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Journal of Investigative Medicine : the... Apr 2024Cisplatin use is often limited by its ototoxic side effects, which can lead to irreversible hearing loss. Preventing cisplatin-induced ototoxicity is crucial to improve...
Cisplatin use is often limited by its ototoxic side effects, which can lead to irreversible hearing loss. Preventing cisplatin-induced ototoxicity is crucial to improve patient outcomes. Fluoxetine and fluvoxamine, both selective serotonin reuptake inhibitors antidepressants, inhibit the NLR pyrin domain-containing protein 3 inflammasome, a potential therapeutic target for preventing ototoxicity. However, human studies have not evaluated if these antidepressants may protect against cisplatin-induced ototoxicity. The object of this study is to assess the association between fluoxetine or fluvoxamine use and incidence of hearing loss or tinnitus in a large cohort of patients receiving cisplatin chemotherapy. We use a retrospective cohort study within the U.S. Department of Veterans Affairs healthcare system. Adult patients with cancer who received cisplatin chemotherapy between 2000 and 2023 are included. Incidence of ototoxicity, defined by international classification of diseases revision 9-CM or international classification of diseases revision 10-CM diagnoses of hearing loss or tinnitus is compared between concurrent use of fluoxetine or fluvoxamine and cisplatin alone. A total of 20,552 patients were included. Of those, 489 received cisplatin and fluoxetine or fluvoxamine. After propensity score adjustment, the hazard of ototoxicity was lower in the group receiving fluoxetine or fluvoxamine compared to the group receiving cisplatin alone (HR = 0.62, 95% CI = (0.41-0.94)). Fluoxetine or fluvoxamine use may be associated with a reduced risk of cisplatin-induced ototoxicity. Randomized clinical trials are needed to confirm these findings and establish the efficacy of the medications in ototoxicity prevention. Further research is also warranted to investigate the potential mechanisms underlying this protective effect.
PubMed: 38597272
DOI: 10.1177/10815589241247796 -
Journal of Pharmaceutical Policy and... 2024Early detection, monitoring, and managing adverse events (AEs) are crucial in optimising treatment for multidrug-resistant tuberculosis (MDR-TB) patients.
BACKGROUND
Early detection, monitoring, and managing adverse events (AEs) are crucial in optimising treatment for multidrug-resistant tuberculosis (MDR-TB) patients.
OBJECTIVES
To investigate the incidence, factors, management, and impact of AEs on treatment outcomes in MDR-TB patients.
METHODS
This study reviewed the medical records of 275 MDR-TB patients at Fatimah Jinnah Institute of Chest Diseases in Quetta, Pakistan. Patient information was collected using a designed data collection form. Mann-Whitney and Kruskal-Wallis tests examined the difference in AEs occurrences based on patients' characteristics. Multiple binary logistic regression identified factors associated with unsuccessful outcomes, with statistical significance set at a -value < 0.05.
RESULTS
Almost all patients (99.6%) experienced at-least one AE (median = 4/patient, interquartile range:3-6). The most common were GI disturbance (95.3%), arthralgia (80.4%), body pain and headache (61.8%), ototoxicity (61.4%), psychiatric disturbance (44%), hypokalaemia (40.4%), dermatological reactions (26.2%) and hypothyroidism (21.5%). AEs led to treatment modification in 7.3% patients. Educated patients, those with a history of TB treatment, previous use and resistance to any second-line drug had significantly higher number of AEs. A total of 64.0% were declared cured, 3.6% completed treatment, 19.6% died and 12.7.9% were lost to follow-up. Patients' age of 41-60(OR = 9.225) and >60 years(OR = 23.481), baseline body weight of 31-60 kg(OR = 0.180), urban residence(OR = 0.296), and experiencing ototoxicity (OR = 0.258) and hypothyroidism (OR = 0.136) were significantly associated with unsuccessful treatment outcomes.
CONCLUSION
AEs were highly prevalent but did not negatively impact treatment outcomes. Patients at higher risk of developing AEs and unsuccessful outcomes should receive special attention for its early management.
PubMed: 38572376
DOI: 10.1080/20523211.2024.2332878 -
Scientific Reports Apr 2024Nobiletin, a citrus polymethoxy flavonoid with antiapoptotic and antioxidative properties, could safeguard against cisplatin-induced nephrotoxicity and neurotoxicity....
Nobiletin, a citrus polymethoxy flavonoid with antiapoptotic and antioxidative properties, could safeguard against cisplatin-induced nephrotoxicity and neurotoxicity. Cisplatin, as the pioneer of anti-cancer drug, the severe ototoxicity limits its clinical applications, while the effect of nobiletin on cisplatin-induced ototoxicity has not been identified. The current study investigated the alleviating effect of nobiletin on cisplatin-induced ototoxicity and the underlying mechanisms. Apoptosis and ROS formation were evaluated using the CCK-8 assay, Western blotting, and immunofluorescence, indicating that nobiletin attenuated cisplatin-induced apoptosis and oxidative stress. LC3B and SQSTM1/p62 were determined by Western blotting, qPCR, and immunofluorescence, indicating that nobiletin significantly activated autophagy. Nobiletin promoted the nuclear translocation of NRF2 and the transcription of its target genes, including Hmox1, Nqo1, and ferroptosis markers (Gpx4, Slc7a11, Fth, and Ftl), thereby inhibiting ferroptosis. Furthermore, RNA sequencing analysis verified that autophagy, ferroptosis, and the NRF2 signaling pathway served as crucial points for the protection of nobiletin against ototoxicity caused by cisplatin. Collectively, these results indicated, for the first time, that nobiletin alleviated cisplatin-elicited ototoxicity through suppressing apoptosis and oxidative stress, which were attributed to the activation of autophagy and the inhibition of NRF2/GPX4-mediated ferroptosis. Our study suggested that nobiletin could be a prospective agent for preventing cisplatin-induced hearing loss.
Topics: Humans; Cisplatin; NF-E2-Related Factor 2; Ototoxicity; Ferroptosis; Prospective Studies; Phospholipid Hydroperoxide Glutathione Peroxidase; Autophagy; Flavones
PubMed: 38570541
DOI: 10.1038/s41598-024-55614-4 -
Redox Report : Communications in Free... Dec 2024Gentamicin is one of the most common ototoxic drugs that can lower patients' quality of life. Oxidative stress is a key factors inducing sensory hair cell death during...
OBJECTIVES
Gentamicin is one of the most common ototoxic drugs that can lower patients' quality of life. Oxidative stress is a key factors inducing sensory hair cell death during gentamicin administration. So far, there are no effective drugs to prevent or treat gentamicin- induced hearing loss. A recent study found cystic fibrosis transmembrane conductance regulator (CFTR) as a new target to modulate cellular oxidative balance. The objective of this study was to estimate the effect of the CFTR activator ivacaftor on gentamicin-induced ototoxicity and determine its mechanism.
METHODS
The hair cell count was analyzed by Myosin 7a staining. Apoptosis was analyzed by TUNEL Apoptosis Kit. Cellular reactive oxygen species (ROS) level was detected by DCFH-DA probes. The Nrf2 related proteins expression levels were analyzed by western blot.
RESULTS
An in vitro cochlear explant model showed that gentamicin caused ROS accumulation in sensory hair cells and induced apoptosis, and this effect was alleviated by pretreatment with ivacaftor. Western blotting showed that ivacaftor administration markedly increased the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO1), and NAD(P)H:quinone oxidoreductase 1 (NQO1). The protective effect of ivacaftor was abolished by the Nrf2 inhibitor ML385.
DISCUSSION
Our results indicate the protective role of the CFTR-Nrf2-HO1/NQO1 pathway in gentamicin-induced ototoxicity. Ivacaftor may be repositioned or repurposed towards aminoglycosides-induced hearing loss.
Topics: Humans; Gentamicins; Reactive Oxygen Species; Ototoxicity; NF-E2-Related Factor 2; Cystic Fibrosis Transmembrane Conductance Regulator; Heme Oxygenase-1; Quality of Life; Oxidative Stress; Apoptosis; Hearing Loss; NAD(P)H Dehydrogenase (Quinone); Aminophenols; Quinolones
PubMed: 38563333
DOI: 10.1080/13510002.2024.2332038 -
Frontiers in Oncology 2024Ototoxicity is a devastating direct, irreversible side effect of platinum use in children with cancer, with its consequent effect on speech, language and social...
Ototoxicity is a devastating direct, irreversible side effect of platinum use in children with cancer, with its consequent effect on speech, language and social development, quality of life and adult productivity. Cisplatin, an essential chemotherapeutic agent for the treatment of solid tumors in children, is a DNA cross-linking agent. Which causes hearing loss in 50-70% of cisplatin treated children. Fortunately, to prevent hearing loss, sodium thiosulfate (STS), which binds to cisplatin, and reduces the superoxides in both tumor and outer hair cells of the cochlea has now been discovered to be an effective and safe otoprotectant if administered correctly. The aim of this perspective paper is to explore the key safety issues and challenges important for pediatric oncologists and pharmacists when considering the clinical use of STS as an otoprotectant for children and adolescents receiving cisplatin. These include: the choice of the formulation; the timing, both that of the STS in relation to cisplatin as well as the timing of the cisplatin infusion itself; the dosing; the challenge left by the definition of localized versus disseminated disease and the difference in indication for STS, between cisplatin treated patients and those receiving another platinum chemotherapeutic agent, carboplatin.
PubMed: 38562178
DOI: 10.3389/fonc.2024.1336714 -
Biomedicines Mar 2024Cisplatin, a chemotherapeutic agent, can cause nephrotoxic and ototoxic injuries. Using a mouse model of repeated low dose cisplatin (RLDC), we compared the kidneys of...
Cisplatin, a chemotherapeutic agent, can cause nephrotoxic and ototoxic injuries. Using a mouse model of repeated low dose cisplatin (RLDC), we compared the kidneys of cisplatin- and vehicle-treated mice on days 3 (early injury phase) and 35 (late injury/recovery phase) after the final treatment. RNA-seq analyses revealed increases in the expression of markers of kidney injury (e.g., lipocalin 2 and kidney injury molecule 1) and fibrosis (e.g., collagen 1, fibronectin, and vimentin 1) in RLDC mice. In addition, we observed increased expression of polyamine catabolic enzymes (spermidine/spermine N-acetyltransferase, , and spermine oxidase, ) and decreased expression of ornithine decarboxylase (), a rate-limiting enzyme in polyamine synthesis in mice subjected to RLDC. Upon confirmation of the RNA-seq results, we tested the hypothesis that enhanced polyamine catabolism contributes to the onset of renal injury and development of fibrosis. To test our hypothesis, we compared the severity of RLDC-induced renal injury and fibrosis in wildtype (WT), -KO, and -KO mice. Our results suggest that the ablation of polyamine catabolic enzymes reduces the severity of renal injury and that modulation of the activity of these enzymes may protect against kidney damage and fibrosis caused by cisplatin treatment.
PubMed: 38540254
DOI: 10.3390/biomedicines12030640 -
Toxics Feb 2024Hearing loss (HL) is associated with poorer language development and school performance. Ototoxic substances such as metals and solvents, including benzene, are a risk...
Hearing loss (HL) is associated with poorer language development and school performance. Ototoxic substances such as metals and solvents, including benzene, are a risk factor associated with HL. This study examines potential associations between the benzene metabolite ,-muconic acid (,-MA) and HL in youth of the National Health and Nutrition Examination Survey (NHANES). Logistic regression calculated adjusted odds ratio (aOR) associations between HL and urinary ,-MA quartiles, natural-log transformed, and doubled urinary ,-MA. Hearing threshold pure-tone average (PTA) at speech frequencies (SF) 0.5, 1, 2, and 4 kHz and high frequencies (HF) 3, 4, and 6 kHz were analyzed for slight HL (PTA > 15 dB) and mild HL (PTA > 20 dB). Urinary ,-MA was statistically significantly associated with both slight SF and HF HL. For each doubling of ,-MA there were increased odds of having slight SFHL (aOR = 1.42; 95% CI: 1.05, 1.92), slight HFHL (aOR = 1.31; 95% CI: 1.03, 1.66), mild SFHL (aOR = 1.60; 95% CI: 1.10, 2.32), and mild HFHL (aOR = 1.45; 95% CI: 1.03, 2.04). To our knowledge, this is the first population-based report of an association between SFHL, HFHL, and the benzene metabolite ,-MA in youth 6 to 19 years old.
PubMed: 38535923
DOI: 10.3390/toxics12030191 -
Biosensors Feb 2024Vancomycin (VAN) is an effective antibiotic against Gram-positive bacteria and the first-line therapy to prevent and treat methicillin-resistant (MRSA) and severe...
Vancomycin (VAN) is an effective antibiotic against Gram-positive bacteria and the first-line therapy to prevent and treat methicillin-resistant (MRSA) and severe infections. However, low concentrations of VAN can result in resistant strains. High doses of VAN can cause nephrotoxicity and ototoxicity; thus, VAN is a representative drug for which drug monitoring is recommended. Several methods have been proposed to detect VAN. Among them, lateral flow immunoassays (LFIAs) have advantages, such as simple and user-friendly operation, low sample volume requirement, and cost effectiveness. In this study, we developed an LFIA capable of rapid on-site detection such that the VAN concentration in plasma could be monitored within 20 min by a one-step detection process using whole blood without plasma separation. VAN can be detected in whole blood over a wide range of concentrations (20-10,000 ng/mL), and the LFIA reported here has a detection limit of 18 ng/mL. The applicability of the developed LFIA compared to the results of measuring VAN with a commercial enzyme-linked immunosorbent assay kit showed a satisfactory correlation (Spearman's rho, ρ = 0.891). Therefore, the developed LFIA enables rapid and wide-range VAN detection in whole blood and can aid in drug monitoring to evaluate patients' responses to treatment.
Topics: Humans; Vancomycin; Methicillin-Resistant Staphylococcus aureus; Anti-Bacterial Agents; Immunoassay; Enzyme-Linked Immunosorbent Assay
PubMed: 38534236
DOI: 10.3390/bios14030129 -
Frontiers in Pharmacology 2024Ototoxicity is a debilitating side effect of over 150 medications with diverse mechanisms of action, many of which could be taken concurrently to treat multiple...
Ototoxicity is a debilitating side effect of over 150 medications with diverse mechanisms of action, many of which could be taken concurrently to treat multiple conditions. Approaches for preclinical evaluation of drug-drug interactions that might impact ototoxicity would facilitate design of safer multi-drug regimens and mitigate unsafe polypharmacy by flagging combinations that potentially cause adverse interactions for monitoring. They may also identify protective agents that antagonize ototoxic injury. To address this need, we have developed a novel workflow that we call Parallelized Evaluation of Protection and Injury for Toxicity Assessment (PEPITA), which empowers high-throughput, semi-automated quantification of ototoxicity and otoprotection in zebrafish larvae via microscopy. We used PEPITA and confocal microscopy to characterize in vivo the consequences of drug-drug interactions on ototoxic drug uptake and cellular damage of zebrafish lateral line hair cells. By applying PEPITA to measure ototoxic drug interaction outcomes, we discovered antagonistic interactions between macrolide and aminoglycoside antibiotics that confer protection against aminoglycoside-induced damage to lateral line hair cells in zebrafish larvae. Co-administration of either azithromycin or erythromycin in zebrafish protected against damage from a broad panel of aminoglycosides, at least in part via inhibiting drug uptake into hair cells via a mechanism independent from hair cell mechanotransduction. Conversely, combining macrolides with aminoglycosides in bacterial inhibition assays does not show antagonism of antimicrobial efficacy. The proof-of-concept otoprotective antagonism suggests that combinatorial interventions can potentially be developed to protect against other forms of toxicity without hindering on-target drug efficacy.
PubMed: 38515847
DOI: 10.3389/fphar.2024.1363545 -
Frontiers in Oncology 2024Childhood cancer survivors (CCS) exposed to platinum chemotherapy are at an increased risk of developing hearing loss and reporting decreased quality of life (QOL). This...
BACKGROUND
Childhood cancer survivors (CCS) exposed to platinum chemotherapy are at an increased risk of developing hearing loss and reporting decreased quality of life (QOL). This study compared two QOL measures; one developed for children with hearing loss, The Hearing Environments and Refection on Quality of Life (HEAR-QL), and one validated in CCS, the Patient-Reported Outcomes Measurement Information System (PROMIS), to assess their ability to evaluate QOL deficits in this population.
METHODS
Subject eligibility were restricted to CCS exposed to platinum-based chemotherapy but who were free of known risk factors for cognitive impairment, (non-central nervous system tumor, no cranial radiation, or intrathecal chemotherapy). Participants had to be between 8-17 years, have completed anti-cancer therapy for at least 6 months, and have an audiogram within 1 year, Participants completed the HEAR-QL-26 (7-12 years) or the HEAR-QL-28 (13-18 years) and the PROMIS. Independent samples and/or one sample T-tests were utilized to compare participants with normal hearing and hearing loss, and to compare outcome measures to normative HEAR-QL and PROMIS data. Non-parametric correlations were utilized to evaluate the relationship between QOL and demographic and medical variables, and QOL and severity of hearing loss.
RESULTS
Fifty-four CCS were evaluable. The mean age was 12.0 years. Twenty-eight participants (51.9%) received cisplatin, 30 (55.6%) carboplatin, and 4 (7.4%) received both. Twenty participants (37%) demonstrated hearing loss. Participants with hearing loss scored significantly lower on the HEAR-QL than those with normal hearing (mean: 70.3, SD: 21.7, vs mean: 88.0, SD: 9.3, p =.004 for the HEAR-QL-26; mean: 84.7, SD: 10.2 vs mean: 94.8, SD: 3.4, p =.040 for the HEAR-QL-28). Participants with normal hearing scored significantly lower on the HEAR-QL-26 than the normative mean (mean: 88, SD: 9.3, normative mean: 98, SD: 5, p =.000). The PROMIS failed to identify any differences in QOL between participants based on hearing status, or when compared to the normative mean.
CONCLUSION
The HEAR-QL was more sensitive than the PROMIS in identifying QOL deficits in CCS at risk for hearing loss. The HEAR-QL should be considered in studies seeking to improve the QOL of CCS with hearing loss.
PubMed: 38511136
DOI: 10.3389/fonc.2024.1362315