Fam Pract. 2023 Aug 3:cmad080. doi: 10.1093/fampra/cmad080. Online ahead of print.

ABSTRACT

BACKGROUND: Musculoskeletal corticosteroid injection (CSI) is a frequently used treatment, considered safe with a low incidence of minor side effects.

OBJECTIVE: To investigate whether the incidence of acute coronary syndrome (ACS) is increased following corticosteroid injection for musculoskeletal conditions.

METHODS: Data were reviewed from 41,276 patients aged over 40 years and hospitalised with ACS between January 2015 and December 2019. Each ACS case was allocated up to 10 control patients from their primary care clinic, matched for age and sex. The cases and controls were reviewed for orthopaedic or rheumatological consultation including a CSI procedure and occurring prior to the hospital admission date. The incidence of CSI was compared between the case and control groups.

RESULTS: Data from a total of 413,063 patients were reviewed, 41,276 ACS cases and 371,787 controls. The mean age was 68.1, standard deviation (SD) = 13.1, 69.4% male. In the week prior to their hospital admission, 118 ACS patients were treated with CSI compared with 495 patients in the control group; odds ratio (OR) = 1.95 (1.56-2.43). In total, 98% of CSI procedures were carried out by orthopaedic specialists. An association between ACS and prior CSI was strongest in the days immediately prior to hospitalisation: OR = 3.11 (2.10-4.61) for patients who were injected 1 day before ACS. The association between ACS and CSI declined with increasing time between injection and hospital admission: at 90 days OR = 1.08 (0.98-1.18). The association remained robust when cardiovascular risk factors, history of rheumatological disease, and other co-morbidity were taken into consideration.

CONCLUSIONS: Musculoskeletal corticosteroid injection appears to substantially increase the risk of acute coronary syndrome.

PMID:37535976 | DOI:10.1093/fampra/cmad080

Neurol Res Pract. 2023 Aug 3;5(1):41. doi: 10.1186/s42466-023-00265-5.

ABSTRACT

BACKGROUND: Assessment of quality of life (QoL) has become an important indicator for chronic neurological diseases. While these conditions often limit personal independence and autonomy, they are also associated with treatment-related problems and reduced life expectancy. Epilepsy has a tremendous impact on the QoL of patients and their families, which is often underestimated by practitioners. The aim of this work was to identify relevant factors affecting QoL in adults with epilepsy.

METHODS: This cross-sectional, multicenter study was conducted at four specialized epilepsy centers in Germany. Patients diagnosed with epilepsy completed a standardized questionnaire focusing on QoL and aspects of healthcare in epilepsy. Univariate regression analyses and pairwise comparisons were performed to identify variables of decreased QoL represented by the overall Quality of Life in Epilepsy Inventory (QOLIE-31) score. The variables were then considered in a multivariate regression analysis after multicollinearity analysis.

RESULTS: Complete datasets for the QOLIE-31 were available for 476 patients (279 [58.6%] female, 197 [41.4%] male, mean age 40.3 years [range 18-83 years]). Multivariate regression analysis revealed significant associations between low QoL and a high score on the Liverpool Adverse Events Profile (LAEP; beta=-0.28, p < 0.001), Hospital Anxiety and Depression Scale - depression subscale (HADS-D; beta=-0.27, p < 0.001), Neurological Disorders Depression Inventory in Epilepsy (NDDI-E; beta=-0.19, p < 0.001), revised Epilepsy Stigma Scale (beta=-0.09, p = 0.027), or Seizure Worry Scale (beta=-0.18, p < 0.001) and high seizure frequency (beta = 0.14, p < 0.001).

CONCLUSION: Epilepsy patients had reduced QoL, with a variety of associated factors. In addition to disease severity, as measured by seizure frequency, the patient's tolerability of anti-seizure medications and the presence of depression, stigma, and worry about new seizures were strongly associated with poor QoL. Diagnosed comorbid depression was underrepresented in the cohort; therefore, therapeutic decisions should always consider individual psychobehavioral and disease-specific aspects. Signs of drug-related adverse events, depression, fear, or stigmatization should be actively sought to ensure that patients receive personalized and optimized treatment.

TRIAL REGISTRATION: German Clinical Trials Register (DRKS00022024; Universal Trial Number: U1111-1252-5331).

PMID:37533112 | DOI:10.1186/s42466-023-00265-5

J Vet Sci. 2023 Jul;24(4):e59. doi: 10.4142/jvs.23002.

ABSTRACT

BACKGROUND: Rocuronium bromide has been evaluated as a mydriatic agent in birds, but the species applied were limited and the dose and effect were variable.

OBJECTIVE: This study aims to evaluate the efficacy of topical rocuronium bromide as mydriatics in 4 species according to horizontal palpebral fissure length: Feral pigeon (Columba livia), Common kestrel (Falco tinnunculus), Northern boobook (Ninox japonica), and Eurasian eagle owl (Bubo bubo).

METHODS: A total of 32 birds (8 for each species) were included as pre-releasing examination. Rocuronium bromide was instilled in one randomly selected eye of each bird based on palpebral fissure length criteria (0.5 mg/50 µL for pigeons, 1 mg/100 µL for kestrels and boobook owls, and 2 mg/200 µL for eagle owls). The contralateral eye was used as control and treated with normal saline. After instillation of the drug, pupil diameter, pupillary light reflex, intraocular pressure, heart rate, and respiratory rate were evaluated at 10 min intervals up to 180 min and at 30 min intervals up to 360 min.

RESULTS: Statistically significant mydriasis was obtained in all birds (p < 0.001). However, in boobook and eagle owls, marked mydriasis persisted until 360 min. Side effects including corneal erosion and lower eyelid paralysis were common, which was observed in 26/32 birds. Blepharospasm was also noted during this study. No systemic adverse signs were observed.

CONCLUSIONS: Rocuronium bromide could be a good mydriatics option for 4 species of birds, however, further studies are needed to find lowest effective dose to reduce drug-related side effects.

PMID:37532302 | DOI:10.4142/jvs.23002

JAMA Dermatol. 2023 Aug 2. doi: 10.1001/jamadermatol.2023.2428. Online ahead of print.

ABSTRACT

IMPORTANCE: Dupilumab is a theoretically novel therapy for bullous pemphigoid (BP). However, its effectiveness and safety have yet to be confirmed in a large-scale study.

OBJECTIVE: To assess the efficacy and safety of dupilumab in patients with BP and evaluate factors that potentially affect short-term and long-term outcomes.

DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was conducted from January 1, 2021, to July 31, 2022. The median (IQR) follow-up period was 24.6 (11.5-38.4) weeks. This multicenter study was performed in 6 dermatology departments of the National Autoimmune Bullous Diseases Cooperative Group of China. Adult patients with BP that received 300 mg of dupilumab every 2 weeks following an initial dose of 600 mg were included. Patients were eligible if they had a clinical presentation of BP combined with immunological or pathological evidence. Patients with drug-induced BP, with less than 4 weeks of follow-up, and who received dupilumab or any other biologics within 6 months were excluded.

MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of patients who achieved disease control within 4 weeks. Disease control was defined as the absence of new lesions and pruritus, combined with the healing of existing lesions. Complete remission rates, relapse rates, changes in Bullous Pemphigoid Disease Area Index (BPDAI) scores, itching numerical rating scale (NRS) scores, laboratory results within 64 weeks, and adverse events (AEs) were also assessed.

RESULTS: Among 146 patients (median [IQR] age, 73 [64-85] years; 86 [58.9%] male patients) included in the study, 127 (87.0%) patients achieved disease control within 4 weeks, with a median (IQR) time of 14 (7-14) days. A total of 52 (35.6%) patients achieved complete remission, and 13 (8.9%) patients relapsed during the observation period. The complete remission rate and cumulative relapse rate at week 64 were 62.5% (5 of 8) and 30.9%, respectively. There was rapid and sustained improvement in clinical indicators and laboratory examination results after dupilumab treatment, including BPDAI scores, itching NRS scores, serum anti-BP180 and anti-BP230 antibodies, total IgE levels, and eosinophil count. Of these 146 patients, 107 (73.3%) did not report any AEs. The most common AEs were infections and eosinophilia. Serum anti-BP180 antibody levels of greater than 50 relative units (RU)/mL (OR, 3.63; 95% CI, 0.97-12.61; P = .045) were associated with 4-week disease control, and male patients were more likely to relapse (HR, 10.97; 95% CI, 1.42-84.92; P = .02).

CONCLUSIONS AND RELEVANCE: In this retrospective cohort study, dupilumab treatment was associated with improved clinical symptoms in patients with BP. The safety profile was favorable, although concurrent infection and eosinophilia might pose potential concerns. This study suggests that patients with anti-BP180 antibody levels of at least 50 RU/mL and female sex may respond better.

PMID:37531116 | DOI:10.1001/jamadermatol.2023.2428

Immunotherapy. 2023 Sep;15(13):993-999. doi: 10.2217/imt-2022-0213. Epub 2023 Jul 31.

ABSTRACT

The overall survival of melanoma patients has improved using antibodies targeting immune checkpoints (anti-PD-1, anti-CTLA-4 and anti-LAG-3). Systemic chemotherapy was administered in melanoma for many years with limited effectiveness. Here we report a case of a patient who experienced immune-mediated adverse effects from checkpoint blockade therapy and subsequently responded to chemotherapy. The patient presented with melanoma and paraneoplastic digital ischemia. She received a combination of ipilimumab/nivolumab and experienced G3 myocarditis, followed by melanoma progression after a steroid taper. This patient achieved a partial and durable response with platinum and taxane-based chemotherapy. This report suggests the possibility of a subset of patients who experience progression after immune-based side effects where chemotherapy may be effective in the modern age of melanoma treatment.

PMID:37525573 | DOI:10.2217/imt-2022-0213

BMC Med Educ. 2023 Aug 1;23(1):547. doi: 10.1186/s12909-023-04542-4.

ABSTRACT

OBJECTIVES: To compare the pediatric neurologists' knowledge, practice, and barriers to the pharmacovigilance (PV) process in Poland and Germany.

METHODS: The research tool was an online anonymous questionnaire on Google Forms e-mailed to pediatric neurologists from Poland and Germany.

RESULTS: The questionnaires were handed out to 830 pediatric neurologists and 371 expressed their consent to participate in the study. Most of the neurologists were familiar with the definition of PV and adverse drug reactions (ADRs). Only 34.10% of pediatric neurologists from Poland, and 38.88% from Germany believe that many ADRs are preventable and almost most of them believe it is necessary to report ADRs from children with epilepsy. Unfortunately, in opposite to this knowledge, only 37.79% of respondents from Poland and 40.32% from Germany felt co-responsible for reporting ADRs. The main reason for the neurologists not to report ADRs was a conviction that reporting ADRs would be an additional burden generating extra work.

CONCLUSION: There is no big difference between the practice of PV by pediatric neurologists in Poland and Germany. System-regulated PV stabilization in the country translates into the practice of maintaining PV. Monitoring the safety of pharmacotherapy and knowledge of risks associated with ADRs should be included in the curricula of academic neurologics courses.

PMID:37528387 | PMC:PMC10394771 | DOI:10.1186/s12909-023-04542-4

J Korean Med Sci. 2023 Jul 31;38(30):e234. doi: 10.3346/jkms.2023.38.e234.

ABSTRACT

BACKGROUND: This study characterized coronavirus disease 2019 (COVID-19) vaccination behavior in the Korean general population using cluster analysis and explored related psychological factors.

METHODS: We categorized 1,500 individuals based on their attitudes toward COVID-19 vaccination using hierarchical clustering and identified their level of vaccine acceptance. We examined the associations between vaccine acceptance and behavioral and psychological characteristics.

RESULTS: Clustering revealed three groups according to vaccine acceptance: 'totally accepting' (n = 354, 23.6%), 'somewhat accepting' (n = 523, 34.9%), and 'reluctant' (n = 623, 41.5%). Approximately 60% of all participants who belonged to the 'totally accepting' and 'somewhat accepting' groups were willing to receive a COVID-19 vaccine despite concerns about its side effects. High vaccine acceptance was associated with older age, regular influenza vaccination, and trust in formal sources of information. Participants with high vaccine acceptance had higher levels of gratitude, extraversion, agreeableness, and conscientiousness, and lower levels of depression, anxiety, and neuroticism.

CONCLUSIONS: People weighed the benefits of COVID-19 vaccination against the risk of side effects when deciding to receive the COVID-19 vaccine. Our findings also indicate that this vaccination behavior may be affected by coping mechanisms and psychological factors.

PMID:37527911 | PMC:PMC10396430 | DOI:10.3346/jkms.2023.38.e234

Ann Med. 2023;55(2):2242248. doi: 10.1080/07853890.2023.2242248.

ABSTRACT

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly utilized to reduce pain, inflammation, and fever. This study aimed to assess patterns of use and awareness of NSAID-related side-effects in an adult Jordanian. And the associations with sociodemographic factors. Methods: This cross-sectional study among a representative sample of 604 adults >18 years. A validated, self-administered questionnaire was used to collect basic sociodemographic data from the participants, as well as information regarding NSAID use. Results: Most respondents were NSAID users (65.7%), female (53.4%) and under 50 years of age (74.5%). Overall, 42.6% had been prescribed NSAIDs by a physician. Male gender and smoking were negatively correlated with NSAIDs use (multivariable odds ratio [OR]: 0.5, 95% confidence interval [CI]: 0.4-0.8, p = 0.001 and OR: 0.6, 95% CI 0.4-0.8, p = 0.003). In contrast, the Ministry of Health Insurance was associated with NSAIDs use with OR: 1.6, 95% CI: 1.1-2.6, p = 0.03. Overall, 65.1% were aware of kidney NSAID-related side-effects and 22.4% were aware of the increased risk of asthma and allergy. Conclusion: Despite the high frequency of NSAID use in the Jordanian general population, there is limited knowledge of their side-effects as well as drug interactions. This is cause for concern, particularly as many participants reported having been prescribed NSAIDs by physicians without adequate patient safety education.

PMID:37527416 | DOI:10.1080/07853890.2023.2242248

Geriatr Psychol Neuropsychiatr Vieil. 2023 Jun 1;21(2):214-220. doi: 10.1684/pnv.2023.1103.

ABSTRACT

INTRODUCTION: Inappropriate drug prescriptions (IP) lead to a high risk of adverse effects, especially for the elderly. Their detection is essential - which can be done using therapeutic lists, including the Stopp/Start scale version 2.

METHODS: Observational study - from August 1, 2016, to November 30, 2016, in an advanced geriatric unit at Rouen University Hospital - using the Stopp/Start version 2 list.

RESULTS: Eighty-five patients were included, with a ratio of 1.36 women per every man. Sixty-one patients (71.8%) had prescriptions for more than five drugs. The average Charlson comorbidity score was 6.05. One hundred ninety-one IPs were found. Classes E and G (kidney function and respiratory system prescriptions, respectively) were not uncovered. Fifty-four Stopp criteria - 66% of Stopp criteria - never emerged during our study. Using the 34 Start criteria, 187 omissions of prescriptions were found. Classes F and G (endocrine system and urogenital system drugs, respectively) were not observed at any time. Ten criteria were never seen (B3/C1/C4/C5/E6/E7/F1/G1/G2/G3). Nineteen criteria were mentioned less than three times - i.e., in approximately 10% of omissions.

CONCLUSION: Our study is part of an approach to protecting the elderly. A significant number of IP and prescription drug omissions were uncovered using this Stopp/Start version 2 tool.

PMID:37519079 | DOI:10.1684/pnv.2023.1103

Syst Rev. 2023 Jul 31;12(1):131. doi: 10.1186/s13643-023-02289-z.

ABSTRACT

BACKGROUND: Overviews (i.e., systematic reviews of systematic reviews, meta-reviews, umbrella reviews) are a relatively new type of evidence synthesis. Among others, one reason to conduct an overview is to investigate adverse events (AEs) associated with a healthcare intervention. Overviews aim to provide easily accessible information for healthcare decision-makers including clinicians. We aimed to evaluate the clinical utility of overviews investigating AEs.

METHODS: We used a sample of 27 overviews exclusively investigating drug-related adverse events published until 2021 identified in a prior project. We defined clinical utility as the extent to which overviews are perceived to be useful in clinical practice. Each included overview was assigned to one of seven pharmacological experts with expertise on the topic of the overview. The clinical utility and value of these overviews were determined using a self-developed assessment tool. This included four open-ended questions and a ranking of three clinical utility statements completed by clinicians. We calculated frequencies for the ranked clinical utility statements and coded the answers to the open-ended questions using an inductive approach.

RESULTS: The overall agreement with the provided statements was high. According to the assessments, 67% of the included overviews generated new knowledge. In 93% of the assessments, the overviews were found to add value to the existing literature. The overviews were rated as more useful than the individual included systematic reviews (SRs) in 85% of the assessments. The answers to the open-ended questions revealed two key aspects of clinical utility in the included overviews. Firstly, it was considered useful that they provide a summary of available evidence (e.g., along with additional assessments, or across different populations, or in different settings that have not been evaluated together in the included SRs). Secondly, it was found useful if overviews conducted a new meta-analysis to answer specific research questions that had not been answered previously.

CONCLUSIONS: Overviews on drug-related AEs are considered valuable for clinical practice by clinicians. They can make available evidence on AEs more accessible and provide a comprehensive view of available evidence. As the role of overviews evolves, investigations such as this can identify areas of value.

PMID:37525235 | DOI:10.1186/s13643-023-02289-z

Georgian Med News. 2023 Jun;(339):105-112.

ABSTRACT

Immunotherapy causes cancer patients' immune systems to activate in search of and eliminate cancer cells. As a therapeutic area for cancer, it has expanded in importance and demonstrated promising results in treating many cancers. Checkpoint blockade (CPB) therapy may stimulate a suppressed immune response to provide long-lasting therapeutic results. However, the absence of a tumor-reactive immune infiltration is probably why response rates are still low. Using chimeric antigen receptor (CAR)-modified T cells to fight cancer may significantly impact immunology. This study explored using checkpoint inhibitors, car-T cells, and vaccines in immunotherapy to treat cancers. Drugs used for CPB aim to reduce immunological suppression, allowing for more effective CAR T cells and dendritic cell (DC) vaccines, providing some optimism that this may be increased, both of which have proven therapeutic efficacy in specific cancers. However, drug-induced side effects and the tumor microenvironment's propensity for immunosuppression mean treatment effectiveness is still inadequate. The outcomes of current preclinical tests suggest that novel therapies targeting lymphocyte-activation gene 3 (LAG3), T cell immunoglobulin and mucin-domain containing-3 (TIM3), cytotoxic T lymphocyte-associated protein 4 (CTLA-4), and programmed cell death protein 1 (PD-1) could be used as adjuvant therapies to modify the tumor microenvironment.

PMID:37522784

Ann Pharmacother. 2023 Jul 31:10600280231189897. doi: 10.1177/10600280231189897. Online ahead of print.

ABSTRACT

BACKGROUND: Drug-induced immune hemolytic anemia (DIIHA) is a rare but potentially life-threatening pharmacogenic hematological adverse effect. Updating the risk of DIIHA among the currently available drugs based on spontaneously reported adverse event data is of great significance.

OBJECTIVE: This study aimed to identify the top 50 drugs associated with immune hemolytic anemia in adults as well as common drugs that could cause immune hemolytic anemia in children based on the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database.

METHODS: We extracted adverse events (AE) in the FAERS database from Q1 2004 to Q3 2022 using Open vigil2.1. We use the high-level term "anaemias haemolytic immune" according to the Medical Dictionary for Regulatory Activities (MedDRA) Dictionary (version 24.0). The reported correlation between drugs and DIIHA risk was identified by reported odds ratio (ROR) and proportional reporting ratio (PRR).

RESULTS: There were 10500309 AEs in FAERS from 2004Q1 to 2022Q3, of which 2326 (0.02%) were DIIHA cases. The incidence of DIIHA is comparable between males and females. The most common drugs associated with DIIHA in adults and children are summarized according to the number of AE reports. The top 3 categories in terms of quantity of drugs are antineoplastic agents, immunosuppressants, and antibiotics for systemic use. The top 5 drugs in terms of ROR and PRR are alemtuzumab, daclizumab, fludarabine, busulfan, and bendamustine in adults, with entecavir, treosulfan, vinorelbine, pegademase, and alemtuzumab for children.

CONCLUSIONS: Our study identified the most common drugs that could induce DIIHA in adults and children, as well as the respective ROR and PRR value to discover new drug signals. This study provides references to clinicians for the management of rare DIIHA.

PMID:37522435 | DOI:10.1177/10600280231189897

Support Care Cancer. 2023 Jul 29;31(8):498. doi: 10.1007/s00520-023-07965-3.

ABSTRACT

PURPOSES: In patients with advanced lung cancer, immune checkpoint inhibitors (ICIs) dramatically extended survival. We aimed to investigate the experiences of patients with advanced lung cancer who are receiving ICIs, with a focus on perceptions and sentiments on ICIs, to inform future research and clinical care.

METHODS: Patients were recruited from January to July 2022 at Tianjin Medical University Hospital Cancer Institute & Hospital. The method of purposive sampling was used. Patients with stage IV lung cancer who were taking ICIs as a single therapy were recruited. Data were gathered using semi-structured and face-to-face interview. An inductive approach to analysis was used.

RESULTS: Of the 42 eligible patients, 27 were invited, 20 agreed to participate, and ultimately 17 patients completed the interview. A total of 5 themes were extracted: suffered from adverse effects but generally tolerable; focus on survival, hope, and expectation; uncertainty about durability of response and the future; poor knowledge and attitude of ICIs; and financial stress and guilt over family.

CONCLUSION: These findings make an important contribution to healthcare professionals' understanding of what it is like to be a patient with advanced lung cancer who is receiving ICIs. In general, the experience of immunotherapy is different from that of chemotherapy; financial and family pressures and uncertainty issues are likely to be heavier in this population. Oncology specialist nurses should provide tailored education to improve the patient's knowledge of immunotherapy, especially to improve risk awareness of immune-related adverse events and objective prognosis expectations.

PMID:37515629 | DOI:10.1007/s00520-023-07965-3

Medicina (Kaunas). 2023 Jul 12;59(7):1286. doi: 10.3390/medicina59071286.

ABSTRACT

Background and Objectives: Magnetic stimulation is a type of conservative treatment of urinary incontinence. Our aim was to evaluate the possible side effects of this method. Materials and Methods: We conducted a systematic literature review. The key search terms were urinary incontinence, magnetic stimulation, and female. All known synonyms were used. Results: 255 titles and abstracts were retrieved, and 28 articles met our inclusion criteria. Out of 28 studies, 15 reported no side effects, five reported side effects, and eight did not report anything. There was no significant difference in the incidence of side effects between the sham and active treatment groups. Conclusions: Side effects of magnetic stimulation in comparison to other active treatments are minimal and transient. Among the conservative UI treatment methods, magnetic stimulation is one of the safest methods for the patient and as such a suitable first step in treating UI.

PMID:37512097 | PMC:PMC10383588 | DOI:10.3390/medicina59071286

Int J Mol Sci. 2023 Jul 20;24(14):11694. doi: 10.3390/ijms241411694.

ABSTRACT

Atezolizumab is an immune checkpoint inhibitor (ICI) targeting PD-L1 for treatment of solid malignancies. Immune checkpoints control the immune tolerance, and the adverse events such as hepatotoxicity induced by ICIs are often considered as an immune-related adverse event (irAE). However, PD-L1 is also highly expressed in normal tissues, e.g., hepatocytes. It is still not clear whether, targeting PD-L1 on hepatocytes, the atezolizumab may cause damage to liver cells contributing to hepatotoxicity. Here, we reveal a novel mechanism by which the atezolizumab induces hepatotoxicity in human hepatocytes. We find that the atezolizumab treatment increases a release of LDH in the cell culture medium of human hepatocytes (human primary hepatocytes and THLE-2 cells), decreases cell viability, and inhibits the THLE-2 and THLE-3 cell growth. We demonstrate that both the atezolizumab and the conditioned medium (T-CM) derived from activated T cells can induce necroptosis of the THLE-2 cells, which is underscored by the fact that the atezolizumab and T-CM enhance the phosphorylation of RIP3 and MLKL proteins. Furthermore, we also show that necrostatin-1, a necrosome inhibitor, decreases the amount of phosphorylated RIP3 induced by the atezolizumab, resulting in a reduced LDH release in the culture media of the THLE-2 cells. This finding is further supported by the data that GSK872 (a RIP3 inhibitor) significantly reduced the atezolizumab-induced LDH release. Taken together, our data indicate that the atezolizumab induces PD-L1-mediated necrosome formation, contributing to hepatotoxicity in PD-L1+-human hepatocytes. This study provides the molecular basis of the atezolizumab-induced hepatotoxicity and opens a new avenue for developing a novel therapeutic approach to reducing hepatotoxicity induced by ICIs.

PMID:37511454 | PMC:PMC10380327 | DOI:10.3390/ijms241411694

Int J Mol Sci. 2023 Jul 14;24(14):11486. doi: 10.3390/ijms241411486.

ABSTRACT

Cisplatin (CDDP) is an efficient chemotherapeutic agent broadly used to treat solid cancers. Chemotherapy with CDDP can cause significant unwanted side effects such as renal toxicity and peripheral neurotoxicity. CDDP is a substrate of organic cation transporters (OCT), transporters that are highly expressed in renal tissue. Therefore, CDDP uptake by OCT may play a role in causing unwanted toxicities of CDDP anticancer treatment. In this study, the contribution of the mouse OCT2 (mOCT2) to CDDP nephro- and peripheral neurotoxicity was investigated by comparing the effects of cyclic treatment with low doses of CDDP on renal and neurological functions in wild-type (WT) mice and mice with genetic deletion of OCT2 (OCT2-/- mice). This CDDP treatment protocol caused significant impairment of kidneys and peripherical neurological functions in WT mice. These effects were significantly reduced in OCT2-/- mice, however, less profoundly than what was previously measured in mice with genetic deletion of both OCT1 and 2 (OCT1-2-/- mice). Comparing the apparent affinities (IC50) of mOCT1 and mOCT2 for CDDP, the mOCT1 displayed a higher affinity for CDDP than the mOCT2 (IC50: 9 and 558 µM, respectively). Also, cellular toxicity induced by incubation with 100 µM CDDP was more pronounced in cells stably expressing mOCT1 than in cells expressing mOCT2. Therefore, in mice, CDDP uptake by both OCT1 and 2 contributes to the development of CDDP undesired side effects. OCT seem to be suitable targets for establishing treatment protocols aimed at decreasing unwanted CDDP toxicity and improving anticancer treatment with CDDP.

PMID:37511245 | PMC:PMC10380567 | DOI:10.3390/ijms241411486

Int J Mol Sci. 2023 Jul 14;24(14):11437. doi: 10.3390/ijms241411437.

ABSTRACT

In this work, we propose a comprehensive perspective on genomic instability comprising not only the accumulation of mutations but also telomeric shortening, epigenetic alterations and other mechanisms that could contribute to genomic information conservation or corruption. First, we present mechanisms playing a role in genomic instability across the kingdoms of life. Then, we explore the impact of genomic instability on the human being across its evolutionary history and on present-day human health, with a particular focus on aging and complex disorders. Finally, we discuss the role of non-coding RNAs, highlighting future approaches for a better living and an expanded healthy lifespan.

PMID:37511197 | PMC:PMC10380557 | DOI:10.3390/ijms241411437

Int J Mol Sci. 2023 Jul 12;24(14):11347. doi: 10.3390/ijms241411347.

ABSTRACT

Over a third of patients with temporal lobe epilepsy (TLE) are not effectively treated with current anti-seizure drugs, spurring the development of gene therapies. The injection of adeno-associated viral vectors (AAV) into the brain has been shown to be a safe and viable approach. However, to date, AAV expression of therapeutic genes has not been regulated. Moreover, a common property of antiepileptic drugs is a narrow therapeutic window between seizure control and side effects. Therefore, a long-term goal is to develop drug-inducible gene therapies that can be regulated by clinically relevant drugs. In this study, a first-generation doxycycline-regulated gene therapy that delivered an engineered version of the leak potassium channel Kcnk2 (TREK-M) was injected into the hippocampus of male rats. Rats were electrically stimulated until kindled. EEG was monitored 24/7. Electrical kindling revealed an important side effect, as even low expression of TREK M in the absence of doxycycline was sufficient to cause rats to develop spontaneous recurring seizures. Treating the epileptic rats with doxycycline successfully reduced spontaneous seizures. Localization studies of infected neurons suggest seizures were caused by expression in GABAergic inhibitory neurons. In contrast, doxycycline increased the expression of TREK-M in excitatory neurons, thereby reducing seizures through net inhibition of firing. These studies demonstrate that drug-inducible gene therapies are effective in reducing spontaneous seizures and highlight the importance of testing for side effects with pro-epileptic stressors such as electrical kindling. These studies also show the importance of evaluating the location and spread of AAV-based gene therapies in preclinical studies.

PMID:37511107 | PMC:PMC10379297 | DOI:10.3390/ijms241411347

Viruses. 2023 Jun 30;15(7):1489. doi: 10.3390/v15071489.

ABSTRACT

About 5% of chronic hepatitis C (CHC) patients experienced treatment failure with direct-acting antiviral (DAA) treatment. The global data on the practice and treatment outcomes of Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX) in DAA-experienced CHC patients remains sparse. We performed a systematic review and meta-analysis to evaluate the efficacy and safety of SOF/VEL/VOX as a salvage treatment in DAA-experienced CHC patients. We searched five electronic databases from inception to 31 January 2023. The study outcomes were SVR12 and treatment-related adverse effects, with subgroup analysis performed based on genotype, cirrhosis, HCC, prior SOF/VEL exposure, and region. We identified and analyzed data from 24 studies (2877 DAA-experienced CHC patients); 17.2% had prior SOF/VEL exposure, 25% received ribavirin with SOF/VEL/VOX, and 42% had pre-treatment resistance-associated substitution (RAS) testing performed. Eastern Mediterranean had a higher pooled SVR12 than the America and Europe regions (p < 0.05). Predictors of SOF/VEL/VOX failure were genotype 3, active HCC, baseline cirrhosis, and prior SOF/VEL. Baseline RAS mutation and ribavirin supplementation were not associated with higher SVR12. Treatment discontinuation because of drug-related adverse events was uncommon (10 studies, 0.2%). In summary, SOF/VEL/VOX is efficacious and safe for retreatment in DAA-experienced CHC patients, even with RAS mutation. Our findings support SOF/VEL/VOX as a first-line rescue treatment for DAA-experienced CHC patients.

PMID:37515176 | DOI:10.3390/v15071489

Pharmaceuticals (Basel). 2023 Jul 20;16(7):1031. doi: 10.3390/ph16071031.

ABSTRACT

A potential complication of pharmacotherapy for a given patient is the possibility of various side effects of drugs, which are manifested in many ways and constitute iatrogenic causes of diseases. Among the systemic side effects of drugs, there are also those involving the urinary tract, although these are less reported in the literature. The use of numerous drugs-especially of anticholinergics or drugs with anticholinergic potential, opioid analgesics, non-steroidal anti-inflammatory drugs, antidepressants, first-generation antipsychotics (classic neuroleptics) and selected cardiovascular drugs (beta-blockers, thiazides potassium-sparing diuretics, statins), as well as others-may increase the risk of developing urological disorders, such as urinary retention or incontinence, urinary tract infections, urolithiasis, erectile dysfunction in men and retroperitoneal fibrosis. The purpose of this paper is to characterise the abovementioned drug-induced disorders of the lower urinary tract on the basis of a non-systematic literature review.

PMID:37513941 | DOI:10.3390/ph16071031