Am J Mens Health. 2023 Mar-Apr;17(2):15579883231158531. doi: 10.1177/15579883231158531.

ABSTRACT

Sexual enhancement supplements (SESs) that have illegal additions of pharmaceuticals or analogues pose a significant health risk, particularly with long-term usage. When supplements are adulterated with phosphodiesterase type 5 (PDE-5) inhibitors, dosages can vary widely and there may be an increase in adverse effects and drug-drug interactions which cannot be avoided. Consequently, there is a need to evaluate the public risk awareness toward SES and the associated adverse events as well as explore significant factors associated with knowledge and risk awareness. A cross-sectional community-based study was conducted among University male students and staff at Ajman University, United Arab Emirates (UAE), using a self-administered survey via a web-based electronic link to explore key issues. A total of 1,101 male subjects participated in the study and completed the questionnaire. Four hundred and thirty-three(39.3%) (95% confidence interval [CI]: 33.2-44.5) participants reported using SES products. Of these, 137 (31.6%) [95% CI: 28.6-37.2] experienced adverse effects from SES product use. SES use was more prevalent among participants aged 60 to 69 years (odds ratio [OR]: 2.94; 95% CI: 1.63-5.28), diabetic patients (OR: 2.61; 95% CI: 1.75-3.90), hypertension patients (OR: 2.12; 95% CI: 1.45-3.1), and those overweight or obese (OR: 1.84; 95% CI: 1.44-2.35). This study indicates that SES is a popular practice among the UAE university staff and students. However, there is a need to implement risk awareness programs to raise public awareness regarding SES use and safety. Regulatory bodies are encouraged to provide additional advice on the proper use and possible risks of consuming SES.

PMID:36987378 | DOI:10.1177/15579883231158531

Medicina (Kaunas). 2023 Mar 3;59(3):501. doi: 10.3390/medicina59030501.

ABSTRACT

Background and Objectives: Vaccination has been critical to managing the COVID-19 pandemic. Autoimmunity of the nervous system, especially among a select set of high-risk groups, can be triggered or enhanced by the contents of vaccines. Here, we report a case series of acute peripheral neuropathies following vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report on 11 patients (range: 30-90 years old) who presented at our center between January 2021 and February 2022. Methods: We obtained the patients' history and performed clinical neurological examination and electromyoneurography on all subjects. If necessary, magnetic resonance imaging and laboratory testing, including cerebrospinal fluid analysis and specific antibody testing, were performed. Results: Patients presented with peripheral neuropathies of acute onset between 1 and 40 days after vaccination with different types of COVID-19 vaccines. Most cases (9/11) resolved with a rapid, complete or partial recovery. Conclusions: We found acute peripheral neuropathies in a set of individuals after they received vaccines against SARS-CoV-2. Albeit our observation shows that during extensive vaccination programs, negative side effects on the peripheral nervous system might occur, most of them showed benign clinical evolution. Thus, potential side effects should not hinder the prescription of vaccines. More extensive studies are needed to elucidate populations at risk of developing peripheral neuropathies and mechanisms of autoimmune response in the nervous system.

PMID:36984503 | DOI:10.3390/medicina59030501

Int J Mol Sci. 2023 Mar 16;24(6):5679. doi: 10.3390/ijms24065679.

ABSTRACT

Life is chiral, as its constituents consist, to a large degree, of optically active molecules, be they macromolecules (proteins, nucleic acids) or small biomolecules. Hence, these molecules interact disparately with different enantiomers of chiral compounds, creating a preference for a particular enantiomer. This chiral discrimination is of special importance in medicinal chemistry, since many pharmacologically active compounds are used as racemates-equimolar mixtures of two enantiomers. Each of these enantiomers may express different behaviour in terms of pharmacodynamics, pharmacokinetics, and toxicity. The application of only one enantiomer may improve the bioactivity of a drug, as well as reduce the incidence and intensity of adverse effects. This is of special significance regarding the structure of natural products since the great majority of these compounds contain one or several chiral centres. In the present survey, we discuss the impact of chirality on anticancer chemotherapy and highlight the recent developments in this area. Particular attention has been given to synthetic derivatives of drugs of natural origin, as naturally occurring compounds constitute a major pool of new pharmacological leads. Studies have been selected which report the differential activity of the enantiomers or the activities of a single enantiomer and the racemate.

PMID:36982753 | DOI:10.3390/ijms24065679

Int J Mol Sci. 2023 Mar 13;24(6):5496. doi: 10.3390/ijms24065496.

ABSTRACT

Multi-kinase inhibitors (MKIs) represent the best therapeutic option in advanced thyroid cancer patients. The therapeutic efficacy and toxicity of MKIs are very heterogeneous and are difficult to predict before starting treatment. Moreover, due to the development of severe adverse events, it is necessary to interrupt the therapy some patients. Using a pharmacogenetic approach, we evaluated polymorphisms in genes coding for proteins involved with the absorption and elimination of the drug in 18 advanced thyroid cancer patients treated with lenvatinib, and correlated the genetic background with (1) diarrhea, nausea, vomiting and epigastric pain; (2) oral mucositis and xerostomia; (3) hypertension and proteinuria; (4) asthenia; (5) anorexia and weight loss; (6) hand foot syndrome. Analyzed variants belong to cytochrome P450 (CYP3A4 rs2242480 and rs2687116 and CYP3A5 rs776746) genes and to ATP-binding cassette transporters (ABCB1 rs1045642, rs2032582 and rs2235048 and ABCG2 rs2231142). Our results suggest that the GG genotype for rs2242480 in CYP3A4 and CC genotype in rs776746 for CYP3A5 were both associated with the presence of hypertension. Being heterozygous for SNPs in the ABCB1 gene (rs1045642 and 2235048) implicated a higher grade of weight loss. The ABCG2 rs2231142 statistically correlated with a higher extent of mucositis and xerostomia (CC genotype). Heterozygous and rare homozygous genotypes for rs2242480 in CYP3A4 and for rs776746 for CYP3A5 were found to be statistically linked to a worse outcome. Evaluating the genetic profile before starting lenvatinib treatment may help to predict the occurrence and grade of some side effects, and may contribute to improving patient management.

PMID:36982571 | DOI:10.3390/ijms24065496

Genes (Basel). 2023 Mar 10;14(3):689. doi: 10.3390/genes14030689.

ABSTRACT

Treatment-resistant schizophrenia (TRS) is often associated with severe burden of disease, poor quality of life and functional impairment. Clozapine is the gold standard for the treatment of TRS, although it is also known to cause significant side effects in some patients. In view of the burgeoning interest in the role of genetic factors in precision psychiatry, we conducted a scoping review to narratively summarize the current genetic factors associated with TRS, clozapine resistance and side effects to clozapine treatment. We searched PubMed from inception to December 2022 and included 104 relevant studies in this review. Extant evidence comprised associations between TRS and clozapine resistance with genetic factors related to mainly dopaminergic and serotoninergic neurotransmitter systems, specifically, TRS and rs4680, rs4818 within COMT, and rs1799978 within DRD2; clozapine resistance and DRD3 polymorphisms, CYP1A2 polymorphisms; weight gain with LEP and SNAP-25 genes; and agranulocytosis risk with HLA-related polymorphisms. Future studies, including replication in larger multi-site samples, are still needed to elucidate putative risk genes and the interactions between different genes and their correlations with relevant clinical factors such as psychopathology, psychosocial functioning, cognition and progressive changes with treatment over time in TRS and clozapine resistance.

PMID:36980961 | DOI:10.3390/genes14030689

Cells. 2023 Mar 8;12(6):837. doi: 10.3390/cells12060837.

ABSTRACT

Parkinson's Disease (PD) is a neurodegenerative disorder characterized by motor symptoms that result from loss of nigrostriatal dopamine (DA) cells. While L-DOPA provides symptom alleviation, its chronic use often results in the development of L-DOPA-induced dyskinesia (LID). Evidence suggests that neuroplasticity within the serotonin (5-HT) system contributes to LID onset, persistence, and severity. This has been supported by research showing 5-HT compounds targeting 5-HT1A/1B receptors and/or the 5-HT transporter (SERT) can reduce LID. Recently, vortioxetine, a multimodal 5-HT compound developed for depression, demonstrated acute anti-dyskinetic effects. However, the durability and underlying pharmacology of vortioxetine's anti-dyskinetic actions have yet to be delineated. To address these gaps, we used hemiparkinsonian rats in Experiment 1, examining the effects of sub-chronic vortioxetine on established LID and motor performance. In Experiment 2, we applied the 5-HT1A antagonist WAY-100635 or 5-HT1B antagonist SB-224289 in conjunction with L-DOPA and vortioxetine to determine the contributions of each receptor to vortioxetine's effects. The results revealed that vortioxetine consistently and dose-dependently attenuated LID while independently, 5-HT1A and 5-HT1B receptors each partially reversed vortioxetine's effects. Such findings further support the promise of pharmacological strategies, such as vortioxetine, and indicate that broad 5-HT actions may provide durable responses without significant side effects.

PMID:36980178 | DOI:10.3390/cells12060837

Biomolecules. 2023 Feb 23;13(3):418. doi: 10.3390/biom13030418.

ABSTRACT

Oral mucositis (OM) is a common side effect in patients undergoing chemotherapy (CT), especially in children due to their rapid epithelial mitotic rate. It has been associated with a significant reduction in life quality since it leads to pain, an inadequate intake of nutrients, an increased risk of opportunistic infections, and interruptions of CT. Photobiomodulation (PMB) with low-level laser therapy (LLLT) has shown faster healing, reduction in pain, and the reduced use of analgesic compared to placebo groups. The purpose of this review is to analyze and compare the existing clinical trials and identify their shortcomings in hope to make future research easier. Using MeSH terms and keywords, the Embase, Medline, and PubMed databases we searched for the period of the last 5 years. We identified a total of 15 clinical trials, with a total of 929 pediatric patients analyzed in this review. We compared different light sources and other laser technique characteristics used in clinical trials such as wavelength, energy and power density, spot size, irradiation time, PBM protocol, and OM evaluation. The main findings show inconsistent laser parameter quotations, differences in the PBM protocol along with a laser application technique, and a lack of clinical trials. Based on that, more studies with a high methodological quality should be conducted in order to provide a unified PBM protocol suitable for the pediatric population.

PMID:36979353 | DOI:10.3390/biom13030418

An Bras Dermatol. 2023 Mar 27:S0365-0596(23)00051-X. doi: 10.1016/j.abd.2022.10.004. Online ahead of print.

ABSTRACT

The frequency of the use of drugs that act on the epidermal growth factor receptor (EGFR) is increasing, with the consequent onset of cutaneous toxicity, specifically acneiform eruption. The authors extensively review the topic, focusing on describing how these drugs can affect the skin and its appendages, that is, the pathophysiology that encompasses the cutaneous toxicity related to the use of EGFR inhibitors. In addition, it was possible to list the risk factors that may be associated with adverse effects of these drugs. Based on this recent knowledge, the authors expect to aid in the management of patients who are more vulnerable to toxicity, reduce morbidities, and improve the quality of life of patients undergoing treatment with EGFR inhibitors. Other issues related to the toxicity of EGFR inhibitors, such as the clinical aspects of the acneiform eruption grades, and other different types of cutaneous and mucosal reactions, are also included in the article.

PMID:36990917 | DOI:10.1016/j.abd.2022.10.004

Med J Aust. 2023 Mar 29. doi: 10.5694/mja2.51913. Online ahead of print.

NO ABSTRACT

PMID:36990107 | DOI:10.5694/mja2.51913

Antimicrob Agents Chemother. 2023 Mar 29:e0162322. doi: 10.1128/aac.01623-22. Online ahead of print.

ABSTRACT

Fosmanogepix (FMGX, APX001), a first-in-class, intravenous (i.v.) and oral (p.o.) antifungal prodrug candidate is currently in clinical development for the treatment of invasive fungal infections. Manogepix (MGX, APX001A), the active moiety of FMGX, interferes with cell wall synthesis by targeting fungal glycosylphosphatidylinositol-anchored cell wall transfer protein 1, thereby causing loss of cell viability. Data from two phase 1, placebo-controlled, single-ascending dose (SAD) and multiple-ascending dose (MAD) studies evaluating safety, tolerability, and pharmacokinetics of FMGX (doses up to 1,000 mg, i.v. and p.o.) are presented. Eligible participants were healthy adults (aged 18 to 55 years) randomized to receive either FMGX or placebo. Across both phase 1 studies, 151 of 154 participants (aged 23 to 35 years; FMGX: 116, placebo: 38) completed the study. Administration of FMGX i.v. demonstrated linear- and dose-proportional pharmacokinetics of MGX in terms of geometric mean maximum concentration of drug in serum (Cmax) (SAD: 0.16 to 12.0 μg/mL, dose: 10 to 1,000 mg; MAD: 0.67 to 15.4 μg/mL, dose: 50 to 600 mg) and area under the concentration-time curve (AUC) (SAD: 4.05 to 400, MAD: 6.39 to 245 μg · h/mL). With single and repeat p.o., dose-proportional increases in Cmax (SAD: 1.30 to 6.41 μg/mL, dose: 100 to 500 mg; MAD: 6.18 to 21.3 μg/mL, dose: 500 to 1,000 mg) and AUC (SAD: 87.5 to 205, MAD: 50.8 to 326 μg · h/mL) were also observed, with high oral bioavailability (90.6% to 101.2%). Administration of FMGX p.o. under post cibum conditions improved tolerability versus ante cibum conditions. No severe treatment-emergent adverse events (TEAEs), serious AEs, or withdrawals due to a drug-related TEAEs were reported with single or multiple i.v. and p.o. doses. Preclinical target exposures were achieved and were not accompanied by any serious/unexpected concerns with generally safe and well-tolerated dose regimens.

PMID:36988461 | DOI:10.1128/aac.01623-22

Int J Mol Sci. 2023 Mar 13;24(6):5448. doi: 10.3390/ijms24065448.

ABSTRACT

Drug-induced gingival overgrowth (DIGO) is one of the side effects produced by therapeutic agents, most commonly phenytoin, nifedipine and cyclosporin A. However, the precise mechanism of DIGO is not entirely understood. A literature search of the MEDLINE/PubMed databases was conducted to identify the mechanisms involved in DIGO. The available information suggests that the pathogenesis of DIGO is multifactorial, but common pathogenic sequelae of events emerge, i.e., sodium and calcium channel antagonism or disturbed intracellular handling of calcium, which finally lead to reductions in intracellular folic acid levels. Disturbed cellular functions, mainly in keratinocytes and fibroblasts, result in increased collagen and glycosaminoglycans accumulation in the extracellular matrix. Dysregulation of collagenase activity, as well as integrins and membrane receptors, are key mechanisms of reduced degradation or excessive synthesis of connective tissue components. This manuscript describes the cellular and molecular factors involved in the epithelial-mesenchymal transition and extracellular matrix remodeling triggered by agents producing DIGO.

PMID:36982523 | DOI:10.3390/ijms24065448

Cancers (Basel). 2023 Mar 14;15(6):1766. doi: 10.3390/cancers15061766.

ABSTRACT

Small molecule protein kinase inhibitors (PKIs) have become an effective strategy for cancer patients. However, hepatotoxicity is a major safety concern of these drugs, since the majority are reported to increase transaminases, and few of them (Idelalisib, Lapatinib, Pazopanib, Pexidartinib, Ponatinib, Regorafenib, Sunitinib) have a boxed label warning. The exact rate of PKI-induced hepatoxicity is not well defined due to the fact that the majority of data arise from pre-registration or registration trials on fairly selected patients, and the post-marketing data are often based only on the most severe described cases, whereas most real practice studies do not include drug-related hepatotoxicity as an end point. Although these side effects are usually reversible by dose adjustment or therapy suspension, or by switching to an alternative PKI, and fatality is uncommon, all patients undergoing PKIs should be carefully pre-evaluated and monitored. The management of this complication requires an individually tailored reappraisal of the risk/benefit ratio, especially in patients who are responding to therapy. This review reports the currently available data on the risk and management of hepatotoxicity of all the approved PKIs.

PMID:36980652 | DOI:10.3390/cancers15061766

Biomedicines. 2023 Mar 6;11(3):798. doi: 10.3390/biomedicines11030798.

ABSTRACT

Atherosclerosis-related coronary artery disease (CAD) is the leading cause of mortality and morbidity worldwide. This requires effective primary and secondary prevention in reducing the complications related to CAD; the regression or stabilization of the pathology remains the mainstay of treatment. Statins have proved to be the most effective treatment in reducing adverse effects, but there are limitations related to the administration and achievement of effective doses as well as side effects due to the lack of target-related molecular specificity. The implemented technological steps are polymers and nanoparticles for the administration of statins, as it has been seen how the conjugation of drug delivery systems (DDSs) with statins increases bioavailability by circumventing the hepatic-renal filter and increases the related target specificity, enhancing their action and decreasing side effects. Reduction of endothelial dysfunction, reduced intimal hyperplasia, reduced ischemia-reperfusion injury, cardiac regeneration, positive remodeling in the extracellular matrix, reduced neointimal growth, and increased reendothelialization are all drug-related effects of statins enhanced by binding with DDSs. Recent preclinical studies demonstrate how the effect of statins stimulates the differentiation of endogenous cardiac stem cells. Poly-lactic-co-glycolic acid (PLGA) seems to be the most promising DDS as it succeeds more than the others in enhancing the effect of the bound drug. This review intends to summarize the current evidence on polymers and nanoparticles for statin delivery in the field of cardiovascular disease, trying to shed light on this topic and identify new avenues for future studies.

PMID:36979777 | DOI:10.3390/biomedicines11030798

Biomolecules. 2023 Feb 21;13(3):405. doi: 10.3390/biom13030405.

ABSTRACT

Drug abuse is a worldwide problem that leads to negative physical, mental, and economic consequences. Although pharmacological strategies for drug addiction management have been widely studied, therapeutic options with high efficacy and a low side-effects profile are still limited. Recently, there has been a growing interest in oxytocin (OT) and vasopressin (AVP) systems as potential therapeutic targets for the treatment of drug abuse. OT and AVP are hypothalamic neuropeptides involved in numerous physiological processes. Additionally, studies show that these neurohormones are highly implicated in the modulation of a wide range of behaviors. Interestingly, ample evidence has shown that both, OT and AVP are able to decrease the consumption of different drugs of abuse, as well as to ameliorate their rewarding and reinforcing effects. Furthermore, OT and AVP have been strongly involved in prosocial effects and social reward. In particular, OT has been shown to be able to shift drug-induced reward into social-induced reward, mainly due to its interaction with the dopaminergic system. This phenomenon is also reflected in the results of clinical trials where intranasal OT shows promising efficacy in managing substance use disorder. Therefore, the aim of this review is to comprehensively characterize the involvement of OT and AVP in the rewarding and other behavioral effects of drugs of abuse in animal models, with a particular highlight on the impact of social factors on the observed effects. Understanding this relationship may contribute to higher drug development success rates, as a result of a more profound and deliberate studies design.

PMID:36979340 | DOI:10.3390/biom13030405

Drug Des Devel Ther. 2023 Mar 21;17:851-861. doi: 10.2147/DDDT.S402362. eCollection 2023.

ABSTRACT

Tapentadol is an analgesic compound that acts centrally to attenuate pain. Previous studies have shown that tapentadol has dual mechanisms of action as a mu-opioid receptor agonist and noradrenaline re-uptake inhibition. Therefore, tapentadol provides a great advantage over classic opioids in pain management from nociceptive to neuropathic. Cumulative evidence from in vitro data suggests that tapentadol effect of norepinephrine re-uptake could be a new target that overcomes other classic opioids in chronic neuropathic pain. Compared to tramadol and other opioids, tapentadol is associated with fewer adverse effects than tramadol. Tapentadol is a new alternative to treat acute, chronic, and neuropathic pain. Thus, this review article was focused on understanding the studies that led to the development of tapentadol as a novel analgesic drug and its advantages over conventional opioids. Thus, tapentadol is a good alternative with fewer adverse effects and is available for human use.

PMID:36974332 | PMC:PMC10039632 | DOI:10.2147/DDDT.S402362

Hypertens Res. 2023 Mar 28. doi: 10.1038/s41440-023-01260-8. Online ahead of print.

ABSTRACT

Although renin-angiotensin system (RAS) inhibitors reduce the risk of cardiovascular diseases and end-stage kidney disease (ESKD) in chronic kidney disease (CKD) patients, they are often discontinued in clinical practice due to drug-related adverse events. However, limited evidence is available about the clinical impact of RAS inhibitor discontinuation in CKD patients. A comprehensive search of publications investigating the effect of discontinuing RAS inhibitors on clinical outcomes in CKD patients in PubMed, the Cochrane Library, and Web of Science was conducted (inception to November 7, 2022), and potentially relevant studies were searched by hand (through November 30, 2022). Two reviewers independently extracted data according to the PRISMA and MOOSE guidelines and assessed the quality of each study with risk-of-bias tools, RoB2 and ROBINS-I. The pooled hazard ratio (HR) for each outcome was integrated with a random-effect model. A total of 1 randomized clinical trial and 6 observational studies involving 248,963 patients were included in the systematic review. The meta-analysis of observational studies showed that discontinuation of RAS inhibitors was associated with a higher risk of all-cause mortality (HR, 1.41 [95% CI, 1.23-1.62]; I2 = 97%), ESKD (1.32 [95% CI, 1.10-1.57]; I2 = 94%) and MACE (1.20 [95% CI 1.15-1.25]; I2 = 38%), but not with hyperkalemia (0.79 [95% CI 0.55-1.15]; I2 = 90%). Overall risk of bias was moderate-to-serious, and quality of evidence (GRADE system) was low-to-very low. The present study suggests that CKD patients would benefit from continuing RAS inhibitors.

PMID:36977900 | DOI:10.1038/s41440-023-01260-8

Int J Clin Pharm. 2023 Mar 28. doi: 10.1007/s11096-023-01564-2. Online ahead of print.

ABSTRACT

BACKGROUND: Antiepileptic drugs may cause delirium, and the risk may vary with each drug. However, related studies have provided inconsistent results.

AIM: The aim of this study was to investigate whether the use of antiepileptic drugs is a risk factor for delirium development.

METHOD: Using the Japanese Adverse Drug Event Report database, we analysed 573,316 reports pertaining to the period from 2004 to 2020. Reporting odds ratios and 95% confidence intervals of delirium associated with use of antiepileptic drugs were calculated after adjusting for potential confounders. Furthermore, for each antiepileptic drug, we performed an analysis stratified based on older age and benzodiazepine receptor agonist usage.

RESULTS: There were 27,439 reports of antiepileptic drug-related adverse events. Of these, 191 reports were associated with antiepileptic drugs and delirium (crude reporting odds ratio [cROR], 1.66; 95% confidence interval [CI], 1.43-1.93). The use of lacosamide (adjusted reporting odds ratio [aROR], 2.44; 95% CI, 1.24-4.80), lamotrigine (aROR, 1.54; 95% CI, 1.05-2.26), levetiracetam (aROR, 1.91; 95% CI, 1.35-2.71), and valproic acid (aROR, 1.49; 95% CI, 1.16-1.91) was related to a significantly higher reporting odds ratio for delirium, even after adjustment for possible confounding factors. However, when used in combination with benzodiazepine receptor agonists, none of the antiepileptic drugs were found to be associated with delirium.

CONCLUSION: Our study's findings suggest that antiepileptic drug usage may be associated with delirium development.

PMID:36977859 | DOI:10.1007/s11096-023-01564-2

Diabetes Obes Metab. 2023 Mar 27. doi: 10.1111/dom.15064. Online ahead of print.

ABSTRACT

AIM: To report a Phase I study of subcutaneous glucagon receptor (GCGR)/glucagon-like peptide 1 receptor (GLP-1R) dual agonist BI 456906 versus placebo in healthy Japanese men with overweight/obesity.

MATERIALS AND METHODS: We investigated multiple rising doses of BI 456906 escalated over 16 weeks (maximum doses: 1.8 mg once weekly [qw; dose group (DG) 1], 4.8 mg qw [DG 2] and 2.4 mg twice weekly [DG 3]) in Japanese men with a body mass index of 23-40 kg/m2 .

RESULTS: Thirty-six participants were treated (n=9 per DG and placebo). Overall, 10 participants (37.0%) treated with BI 456906 withdrew from dose escalation; all due to adverse events (amylase increase, n=1; decreased appetite, n=9), and the proportion of participants was higher in DG 2 (n=6, 66.7%) versus DGs 1 and 3 (both n=2, 22.2%). No participants receiving placebo withdrew from dose escalation. BI 456906 exposure increased with dose and dose escalation in each DG. Treatment with BI 456906 decreased placebo-corrected bodyweight after 16 weeks (placebo +1.06%): DG 1, -5.57%; DG 2, -12.37%; DG 3, -9.62%. Paracetamol absorption decreased in Week 1 for DGs 2 and 3, indicating transient delayed gastric emptying. BI 456906 reduced plasma alanine and glucagon levels, indicating indirect target engagement at GCGRs and GLP-1Rs. Drug-related adverse events were reported for all participants receiving BI 456906 and four receiving placebo; most frequently decreased appetite (n=24, 66.7%).

CONCLUSIONS: BI 456906 showed no unexpected tolerability concerns and reduced placebo-corrected bodyweight by up to 12.37% in Japanese men with overweight/obesity after 16 weeks' treatment. This article is protected by copyright. All rights reserved.

PMID:36974349 | DOI:10.1111/dom.15064

Br J Haematol. 2023 Mar 27. doi: 10.1111/bjh.18772. Online ahead of print.

ABSTRACT

Lenalidomide maintenance in myeloma is well established. Nevertheless, pomalidomide could provide an alternative. Myeloma patients in first relapse, initially treated in the Intergroupe Francophone du Myélome (IFM) 2009 trial, and subsequently in the IFM 2013-01 phase 2 trial, received four cycles of salvage therapy with pomalidomide plus cyclophosphamide plus dexamethasone (PCD) with transplantation plus 2 PCD consolidation or without transplantation but with 5 PCD and for all patients pomalidomide plus dexamethasone maintenance therapy. This consisted of 28-day cycles of pomalidomide 4 mg daily on days 1-21 and dexamethasone 20 mg weekly until progression. The primary endpoint was an improved response to treatment. A total of 75/100 patients reached therapy. The median follow-up time was 73 months. The median duration of treatment was 23.7 months. One third of patients improved their response from the initiation of treatment: 11%, 19% and 4% to a very good partial response, complete response or stringent complete response respectively. The median progression-free survival time was 33.2 months and the median overall survival time was not reached. Among the 75 patients, the reasons for pomalidomide discontinuation were progressive disease (54%), adverse events (AEs) (30%), investigator discretion (11%) and consent withdrawal (5%). Grade (G) 3/4 haematological AEs included neutropenia (51%) and lymphopenia (35%); G3/4 drug-related non-haematological AEs (>5%) comprised 13% infections. Long-term administration of pomalidomide and dexamethasone is feasible and one third of the patients improved their response.

PMID:36974007 | DOI:10.1111/bjh.18772

BMC Med Res Methodol. 2023 Mar 27;23(1):71. doi: 10.1186/s12874-023-01885-w.

ABSTRACT

BACKGROUND: Drug toxicity does not affect patients equally; the toxicity may only exert in patients who possess certain attributes of susceptibility to specific drug properties (i.e., drug-host interaction). This concept is crucial for personalized drug safety but remains under-studied, primarily due to methodological challenges and limited data availability. By monitoring a large volume of adverse event reports in the postmarket stage, spontaneous adverse event reporting systems provide an unparalleled resource of information for adverse events and could be utilized to explore risk disparities of specific adverse events by age, sex, and other host factors. However, well-formulated statistical methods to formally address such risk disparities are currently lacking.

METHODS: In this paper, we present a statistical framework to explore spontaneous adverse event reporting databases for drug-host interactions and detect risk disparities in adverse drug events by various host factors, adapting methods for safety signal detection. We proposed four different methods, including likelihood ratio test, normal approximation test, and two tests using subgroup ratios. We applied our proposed methods to simulated data and Food and Drug Administration (FDA) Adverse Event Reporting Systems (FAERS) and explored sex-/age-disparities in reported liver events associated with specific drug classes.

RESULTS: The simulation result demonstrates that two tests (likelihood ratio, normal approximation) can detect disparities in adverse drug events associated with host factors while controlling the family wise error rate. Application to real data on drug liver toxicity shows that the proposed method can be used to detect drugs with unusually high level of disparity regarding a host factor (sex or age) for liver toxicity or to determine whether an adverse event demonstrates a significant unbalance regarding the host factor relative to other events for the drug.

CONCLUSION: Though spontaneous adverse event reporting databases require careful data processing and inference, the sheer size of the databases with diverse data from different countries provides unique resources for exploring various questions for drug safety that are otherwise impossible to address. Our proposed methods can be used to facilitate future investigation on drug-host interactions in drug toxicity using a large number of reported adverse events.

PMID:36973693 | DOI:10.1186/s12874-023-01885-w