Pharmacotherapy. 2023 Dec 4. doi: 10.1002/phar.2897. Online ahead of print.

ABSTRACT

Concomitant pain syndromes and cardiovascular disease (CVD) and disorders are associated with significant morbidity, impaired quality of life, and neuropsychiatric disorders. There is an interplay between the mechanisms of pathophysiology of both CVD and pain syndromes. Patients with CVD (and/or disorders) as well as pain syndromes have an increased propensity for drug-drug/disease interactions. Therefore, an understanding of how to use pharmacotherapy to treat pain syndromes, in the context of patients who have diagnoses of CVD and/or disorders, is paramount to patients' success in achieving adequate pain control and appropriately managing CVD and/or disorders, all while decreasing the risk of adverse events (AEs) both from pharmacotherapy to treat pain and CVD (and/or disorders). Based on the appraisal of literature and authors' clinical expertise, it was determined that gabapentinoids, opioids, skeletal muscle relaxants, tricyclic antidepressants, clonidine, serotonin norepinephrine-reuptake inhibitors, dronabinol, carbamazepine, second generation antipsychotics, non-steroidal anti-inflammatory drugs, aspirin, corticosteroids, and topical anesthetics have the most evidence with use in patients with CVD and/or disorders. However, the literature surrounding the use of pharmacotherapy for pain management are limited to retrospective studies and there is a lack of well-designed, prospective, randomized trials; this also included head-to-head comparator studies. Unlike many CVD-related pharmacotherapy studies, data studying pain management in patients with CVD lacks standardized outcomes that are consistent among the pool of data. Overall, the decision of prescribing specific pain management therapies in patients with CVD and/or disorders should include assessment of pain severity, type of pain, drug-drug/disease interactions, adjuvant therapies required, and the risk or presence of AEs.

PMID:38049207 | DOI:10.1002/phar.2897

Epilepsia Open. 2023 Dec 4. doi: 10.1002/epi4.12875. Online ahead of print.

ABSTRACT

OBJECTIVE: To evaluate the pharmacokinetics (PK), safety and tolerability of brivaracetam (BRV) in neonates with repeated electroencephalographic seizures not controlled with previous antiseizure medications (ASMs).

METHODS: Phase 2/3, multicenter, open-label, single-arm study (N01349/NCT03325439) in neonates with repeated electroencephalographic seizures (lasting ≥10 seconds) confirmed by video-electroencephalography, and inadequate seizure control with ≥1 ASMs. A screening period (up to 36 hours) was followed by a 48-hour evaluation period during which patients received 0.5 mg/kg BRV twice daily (b.i.d) intravenously (IV). Patients who benefitted from BRV (investigator's opinion) could continue 0.5 mg/kg b.i.d (IV or oral solution) in an extension period. Outcomes included plasma concentrations of BRV following the first dose (primary), and incidence of treatment-emergent adverse events (TEAEs).

RESULTS: Six patients (median [range] postnatal age: 1.5 [1.0, 6.0] days) received ≥1 dose of BRV. All 6 patients completed the evaluation period; 2 entered and completed the extension period. Overall (evaluation and extension periods), 3 patients received 1 dose of 0.5 mg/kg BRV and 3 received >1 dose. The median (range) duration of exposure to BRV (IV and oral solution) was 1.5 (1.0, 29.0) days (n=6). At 0.5-1, 2-4, and 8-12 hours following IV BRV administration, the GeoMean (GeoCV) plasma concentrations of BRV were 0.53 mg/L (15.40% [n=5]), 0.50 mg/L (28.20% [n=6]) and 0.34 mg/L (13.20% [n=5]), respectively. Individual and population BRV PK profiles were estimated, and individual PK parameters were calculated using Bayesian feedback. The observed concentrations were consistent with the predicted PK. Three patients experienced 4 TEAEs, none of which were considered related to BRV.

SIGNIFICANCE: BRV plasma concentrations in neonates were consistent with data in older children receiving BRV oral solution, and with data from adults receiving a nominal IV dose of 25 mg twice daily. BRV was well-tolerated, with no drug-related TEAEs reported.

PMID:38049197 | DOI:10.1002/epi4.12875

Front Immunol. 2023 Nov 17;14:1275368. doi: 10.3389/fimmu.2023.1275368. eCollection 2023.

ABSTRACT

INTRODUCTION: Hepatotoxicity induced by immunotherapeutics is an appearing cause for immune-mediated drug-induced liver injury. Such immuno-toxic mechanisms are difficult to assess using current preclinical models and the incidence is too low to detect in clinical trials. As hepatotoxicity is a frequent reason for post-authorisation drug withdrawal, there is an urgent need for immuno-inflammatory in vitro models to assess the hepatotoxic potential of immuno-modulatory drug candidates. We developed several immuno-inflammatory hepatotoxicity test systems based on recombinant human interleukin-2 (aldesleukin).

METHODS: Co-culture models of primary human CD8+ T cells or NK cells with the hepatocyte cell line HepaRG were established and validated with primary human hepatocytes (PHHs). Subsequently, the HepaRG model was refined by increasing complexity by inclusion of monocyte-derived macrophages (MdMs). The main readouts were cytotoxicity, inflammatory mediator release, surface marker expression and specific hepatocyte functions.

RESULTS: We identified CD8+ T cells as possible mediators of aldesleukin-mediated hepatotoxicity, with MdMs being implicated in increased aldesleukin-induced inflammatory effects. In co-cultures of CD8+ T cells with MdMs and HepaRG cells, cytotoxicity was induced at intermediate/high aldesleukin concentrations and perforin was upregulated. A pro-inflammatory milieu was created measured by interleukin-6 (IL-6), c-reactive protein (CRP), interferon gamma (IFN-γ), and monocyte chemoattractant protein-1 (MCP-1) increase. NK cells responded to aldesleukin, however, only minor aldesleukin-induced cytotoxic effects were measured in co-cultures. Results obtained with HepaRG cells and with PHHs were comparable, especially regarding cytotoxicity, but high inter-donor variations limited meaningfulness of the PHH model.

DISCUSSION: The in vitro test systems developed contribute to the understanding of potential key mechanisms in aldesleukin-mediated hepatotoxicity. In addition, they may aid assessment of immune-mediated hepatotoxicity during the development of novel immunotherapeutics.

PMID:38045689 | PMC:PMC10693457 | DOI:10.3389/fimmu.2023.1275368

J Arrhythm. 2023 Oct 3;39(6):928-936. doi: 10.1002/joa3.12936. eCollection 2023 Dec.

ABSTRACT

BACKGROUND: Drug-induced life-threatening ventricular arrhythmias including torsade de pointes (TdP), ventricular tachycardia (VT), and ventricular fibrillation (VF) are serious cardiac side effects. Psychotherapeutic drugs are known to be risk factors for arrhythmias. The aim of this study was to evaluate psychotherapeutic drugs associated with life-threatening ventricular arrhythmias using the Japanese Adverse Drug Event Report (JADER) database.

METHODS: From the JADER database (April 2004 to September 2022), cases of TdP, VT, VF, and QT prolongation in patients taking psychotherapeutic drugs as 'suspected drugs' were extracted. The adjusted reported odds ratio (aROR) was calculated to identify potential drugs involved in combined TdP/VF/VT or combined QT prolongation/TdP.

RESULTS: Of the 4,530,772 cases reported, life-threatening arrhythmia-related adverse events were reported in 1760 cases (QT prolongation 1261, TdP 192, VF 108, VT 199) among 909 patients; 58.9% of patients were female, and the highest incidence was among patients aged 80-89 years (18.6%), followed by patients aged 70-79 years (15.4%). The highest aROR for TdP/VF/VT was found for trazodone (17.1), followed by sulpiride (10.8), haloperidol (9.8), donepezil (9.1), and fluvoxamine (7.9). The highest aROR for QT prolongation/TdP was found for guanfacine (87.8), followed by sultopride (60.1), escitalopram (21.0), trazodone (12.8), and donepezil (9.3).

CONCLUSIONS: This study showed that typical antipsychotics, antidepressants, and antidementia drugs were associated with life-threatening arrhythmia-related adverse events in a Japanese clinical setting. These events were more frequent in women and elderly individuals.

PMID:38045460 | PMC:PMC10692844 | DOI:10.1002/joa3.12936

Front Pharmacol. 2023 Nov 17;14:1204075. doi: 10.3389/fphar.2023.1204075. eCollection 2023.

ABSTRACT

Background: Captisol®-enabled-fosphenytoin sodium (CE-fosphenytoin sodium) injection is a modified formulation of fosphenytoin sodium. Objective: We aim to compare the intravenous and intramuscular bioavailability and safety between CE-fosphenytoin sodium, fosphenytoin sodium (Cerebyx®), and phenytoin sodium (intravenous injection only). Methods: In pivotal study 1, 54 subjects were divided into three sequence groups that receive intravenous injection of 250 mg of phenytoin sodium equivalent (PE), CE-fosphenytoin sodium (T), or fosphenytoin sodium (R1) and 250 mg of phenytoin sodium (R2) in period 1. After a 14-day washout period, 36 subjects were randomized to two treatment sequence groups (T-R1 or R1-T, n = 18 per group) in period 2, in which the subjects who received R2 in period 1 were removed, those who received T in period 1 used R1 (T-R1), while those who previously received R1 used T (R1-T). In pivotal study 2, a single intramuscular dose of T (400 mg PE) or R1 (400 mg PE) was administered according to the individual sequential treatment assignment in each period. There was a washout (14 days) period before receiving the next period study drug. Results: T and R1 have similar pharmacokinetic characteristics regarding total and free phenytoin, showing bioequivalence of both drugs in the intravenous and intramuscular administration. The geometric mean ratio was close to 1 (0.98-1.06). The AUC of total and free phenytoin in subjects who intravenously received T and R1 was very similar to those who received R2, although their Cmax was lower than that of the subjects who received R2. Overall, treatment with T and R1 was safe and well-tolerated, without serious adverse events (SAEs) or grade III adverse events (AEs). With intravenous (i.v.) or intramuscular (i.m.) treatment, the incidence of drug-related AEs using T was similar to that using R1. Treatment with T and R1 had clearly superior tolerability than that with R2. Conclusion: CE-fosphenytoin sodium is a promising substitute for fosphenytoin sodium. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/, CTR20202154 (11 November 2020).

PMID:38044946 | PMC:PMC10691362 | DOI:10.3389/fphar.2023.1204075

Front Pharmacol. 2023 Nov 17;14:1231320. doi: 10.3389/fphar.2023.1231320. eCollection 2023.

ABSTRACT

Objective: While several drugs have been linked to acute pancreatitis (AP), the AP-related risk of most drugs remains unclear. This study investigated the risk factors for drug-induced AP by analyzing a large dataset from the FDA Adverse Event Reporting System (FAERS). Methods: The reporting odds ratios (ROR) were used to assess the reports of drug-induced AP from the first quarter of 2004 to the second quarter of 2022. Single-factor, LASSO, and multi-factor regression analysis were performed to explore drug-related AP-related risk factors. Bonferroni correction was applied for the multiple comparisons performed. Results: A total of 264 drugs associated with AP, including antineoplastic drugs (35/264), antidiabetic drugs (28/264), antibacterial drugs (24/264), immunomodulatory drugs (11/264), antipsychotic drugs (6/264), and other drugs (160/264) were retrieved. Multi-factor analysis showed that males, age 41-54 years old, and 36 drugs, including Tigecycline, were risk factors for drug-related AP. The median time to drug-related AP onset was 31 days (interquartile range [IQR] 7-102 days) and about 75% of adverse events occurred within 100 days. Conclusion: These findings may help clinicians to identify drug-related AP at the early stage and can be used to inform future studies of drug-related AP pathogenesis.

PMID:38044938 | PMC:PMC10690789 | DOI:10.3389/fphar.2023.1231320

Iran J Kidney Dis. 2023 Nov;17(6):294-305.

ABSTRACT

INTRODUCTION: Farnesoid-X-activated receptor (FXR) is considered as an upstream controller which could influence the other key regulatory genes encoding cellular antioxidant defense system.

METHODS: Thirty-five male Wistar rats (240 ± 20 g) were randomly allocated into five groups: 1) control, 2) received gentamicin (100 mg/kg/d) for three days (GM-3d), 3) seven days (GM-7d), 4) 10 days (GM-10d), and 5) 14 consecutive days (GM-14d). Biochemical measurements of BUN and serum creatinine (SCr), histological assessment of renal samples as well as molecular analysis using real-time qRT-PCR were used to investigate the pattern of changes in different levels.

RESULTS: Administration of gentamicin was associated with a significant increase in the BUN and SCr until the 10th day, which then suddenly dropped at the day 14. Meantime, the maximum histological distortion was also seen on the 10th day but in a similar pattern, 14th day was associated with clear improvement. Compared to the control value, the maximum reduction in the mRNA expression of Farnesoid X-activated receptor (FXR), nuclear factor erythroid 2-related factor 2 (Nrf2) and Glutathione cysteine ligase-modulatory subunit (GCLM), occurred at the 3rd and 7th days, respectively. Compared to the control, the mRNA expression of the mentioned genes significantly increased up to day 14. Apart from the 3rd day, the mRNA expression of alpha-glutathione S-transferase (α-GST) and superoxide dismutase (SOD) showed a similar descending and ascending pattern at 7th and 10th days, respectively.

CONCLUSION: The expression of FXR, as an upstream controller gene and its downstream pathways mediated by Nrf2, could play a role in gentamicin-induced nephrotoxicity but the pattern of expression was rather biphasic at the acute phase or the subacute ones. DOI: 10.52547/ijkd.7523.

PMID:38043107

Sr Care Pharm. 2023 Dec 1;38(12):506-523. doi: 10.4140/TCP.n.2023.506.

ABSTRACT

Background Polypharmacy is common among older people and may be associated with adverse drug events (ADEs) and poor health outcomes. Pharmacists are well-positioned to reduce polypharmacy and potentially inappropriate medications. Objective The objective of this narrative review was to summarize the results from randomized-controlled trials that evaluated pharmacist-led interventions with the goal or effect to deprescribe medications in older individuals. Data Sources We searched Medline, Embase, CINAHL Complete, APA PsycInfo, Web of Science Core Collection, and Cochrane Central Register of Controlled Trials. Data Synthesis Of the 25 studies included, the interventions were conducted in nursing facilities (n = 8), outpatient/community dwellings (n = 8), or community pharmacies (n = 9). Interventions were categorized as comprehensive medication reviews (n = 10), comprehensive medication reviews with pharmacist follow-up (n = 11), and educational interventions provided to patients and/or providers (n = 4). Pharmacist-led interventions had a beneficial effect on 22 out of 32 total medication-related outcomes (eg, number of medications, potentially inappropriate medications, or discontinuation). Most (n = 18) studies reported no evidence of an effect for other outcomes such as health care use, mortality, patient-centered outcomes (falls, cognition, function, quality of life), and ADEs. Discussion Interventions led to improvement in 69% of the medication-related outcomes examined across study settings. Five studies measured ADEs with none accounting for adverse drug-withdrawal events. Large well-designed studies that are powered to find an effect on patient-centered outcomes are needed. Conclusion Pharmacist-led interventions had a significant beneficial effect on medication-related outcomes. There was little evidence of benefit on other outcomes.

PMID:38041222 | DOI:10.4140/TCP.n.2023.506

J Clin Pharmacol. 2023 Dec 1. doi: 10.1002/jcph.2389. Online ahead of print.

ABSTRACT

Drug-induced Thrombocytopenia (DIT) deserved both clinical and research attention for the serious clinical consequences and high proportion.The current study aimed to perform a comprehensive pharmacovigilance analysis of DIT reported in the FDA Adverse Event Reporting System (FAERS) database, with a particular focus on drugs associated with Thrombocytopenia events. A disproportionality analysis of DIT was conducted using reports submitted to the FARES from January 2004 to December 2022. The algorithms of Information Component (IC) and Reporting Odds Ratio (ROR) were applied to identify the association between target drugs and DIT events. A total of 15,940,383 cases were gathered in FAERS, 168,657 of which were related to DIT event cases. The top 50 drugs by case number and by signal strength were documented. The top five drugs by case number were lenalidomide (10601 cases), niraparib (3726 cases), ruxolitinib (3624 cases), eltrombopag (3483 cases) and heparin (3478 cases). The top five drugs by signal strength were danaparoid (ROR = 37.61, 95% CI 30.46-46.45), eptifibatide (ROR = 34.75, 95% CI 30.65-39.4), inotersen (ROR = 34.00, 95% CI 29.47-39.23), niraparib (ROR = 30.53, 95% CI 29.42-31.69) and heparin (ROR = 28.84, 95% CI 27.76-29.97). The top 3 involved drug groups were Protein kinase inhibitors, Antimetabolites, and Monoclonal antibodies and antibody-drug conjugates. The current comprehensive pharmacovigilance study identified more drugs associated with thrombocytopenia. While some drugs had been elucidated the mechanisms of DIT, others still required further investigation. This article is protected by copyright. All rights reserved.

PMID:38041205 | DOI:10.1002/jcph.2389

Hepatobiliary Pancreat Dis Int. 2023 Nov 21:S1499-3872(23)00217-5. doi: 10.1016/j.hbpd.2023.11.004. Online ahead of print.

ABSTRACT

BACKGROUND: Cancer-related fatigue (CRF) is a common and debilitating symptom experienced by patients with advanced-stage cancer, especially those undergoing antitumor therapy. This study aimed to evaluate the efficacy and safety of Renshenguben (RSGB) oral solution, a ginseng-based traditional Chinese medicine, in alleviating CRF in patients with advanced hepatocellular carcinoma (HCC) receiving antitumor treatment.

METHODS: In this prospective, open-label, controlled, multicenter study, patients with advanced HCC at BCLC stage C and a brief fatigue inventory (BFI) score of ≥ 4 were enrolled. Participants were assigned to the RSGB group (RSGB, 10 mL twice daily) or the control group (with supportive care). Primary and secondary endpoints were the change in multidimensional fatigue inventory (MFI) score, and BFI and functional assessment of cancer therapy-hepatobiliary (FACT-Hep) scores at weeks 4 and 8 after enrollment. Adverse events (AEs) and toxicities were assessed.

RESULTS: A total of 409 participants were enrolled, with 206 assigned to the RSGB group. At week 4, there was a trend towards improvement, but the differences were not statistically significant. At week 8, the RSGB group exhibited a significantly lower MFI score (P < 0.05) compared to the control group, indicating improved fatigue levels. Additionally, the RSGB group showed significantly greater decrease in BFI and FACT-Hep scores at week 8 (P < 0.05). Subgroup analyses among patients receiving various antitumor treatments showed similar results. Multivariate linear regression analyses revealed that the RSGB group experienced a significantly substantial decrease in MFI, BFI, and FACT-Hep scores at week 8. No serious drug-related AEs or toxicities were observed.

CONCLUSIONS: RSGB oral solution effectively reduced CRF in patients with advanced HCC undergoing antitumor therapy over an eight-week period, with no discernible toxicities. These findings support the potential of RSGB oral solution as an adjunctive treatment for managing CRF in this patient population.

PMID:38040524 | DOI:10.1016/j.hbpd.2023.11.004

Crit Rev Toxicol. 2023 Dec;53(9):521-571. doi: 10.1080/10408444.2023.2270574. Epub 2023 Dec 5.

ABSTRACT

This scoping review provides an overview of publications reporting adverse effects on the intestines of the food additives carrageenan (CGN) (E 407)/processed Eucheuma seaweed (PES) (E 407a) and carboxymethylcellulose (CMC) (E 466). It includes evidence from human, experimental mammal and in vitro research publications, and other evidence. The databases Medline, Embase, Scopus, Web of Science Core Collection, Cochrane Database of Systematic Reviews and Epistemonikos were searched without time limits, in addition to grey literature. The publications retrieved were screened against predefined criteria. From two literature searches, 2572 records were screened, of which 224 records were included, as well as 38 records from grey literature, making a total of 262 included publications, 196 on CGN and 101 on CMC. These publications were coded and analyzed in Eppi-Reviewer and data gaps presented in interactive maps. For CGN, five, 69 and 33 research publications on humans, experimental mammals and in vitro experiments were found, further separated as degraded or native (non-degraded) CGN. For CMC, three human, 20 animal and 14 in vitro research publications were obtained. The most studied adverse effects on the intestines were for both additives inflammation, the gut microbiome, including fermentation, intestinal permeability, and cancer and metabolic effects, and immune effects for CGN. Further studies should focus on native CGN, in the form and molecular weight used as food additive. For both additives, randomized controlled trials of sufficient power and with realistic dietary exposure levels of single additives, performed in persons of all ages, including potentially vulnerable groups, are needed.

PMID:38032203 | DOI:10.1080/10408444.2023.2270574

Adv Exp Med Biol. 2024;1440:163-191. doi: 10.1007/978-3-031-43883-7_9.

ABSTRACT

Oxysterols or cholesterol oxidation products are a class of molecules with the sterol moiety, derived from oxidative reaction of cholesterol through enzymatic and non-enzymatic processes. They are widely reported in animal-origin foods and prove significant involvement in the regulation of cholesterol homeostasis, lipid transport, cellular signaling, and other physiological processes. Reports of oxysterol-mediated cytotoxicity are in abundance and thus consequently implicated in several age-related and lifestyle disorders such as cardiovascular diseases, bone disorders, pancreatic disorders, age-related macular degeneration, cataract, neurodegenerative disorders such as Alzheimer's and Parkinson's disease, and some types of cancers. In this chapter, we attempt to review a selection of physiologically relevant oxysterols, with a focus on their formation, properties, and roles in health and disease, while also delving into the potential of natural and synthetic molecules along with bacterial enzymes for mitigating oxysterol-mediated cell damage.

PMID:38036880 | DOI:10.1007/978-3-031-43883-7_9

Br J Community Nurs. 2023 Dec 2;28(12):611-614. doi: 10.12968/bjcn.2023.28.12.611.

ABSTRACT

As winter draws on it is timely to look at ways in which nurses in the community may be faced with problems, expected and unexpected, when their patients are particularly affected by cold conditions and at the precautions which need to be taken to avoid or lessen adverse effects on their health. As in the case of heat-related risks to health, examined in an earlier article, so too in the case of cold those most at risk are elderly patients and those who are vulnerable due to a pre-existing condition affecting health even in a more clement climate. Cold weather attracts extra legal responsibilities which are examined in this article.

PMID:38032722 | DOI:10.12968/bjcn.2023.28.12.611

Radiol Case Rep. 2023 Nov 14;19(1):442-444. doi: 10.1016/j.radcr.2023.10.064. eCollection 2024 Jan.

ABSTRACT

This case serves as a reminder of the infrequent, yet consequential occurrence of cerebellar degeneration linked to phenytoin usage. Whilst emphasizes the importance of monitoring patients on long-term phenytoin therapy, and it further suggests considering employing bedside imaging tools such as Ultrasound fusion imaging for follow-up of patients at risk of this type of disorder. We present a case study involving a 23-year-old woman who experienced significant neurological impairment resulting in severe cerebellar atrophy while undergoing phenytoin treatment. On cessation of phenytoin, the patient exhibited improvement with enhanced cerebellar function.

PMID:38033670 | PMC:PMC10684371 | DOI:10.1016/j.radcr.2023.10.064

Postgrad Med. 2023 Nov 21:1-19. doi: 10.1080/00325481.2023.2284650. Online ahead of print.

ABSTRACT

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality globally. In the major revision of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2023 report, the scientific committee concluded that the use of long-acting β2-agonist/inhaled corticosteroids (LABA/ICS) is not encouraged in patients with COPD. However, current prescribing patterns reveal significant use of LABA/ICS. In this paper, the evidence behind the current practice and the latest treatment recommendations is reviewed. We compare the efficacy and safety of combination therapy with long-acting muscarinic antagonist (LAMA) and LABA vs LABA/ICS and note that LAMA/LABA combinations have reduced the annual rate of moderate/severe exacerbations, delayed the time to first exacerbation, and increased post-dose FEV1 vs ICS-based regimens. The GOLD 2023 report recommends treatment with LABA and LAMA combination (preferably as a single inhaler) in patients with persistent dyspnea, with initiation of ICS in patients based on the symptoms (dyspnea and exercise intolerance as indicated by modified Medical Research Council [mMRC] score ≥ 2 and COPD Assessment Test [CAT™] > 20), blood eosinophil count (≥ 300 cells/µL), and exacerbation history (history of hospitalizations for exacerbations of COPD and ≥ 2 moderate exacerbations per year despite appropriate long-acting bronchodilator maintenance therapy). We describe practical recommendations for primary care physicians to optimize therapy for their patients and prevent overuse of ICS-based regimens. We advocate adherence to current recommendations and a greater focus on effective treatments to successfully control symptoms, minimize exacerbation risk, preserve lung function, maximize patient outcomes, and reduce the burden of drug-related adverse events.

PMID:38032494 | DOI:10.1080/00325481.2023.2284650

Expert Rev Anticancer Ther. 2023 Nov 30. doi: 10.1080/14737140.2023.2290196. Online ahead of print.

ABSTRACT

INTRODUCTION: Ifosfamide is an alkylating chemotherapeutic agent used in the treatment of various neoplasms. Its main adverse effects include renal damage.

AREAS COVERED: A comprehensive review was conducted, including 100 articles from the Scielo, Scopus, and EMBASE databases. Ifosfamide-induced nephrotoxicity is attributed to its toxic metabolites, such as acrolein and chloroacetaldehyde, which cause mitochondrial damage and oxidative stress in renal tubular cells. Literature review found a 29-year average age with no gender predominance and a mortality of 13%. Currently, no fully effective strategy exists for preventing ifosfamide-induced nephrotoxicity; however, hydration, forced diuresis, and other interventions are employed to limit renal damage. Long-term renal function monitoring is essential for patients treated with ifosfamide.

EXPERT OPINION: Ifosfamide remains essential in neoplasm treatment, but nephrotoxicity, often compounded by coadministered drugs, poses diagnostic challenges. Preventive strategies are lacking, necessitating further research. Identifying timely risk factors can mitigate renal damage, and a multidisciplinary approach manages established nephrotoxicity. Emerging therapies may reduce ifosfamide induced nephrotoxicity.

PMID:38031874 | DOI:10.1080/14737140.2023.2290196

J Eur Acad Dermatol Venereol. 2023 Nov 29. doi: 10.1111/jdv.19643. Online ahead of print.

ABSTRACT

BACKGROUND: Evidence on the (long-term) safety of systemic immunomodulating therapies in atopic dermatitis (AD) generated by real-world data is sparse.

OBJECTIVES: To describe real-world reported adverse drug reactions (AEs) related to systemic immunomodulating therapy in patients with AD and to compare the incidence rates of AEs with the Summaries of Product Characteristics (SmPCs).

METHODS: We conducted an observational prospective multi-centre cohort study, using the TREAT NL registry. All severe AEs, AEs of special interest and serious AEs in adult and paediatric patients on systemic immunomodulating treatment (ciclosporin, methotrexate, azathioprine, mycophenolic acid, dupilumab, tralokinumab, baricitinib and upadacitinib) were assessed. Incidences rates of all (potentially) drug-related AEs were standardized in patient years and compared to the cumulative incidences in the associated SmPCs.

RESULTS: We collected 422 patient years of safety data from 266 patients, of whom 129 (48.5%) reported a total of 224 (potentially) drug-related AEs. Compared to dupilumab's SmPC, higher incidence rates were found for four AEs (reported ≥5 times): eosinophilia, blepharitis, dry eyes and head and neck erythema (i.e. dupilumab facial redness). A higher incidence rate of fatigue was found in patients on oral methotrexate in our cohort compared to the SmPC. Two new drug-related AEs (reported ≥5 times) were found in patients on dupilumab, including non-infectious conjunctivitis and meibomian gland dysfunction.

CONCLUSIONS: Real-world reported AEs captured in AD patient registries can add information on the estimated incidence of AEs and benefit clinical decision aids. Future studies using data derived from the TREAT NL registry combined with data from other registries within the TREAT Registry Taskforce will provide more information on (rare) AEs associated with immunomodulating therapy in AD patients.

PMID:38031478 | DOI:10.1111/jdv.19643

Drug Des Devel Ther. 2023 Nov 15;17:3429-3437. doi: 10.2147/DDDT.S426898. eCollection 2023.

ABSTRACT

Anti-angiogenesis therapy plays a vital role in the treatment of tumors, with anlotinib as its representative targeted drug. Anlotinib is a novel oral tyrosine kinase inhibitor (TKI) with inhibitory effects on tumor growth tumor angiogenesis. In Phase III clinical trials, anlotinib demonstrated better overall survival and progression-free survival than placebo in patients with advanced non-small cell lung cancer (NSCLC), and was approved for the first time as a third-line treatment for refractory advanced NSCLC. Going far beyond that, anlotinib has shown encouraging results in a variety of malignancies, including medullary thyroid carcinoma, renal cell carcinoma, gastric cancer and esophageal squamous cell carcinoma. Nevertheless, anlotinib has been subject to some controversy in terms of adverse events due to its widespread use. In this review, the mechanism of action, pharmacokinetic characteristics, adverse reactions in clinical use and management of anlotinib were summarized.

PMID:38024530 | PMC:PMC10657757 | DOI:10.2147/DDDT.S426898

Asian Pac J Cancer Prev. 2023 Nov 1;24(11):3795-3804. doi: 10.31557/APJCP.2023.24.11.3795.

ABSTRACT

BACKGROUND: Oxidative stress combined with nullity of xenobiotic metabolizing GSTT1/GSTM1/CYP2E1 genes may increase the susceptibility of agricultural workers to adverse health effects including cancer. The present study was conducted to determine; the prevalence of polymorphisms in GSTM1, GSTT1 and CYP2E1 genes, serum 8-hydroxy-2'-deoxygunosine levels, and the role of these markers in risk of cancer among agricultural workers occupationally exposed to pesticides.

METHODS: A total of 360 participants, of which 180 belonging to farming group diagnosed with leukemia (n=60), lymphoma (n=60) and breast cancers (n=60), 90 in non-farming group diagnosed with similar cancers and the other 90 as healthy controls with neither history of occupational exposure nor diagnosed with any type of cancers were recruited. Following the questionnaire survey, serum 8-OHdG and genetic polymorphisms in the three genes were determined using ELISA and PCR methods respectively.

RESULTS: The results of the study revealed that farm workers carrying GSTT1 null genotype had increased risk for lymphoma (OR = 5.34; 95% CI = 1.80-15.82) and breast cancer (OR=4.04; 95% CI = 1.24-13.07). For farm workers carrying GSTM1 null genotype, the risk was six-fold for breast cancer (OR = 6.88; 95% CI =1.88-25.99). Further, there found a significant difference between 8-OHdG and nullity of CYP2E1 among the farm workers diagnosed with leukemia.

CONCLUSION: The findings of the present study suggest that the polymorphisms in detoxifying genes among farm workers occupationally exposed to pesticides and the oxidative stress may likely be responsible for triggering the mechanism of malignancy.

PMID:38019237 | DOI:10.31557/APJCP.2023.24.11.3795

J Int Med Res. 2023 Nov;51(11):3000605231214065. doi: 10.1177/03000605231214065.

ABSTRACT

Adverse drug reactions represent a major health burden because they cause notable patient morbidity and mortality. From this viewpoint, several strategies have been developed to prevent or reduce adverse drug reactions. One such strategy is the use of pharmacogenomics. Interindividual variability in drug response and adverse effects is mainly attributable to genetic variation in enzymes such as sulfotransferases and cytochrome P450s. The current narrative review discusses the relationship between the structure and activity of drugs. Specifically, the activity of drugs can be increased and/or their adverse effects can be reduced by altering specific positions in their structures.

PMID:38019107 | DOI:10.1177/03000605231214065