). Results: Of the 608 patients enrolled in this study, 325 patients (53.5%) reported 710 adverse events within 24 weeks of treatment. The top 6 most common complications were hematological abnormalities (143 patients, 23.5%), QT prolongation (114 patients, 18.8%), liver toxicity (85 patients, 14.0%), gastrointestinal reaction (41 patients, 6.7%), peripheral neuropathy (25 patients, 4.1%) and mental disorders (21 patients, 3.5%). The prolongation of QT interval mostly occurred in the 12th week after the first dose of medication. Serious adverse reactions occurred in 21 patients (3.5%). There were 7 patients (1.2%) with mental disorders, including 2 patients (0.3%) with severe mental disorders. Conclusions: The safety of dalamanid-based regimen in the staged treatment of MDR/RR-PTB patients was generally good, and the incidence of adverse reactions was similar to that reported in foreign studies. This study found that the incidence of QT interval prolongation in Chinese patients was higher than that reported overseas, suggesting that the monitoring of electrocardiogram should be strengthened when using drugs containing delamanid that may cause QT interval prolongation.

PMID:38955749 | DOI:10.3760/cma.j.cn112147-20240229-00117

Zhonghua Jie He He Hu Xi Za Zhi. 2024 Jul 12;47(7):632-637. doi: 10.3760/cma.j.cn112147-20231124-00339.

ABSTRACT

Objective: To evaluate the safety of umeclidinium/vilanterol in Chinese participants in a real-world setting. Methods: This was a 24-week, prospective, multicenter, single-arm, observational study that enrolled participants treated with umeclidinium/vilanterol in real-world settings from 14 sites in China from 14 December 2020 to 30 January 2022. The primary outcomes were the incidence of adverse events (AEs) and serious adverse events (SAEs) at week 24. Results: A total of 887 participants on umeclidinium/vilanterol were enrolled. The mean (±SD) age of these participants was 67.5 (±9.6) years, with more men (77.7%) enrolled. The majority of the participants (98.1%) had been diagnosed with chronic obstructive pulmonary disease, and 67.6% of them reported comorbidities. More than half of the participants (52.8%) were taking concomitant medication in addition to the study treatment. AEs were reported in 59 (6.7%) participants and were predominantly mild to moderate in severity. SAEs were reported in 21 (2.4%) participants, including 9 fatal SAEs, 10 reported non-fatal SAEs, and 2 reported both non-fatal and fatal SAEs. None of the SAEs, including the fatal events, were considered by the investigators to be related to umeclidinium/vilanterol. Adverse drug reactions (ADRs) were reported in 6 (0.7%) participants with 4 preferred terms (PTs), all of which were considered mild in severity. Of these PTs, 2 were known ADRs of umeclidinium/vilanterol. Three participants (0.3%) reported AEs that were part of serious identified/potential hazards, all of which were considered by the investigators to be unrelated to umeclidinium/vilanterol. Conclusion: The results of this study showed that umeclidinium/vilanterol was well tolerated in Chinese participants in a real-world setting and no new drug-related safety signals were observed.

PMID:38955748 | DOI:10.3760/cma.j.cn112147-20231124-00339

Am J Clin Oncol. 2024 Jul 2. doi: 10.1097/COC.0000000000001126. Online ahead of print.

ABSTRACT

OBJECTIVES: Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug conjugate (ADC) promising in treating metastatic HER2+ and HER2-low breast cancer. This updated systematic review and meta-analysis, integrating data from the latest clinical trials, aimed to evaluate the safety and efficacy of T-DXd in this patient population.

METHODS: We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A comprehensive search was conducted across PubMed, Scopus, and Web of Science up to January 2024, focusing on clinical trials that assessed T-DXd's efficacy and safety. Eligibility criteria were based on the PICOS framework, and selected studies underwent rigorous quality assessment and data extraction. The primary outcomes were progression-free survival (PFS), overall survival (OS), and the incidence of adverse events. A random-effects meta-analysis was performed to synthesize the data.

RESULTS: Seven studies involving 2,201 patients met the inclusion criteria. The pooled analysis revealed that T-DXd significantly improved PFS (OR=0.37, 95% CI: 0.27-0.52), indicating a robust efficacy in slowing disease progression. However, treatment was associated with an increased risk of anemia (OR=2.10, 95% CI: 1.36-3.25), fatigue (OR=1.56, 95% CI: 1.21-2.02), nausea (OR=6.42, 95% CI: 4.37-9.42), vomiting (OR=6.21, 95% CI: 3.14-12.25), constipation (OR=2.26, 95% CI: 1.53-3.34), and notably, drug-related interstitial lung disease (OR=10.89, 95% CI: 3.81-31.12). The efficacy outcomes demonstrated significant heterogeneity, which was addressed through sensitivity analysis.

CONCLUSIONS: T-DXd shows significant efficacy in treating metastatic HER2+ and HER2-low breast cancer, offering a valuable therapeutic option for patients with advanced disease. However, the treatment is associated with notable adverse events, including a heightened risk of ILD. These findings underscore the need for careful patient selection, monitoring, and management strategies to mitigate risks. Future research should focus on optimizing treatment protocols and exploring methods to enhance safety profiles.

PMID:38951994 | DOI:10.1097/COC.0000000000001126

J Am Med Dir Assoc. 2024 Jun 29:105118. doi: 10.1016/j.jamda.2024.105118. Online ahead of print.

ABSTRACT

OBJECTIVES: To produce a consensus list of the top 10 signs and symptoms suggestive of adverse drug events (ADEs) for monitoring in residents of long-term care facilities (LTCFs) who use antipsychotics, benzodiazepines, or antidepressants.

DESIGN: A 3-round Delphi study.

SETTING AND PARTICIPANTS: Geriatricians, psychiatrists, pharmacologists, general practitioners, pharmacists, nurses, and caregivers from 13 Asia Pacific, European, and North American countries.

METHODS: Three survey rounds were completed between April and June 2023. In Round 1, participants indicated their level of agreement on a 9-point Likert scale on whether 41 signs or symptoms identified in a systematic review should be routinely monitored. Participants considered signs and symptoms that reduce quality of life or cause significant harm, are observable or measurable by nurses or care workers, and can be assessed at a single time point. Round 1 statements were included in a list for prioritization in Round 3 if ≥ 70% of participants responded ≥7 on the Likert scale. Statements were excluded if ≤ 30% of participants responded ≥7. In Round 2, participants indicated their level of agreement with statements that did not reach initial consensus, plus amended statements based on Round 1 participant feedback. Round 2 statements were included in Round 3 if ≥ 50% of the participants responded ≥7 on the Likert scale. In Round 3, participants prioritized the signs and symptoms.

RESULTS: Forty-four participants (93.6%) completed all 3 rounds. Four of 41 signs and symptoms reached consensus for inclusion after Round 1, and 9 after Round 2. The top 10 signs and symptoms prioritized in Round 3 were recent falls, daytime drowsiness or sleepiness, abnormal movements (eg, shaking or stiffness), confusion or disorientation, balance problems, dizziness, postural hypotension, reduced self-care, restlessness, and dry mouth.

CONCLUSIONS AND IMPLICATIONS: The top 10 signs and symptoms provide a basis for proactive monitoring for psychotropic ADEs.

PMID:38950588 | DOI:10.1016/j.jamda.2024.105118

Front Pharmacol. 2024 Jun 14;15:1412188. doi: 10.3389/fphar.2024.1412188. eCollection 2024.

ABSTRACT

The management of neurological disorders heavily relies on neurotherapeutic drugs, but notable concerns exist regarding their possible negative effects on reproductive health. Traditional preclinical models often fail to accurately predict reprotoxicity, highlighting the need for more physiologically relevant systems. Organoid models represent a promising approach for concurrently studying neurotoxicity and reprotoxicity, providing insights into the complex interplay between neurotherapeutic drugs and reproductive systems. Herein, we have examined the molecular mechanisms underlying neurotherapeutic drug-induced reprotoxicity and discussed experimental findings from case studies. Additionally, we explore the utility of organoid models in elucidating the reproductive complications of neurodrug exposure. Have discussed the principles of organoid models, highlighting their ability to recapitulate neurodevelopmental processes and simulate drug-induced toxicity in a controlled environment. Challenges and future perspectives in the field have been addressed with a focus on advancing organoid technologies to improve reprotoxicity assessment and enhance drug safety screening. This review underscores the importance of organoid models in unraveling the complex relationship between neurotherapeutic drugs and reproductive health.

PMID:38948466 | PMC:PMC11211546 | DOI:10.3389/fphar.2024.1412188

J Pediatr. 2024 Jun 28:114176. doi: 10.1016/j.jpeds.2024.114176. Online ahead of print.

ABSTRACT

OBJECTIVE: To describe reported adverse events (AEs) associated with elexacaftor/tezacaftor/ivacaftor (ETI) in a pediatric sample with cystic fibrosis (CF) aged 6-18 years, with at least one F508del variant, followed at multiple Italian CF centers.

STUDY DESIGN: This was a retrospective, multicenter, observational study. All children receiving ETI therapy from October 2019 to December 2023 were included. We assessed the prevalence and type of any reported potential drug-related AEs, regardless of discontinuation necessity. Persistent AEs were defined as those continuing at the end of the observation period.

RESULTS: Among 608 patients on ETI, 109 (17.9%) reported at least one AE. The majority (N=85, 77.9%) were temporary, with a median duration of 11 days (range 1-441 days). Only 7 (1.1%) patients permanently discontinued treatment, suggesting good overall safety of ETI. The most common AEs leading to discontinuation were transaminase elevations (temporary 14.1%, persistent 25.9%) and urticaria (temporary 41.2%, persistent 7.4%). Creatinine phosphokinase elevation was uncommon. No significant differences in AEs were observed based on sex, age groups (6-11 vs. 12-18 years), or genotype. Pre-existing CF-related liver disease was associated with an increased risk of transaminase elevations. We identified significant variability in the percentage of reported AEs (ANOVA p-value 0·026).

CONCLUSIONS: This real-world study highlights significant variability in reported AEs. Our findings suggest that ETI is a safe and well-tolerated therapy in children and adolescents with CF. However, further long-term safety and effectiveness investigations are warranted.

PMID:38945446 | DOI:10.1016/j.jpeds.2024.114176

Adv Gerontol. 2024;37(1-2):33-39.

ABSTRACT

In recent years, complications of drug therapy are an important medical problem. Data on adverse drug reactions (ADR) in patients of older age groups were analyzed. The object of the study was notification cards for unwanted reactions received from medical organizations of the Irkutsk region for period 2009-2020 years. The Narangio scale was used to assess the causality between ADR and medicines. Of the 1021 ADR notifications in patients over 65 years of age, 2/3 (668) are presented with ADR notifications in women, 353 (34,6%) in men. The presence of background diseases was registered in 915 notifications (89,6%). There were no gender differences except for a higher incidence of chronic obstructive pulmonary disease in men (7,2 and 3,5% respectively, p<0,05) and diabetes mellitus in women (14 and 3,5% respectively, p<0,05). ADRs for antibacterial agents amounted to 31,8%, drugs for the treatment of cardiovascular diseases - 10,5%, cases of therapeutic inefficiency - 5,1%. The ADR data statement was in line with the recommended form of 76%. The most common filling defect was incomplete patient information. The validity of the Narango causation was high. The deadlines for reporting data were observed in 89,1%. For effective interaction in the pharmacovigilance system, it is necessary in each medical organization to constantly inform about the procedure for pharmacovigilance, types of ADRs, the rules for their detection and the timing of data reporting. The work should be supervised by a trained specialist.

PMID:38944770

Clin Transl Sci. 2024 Jul;17(7):e13871. doi: 10.1111/cts.13871.

ABSTRACT

Electronic health records (EHRs) contain a vast array of phenotypic data on large numbers of individuals, often collected over decades. Due to the wealth of information, EHR data have emerged as a powerful resource to make first discoveries and identify disparities in our healthcare system. While the number of EHR-based studies has exploded in recent years, most of these studies are directed at associations with disease rather than pharmacotherapeutic outcomes, such as drug response or adverse drug reactions. This is largely due to challenges specific to deriving drug-related phenotypes from the EHR. There is great potential for EHR-based discovery in clinical pharmacology research, and there is a critical need to address specific challenges related to accurate and reproducible derivation of drug-related phenotypes from the EHR. This review provides a detailed evaluation of challenges and considerations for deriving drug-related data from EHRs. We provide an examination of EHR-based computable phenotypes and discuss cutting-edge approaches to map medication information for clinical pharmacology research, including medication-based computable phenotypes and natural language processing. We also discuss additional considerations such as data structure, heterogeneity and missing data, rare phenotypes, and diversity within the EHR. By further understanding the complexities associated with conducting clinical pharmacology research using EHR-based data, investigators will be better equipped to design thoughtful studies with more reproducible results. Progress in utilizing EHRs for clinical pharmacology research should lead to significant advances in our ability to understand differential drug response and predict adverse drug reactions.

PMID:38943244 | DOI:10.1111/cts.13871

Rev Fac Cien Med Univ Nac Cordoba. 2024 Jun 28;81(2):254-269. doi: 10.31053/1853.0605.v81.n2.42261.

ABSTRACT

INTRODUCTION: The World Health Organization recommends prioritizing safe and effective drugs proven by clinical or epidemiological studies. However, in population groups with little research, a drug can be used for an indication or pharmaceutical form different from that approved by the regulatory agency (off-label), extrapolating data from studies in adults and exposing pediatric patients. to develop an Adverse Drug Reaction (ADR) due to safety considerations that have not been systematically studied. Intravenous immunoglobulin (IVIg), a high-cost drug, is used with scant evidence in some low-prevalence pathologies. This paper describes and analyzes the off-label use of IVIg at the J. P. Garrahan Pediatric Hospital.

METHODS: Observational, descriptive, prospective study on off-label indications of IVIg. The sampling technique was non-probabilistic and for convenience during 7 months.

RESULTS: 305 IVIg infusions were studied, corresponding to 111 patients. The indication classification showed that 22% (n=67) of the infusions were off-label. In neurology there was a higher percentage of off-label indications (46%) and within them 45% corresponded to the use in neurological disorders. 81% of the doses indicated off-label were in the range 0.8-1g/kg. The off-label infusions presented 61.5% (n=8) of the ADRs. Those from the Neurology service represented 87.5%; 75% being from the "Neurological disorders" group.

CONCLUSION: In some cases, IVIg was indicated in an off-label manner, finding a statistically significant relationship with the appearance of ADR. This finding motivates the proposition of new hypotheses to carry out more studies.

PMID:38941229 | DOI:10.31053/1853.0605.v81.n2.42261

J Immunol. 2024 Jun 28:ji2300893. doi: 10.4049/jimmunol.2300893. Online ahead of print.

ABSTRACT

Catecholamines binding to α- and β-adrenergic receptors on immune cells have recently been shown to play an important role in regulating immune responses. Although α2-adrenergic receptors are known to modulate the immune response in different ways, the therapeutic exploration of their utility has been limited by the lack of agonists selective for the three α2-adrenergic subtypes. We report in this study the identification of the agonist AGN-762, which activates α2B- and α2C-adrenergic subtypes, but not the α2A subtype. We show that AGN-762 reduced clinical disease in an experimental autoimmune encephalitis model of autoimmune disease via direct or indirect effects on T regulatory cells. The activity of AGN-762 was abrogated by depletion of T regulatory cells, which express the α2B-adrenergic receptor. Furthermore, a drug-induced shift to an anti-inflammatory phenotype was demonstrated in immune cells in the spleen of drug-treated experimental autoimmune encephalitis mice. AGN-762 does not display sedative and cardiovascular side effects associated with α2A subtype agonists. Immune modulation by selective α2-adrenergic agonists represents a novel, to our knowledge, approach for treating autoimmune disease.

PMID:38940628 | DOI:10.4049/jimmunol.2300893

JAAD Case Rep. 2024 May 15;49:85-87. doi: 10.1016/j.jdcr.2024.05.007. eCollection 2024 Jul.

NO ABSTRACT

PMID:38938698 | PMC:PMC11208765 | DOI:10.1016/j.jdcr.2024.05.007

Innov Clin Neurosci. 2024 Jun 1;21(4-6):27-30. eCollection 2024 Apr-Jun.

ABSTRACT

INTRODUCTION: Well-known adverse events of antipsychotics are movement disorders, or extrapyramidal symptoms, such as drug-induced parkinsonism and tardive dyskinesia.

OBJECTIVE: With new evidence suggesting a link between low high-density lipoprotein cholesterol (HDL-C) and risk of Parkinson's disease, this study sought to investigate if that link also translated to patients taking antipsychotics with low HDL-C and an increased risk for developing a movement disorder.

DESIGN: Adult patients (n=89) at an inpatient state psychiatric facility taking at least one antipsychotic with at least one HDL-C level were assessed for signs of a movement disorder through their history and physical, progress notes, and Abnormal Involuntary Movement Scale (AIMS) score.

RESULTS: There was no statistical significance when comparing a patient's movement disorder, AIMS scores, and HDL-C levels to suggest that the HDL-C level influenced a patient's movement disorder.

CONCLUSION: This study did not show a correlation between HDL-C levels and a patient's risk of developing a movement disorder while taking an antipsychotic.

PMID:38938537 | PMC:PMC11208005

In Vivo. 2024 Jul-Aug;38(4):2090-2096. doi: 10.21873/invivo.13669.

ABSTRACT

BACKGROUND/AIM: A few case reports of central nervous system (CNS) symptoms caused by amantadine intoxication have been published, detailing various types of symptoms and differing times to onset. We encountered a patient who developed CNS symptoms with amantadine. This prompted us to investigate the types, time to onset, and outcome of CNS adverse reactions to amantadine by analyzing data from a pharmacovigilance database.

PATIENTS AND METHODS: The patient was evaluated at Chutoen General Hospital, Shizuoka, Japan. Analysis was performed using the Japanese Adverse Drug Event Report (JADER) database.

RESULTS: In our case, the amantadine blood concentration was 4,042 ng/ml, i.e., in the toxic range. The time to onset was 26 days for dyskinesia and 90 days for depressed level of consciousness. Symptoms resolved when amantadine was discontinued. The JADER database contained 974 cases of adverse reactions to amantadine. The most frequently reported CNS adverse reaction was hallucination, with a reporting odds ratio of 64.28 (95% confidence interval=52.67-78.46). Positive signals were detected for all CNS adverse reactions. For all CNS reactions, clinical outcomes were poor in a comparatively low percentage of cases. Most CNS reactions occurred soon after administration of amantadine, usually within approximately one month.

CONCLUSION: Because most CNS adverse reactions to amantadine usually occur within approximately one month of initiating treatment, healthcare providers should exercise heightened vigilance in monitoring patients for such reactions during this period.

PMID:38936887 | DOI:10.21873/invivo.13669

Ann Allergy Asthma Immunol. 2024 Jun 25:S1081-1206(24)00376-4. doi: 10.1016/j.anai.2024.06.024. Online ahead of print.

ABSTRACT

BACKGROUND: Limited data exist comparing inhaled corticosteroid (ICS) plus adjunctive therapy versus ICS alone in pediatric asthma patients.

OBJECTIVE: Evaluate the efficacy and safety of fluticasone furoate/vilanterol (FF/VI) versus FF in children and adolescents with asthma.

METHODS: This Phase 3, randomized, double-blind, multicenter study (NCT03248128) included participants aged 5-17 years with ≥6 months' asthma history uncontrolled on ICS monotherapy. Participants received 4 weeks' open-label fluticasone propionate (100 µg) twice daily before 1:1 randomization to 24 weeks' double-blind FF (50 µg:100 µg) or FF/VI (50/25 µg:100/25 µg) once daily. Two populations with different primary endpoints were analyzed to meet United States (Week 12 weighted mean forced expiratory volume in 1 second [FEV1; 0-4 hours]; participants aged 5-17 years) and European (change from baseline pre-dose morning peak expiratory flow [ΔAM PEF] averaged over Weeks 1-12; participants aged 5-11 years) regulator requirements.

RESULTS: Overall, 902 participants were randomized and treated, including 673 children aged 5-11 years. In participants aged 5-17, Week 12 weighted mean FEV1 (0-4 hours) was greater with FF/VI versus FF (difference: 0.083 L; P < .001). In participants aged 5-11, ΔAM PEF over Weeks 1-12 showed numerical improvement with FF/VI versus FF but was not statistically significant (difference: 3.2 L/minute; P = .228). No drug-related serious adverse events or deaths were reported.

CONCLUSION: FF/VI significantly improved weighted mean FEV1 (0-4 hours; participants aged 5-17 years), but not ΔAM PEF (participants aged 5-11 years) versus FF. No new safety concerns were apparent.

PMID:38936466 | DOI:10.1016/j.anai.2024.06.024

Indian J Public Health. 2023 Oct 1;67(4):542-545. doi: 10.4103/ijph.ijph_865_22. Epub 2023 Dec 29.

ABSTRACT

The Saharia tribe of Madhya Pradesh has a very high tuberculosis (TB) burden. However, there is no report of adverse drug reaction (ADR) available in patients receiving anti-TB chemotherapy in the community. Reporting and monitoring of ADRs among TB patients is still rare in marginalized communities. An observational prospective study was performed from November 2019 to June 2020 to assess the patterns of ADRs in 250 Saharia TB patients, who were prescribed Category-I daily DOTS (HRZE) by the physician. Both male and female participants equally experienced ADR during the treatment, but relatively more females (92.6%) than males (88.6%) reported ADR during Phase I. Out of 250 patients, 224 patients (89.6%) experienced one or more ADRs in Phase I. The central nervous system-related (75.6%) ADR was mostly reported followed by any gastrointestinal (74.4%), cardiovascular (49.2%) and any dermatological related (44.4%) ADRs. It is paramount to timely monitor and proactively manages ADRs pertaining to anti-TB drug treatment with minimal alteration in the treatment course.

PMID:38934815 | DOI:10.4103/ijph.ijph_865_22

Am J Hematol. 2024 Jun 27. doi: 10.1002/ajh.27424. Online ahead of print.

ABSTRACT

Belumosudil mesylate is a selective Rho-associated coiled-coil kinase 2 inhibitor with immunomodulatory and antifibrosis effects. This multicenter, open-label, single-arm study evaluated belumosudil 200 mg once daily as second or subsequent line of therapy (LOT) in 21 Japanese patients ≥12 years of age with steroid-dependent/steroid-resistant chronic graft-versus-host disease (cGVHD). The primary endpoint of best overall response rate (ORR) at 24 weeks after enrollment of the last patient was 85.7% (95% confidence interval [CI]: 63.7-97.0), and the lower limit of the 95% CI exceeded the pre-defined threshold of 25%. The Kaplan-Meier estimate of duration of response rate at 24 weeks was 75% (95% CI: 46-90); 13/18 responders (72.2%) had a sustained response for ≥20 weeks. The median time to response was 4.1 weeks (range 3.90-8.10); ORR was 47.6% at 4 weeks and 75.0% at 24 weeks; best ORR was 80% for joints/fascia, 66.7% for the mouth, and 54.5% for skin. Overall, 57.1% of patients had clinically meaningful symptom improvement at least once; the median duration of symptom improvement was 22.2 weeks (range 4.0-51.3). Corticosteroid dose reductions were recorded for 57.1% of patients. Median failure-free and overall survival were not reached. Treatment-emergent adverse events occurred in 85.7% of patients (most commonly diarrhea, 19.0%), of which 38.1% were drug-related. There were no drug-related discontinuations or deaths. In summary, belumosudil 200 mg once daily as second or subsequent LOT in Japanese patients with steroid-dependent/steroid-resistant cGVHD was effective, with no new safety concerns.

PMID:38934629 | DOI:10.1002/ajh.27424

Pharmaceutics. 2024 May 31;16(6):745. doi: 10.3390/pharmaceutics16060745.

ABSTRACT

Acemetacin (ACM) is a new non-steroidal anti-inflammatory drug with anti-inflammatory, analgesic, and antipyretic effects. However, the poor water solubility and gastrointestinal side effects limit its use. Recently, the co-amorphous (CAM) strategy has attracted great interest to improve solubility for poorly water-soluble drugs, and basic amino acids have the potential to protect the gastrointestinal tract. In order to develop a highly efficient and low-toxic ACM formulation, we prepared ACM CAM systems, with basic amino acids (lysine, arginine, and histidine) as co-formers, using a cryo-milling method. The solid-state behaviors of the ACM CAM systems were characterized by polarizing light microscopy, differential scanning calorimetry, and powder X-ray diffraction. Fourier transform infrared spectroscopy and molecular docking were carried out to understand the formation mechanism. Moreover, the gastro-protective effects of ACM CAM systems were evaluated in a rat gastric ulcer model. The results demonstrated that the CAM systems improved the dissolution rates of ACM compared with the neat amorphous counterpart. Furthermore, ACM CAM systems are significantly effective in mitigating the ACM-induced gastric ulcer in rats, and the ulcer inhibition rates were almost 90%. More importantly, this study provided a useful method for mitigating drug-induced gastrointestinal damage and broadened the applications of drug-amino acid CAM systems.

PMID:38931867 | DOI:10.3390/pharmaceutics16060745