UNASSIGNED: The purpose of this research was to investigate the characteristics, clinical manifestations, incidence, and risk factors in ethambutol-induced optic neuropathy (EON) in the Thai population.
UNASSIGNED: Patients treated with ethambutol for tuberculosis (TB) were retrospectively identified in the medical record of a tertiary hospital in Thailand from January 2012 to August 2019. Development of EON was determined through review of ophthalmology records. Comparison was made between patients with EON and those without EON to identify possible risk factors. Ophthalmic outcomes were characterized.
UNASSIGNED: Among 4,141 patients who received ethambutol for TB treatment, 1,062 had an ophthalmology encounter, and 20 (0.5% overall, 1.88% with ophthalmology encounters) developed EON. In unadjusted analysis, compared to patients without EON, those with EON had a similar daily dose, but longer duration of ethambutol treatment (P=0.02). They were older (mean 43.74 vs. 58.60 years, P=0.001), more likely to have hypertension (P=0.02) and smoke (p=0.01). There were no differences in gender, body mass index, diabetes, dyslipidemia, HIV infection or glomerular filtration rate. The peripapillary retinal nerve fiber layer, ganglion cell analysis, and vascular density as measured using retinal optical coherence tomography were impacted by EON. In adjusted logistic regression analysis, age greater than 60 (OR = 8.71, p = 0.01) and smoking (OR = 7.06, p = 0.01) were independent risk factors for EON.
UNASSIGNED: In patients treated with ethambutol, the incidence proportion of EON was 0.5% among those with ethambutol administered and 1.88% among those with ethambutol and an eye visit. Potential EON risk factors were age, hypertension, smoking, and duration of ethambutol medication. Smoking has not been associated with EON in prior studies.

Safety pharmacology examines the potential for new drugs to have unusual, rare side effects such as torsade de pointes (TdP). Recently, as a part of the Comprehensive in vitro Proarrhythmia Assay (CiPA) project, techniques for predicting the development of drug-induced TdP through computer simulations have been proposed and verified. However, CiPA assessment generally does not consider the effect of cardiac cell inter-individual variability, especially related to metabolic status. The study aimed to explore whether rare proarrhythmic effects may be linked to the inter-individual variability of cardiac cells and whether incorporating this variability into computational models could alter the prediction of drugs\' TdP risks. This study evaluated the contribution of two biological characteristics to the proarrhythmic effects. The first was spermine concentration, which varies with metabolic status; the second was L-type calcium permeability that could occur due to mutations. Twenty-eight drugs were examined throughout this study, and qNet was analyzed as an essential feature. Even though there were some discrepancies of TdP risk predictions from the baseline model, we found that considering the inter-individual variability might change the TdP risk of drugs. Several drugs in the high-risk drugs group were predicted to affect as intermediate and low-risk drugs in some individuals and vice versa. Also, most intermediate-risk drugs were expected to act as low-risk drugs. When compared, the effects of inter-individual variability of L-type calcium were more significant than spermine in altering the TdP risk of compounds. These results emphasize the importance of considering inter-individual variability to assess drugs.

Standardization and validation of in vitro drug metabolism is essential for pre-clinical drug development as well as for in vitro toxicity assays including the lymphocyte toxicity assay (LTA) and the in vitro platelet toxicity assay (iPTA). Use of isolated liver microsomes (MIC) in in vitro testing has been utilized for a long time; however, the effect of species of origin and induction agents on the metabolic capacities of MIC is not adequately evaluated. In this study we investigated the impact of species of origin and induction agent on the capacity of MICs to bioactivate carbamazepine (CBZ) using cytotoxicity as a gross endpoint to measure the levels of cytotoxic metabolites generated by each type of MICs. Jurkat E6.1 cell line was used and MICs from human, rat, mouse, minipig and rabbit origin as well as rat MICs that is either non-induced or induced by phenobarbitone (PHB), dexamethasone (DEXA), 3-methylcholanthrene (3MC), clofibrate (CLOF) and isoniazid (INH) were investigated. MICs from minipig and rat MICs induced with 3MC exhibited the highest capacity to produce cytotoxic metabolites of CBZ. These findings will help optimize and standardize in vitro toxicity assays and provide guidance to pre-clinical investigation of drugs.

When compared to the challenges associated with traditional dosage forms, medication delivery systems based on nanotechnology have been a huge boon. One such candidate for medication delivery is spanlastics, an elastic nanovesicle that can transport a diverse array of medicinal compounds. The use of spanlastics has been associated with an increase in interest in alternative administration methods. The non-ionic surfactant or surfactant blend is the main component of spanlastics. The purpose of this review was primarily to examine the potential of spanlastics as a delivery system for a variety of medication classes administered via diverse routes. Science Direct, Google Scholar, and Pubmed were utilized to search the academic literature for this review. Several studies have demonstrated that spanlastics greatly improve therapeutic effectiveness, increase medication absorption, and decrease drug toxicity. This paper provides a summary of the composition and structure of spanlastics along with their utility in the delivery of various therapeutic agents by adopting different routes. Additionally, it provides an overview of the numerous disorders that may be treated using drugs that are contained in spanlastic vesicles.

From 2019 to 2020, antihistamines were found in 15% of all US drug overdose deaths, often co-administered with fentanyl, with 3.6% of overdose deaths due to antihistamines alone. The most common antihistamine found in all these reported deaths is diphenhydramine, a ubiquitous, over-the-counter and clinically important medication. Currently, there is no antidote for diphenhydramine overdose. This review summarizes the adverse health effects and current emergency medicine treatments for diphenhydramine. Several emergency medicine case reports are reviewed, and the efficacy and outcomes of a variety of treatments are compared. The treatments reviewed include the more traditional antihistamine overdose therapeutics physostigmine and sodium bicarbonate, as well as newer ones such as donepezil, dexmedetomidine, and lipid emulsion therapy. We conclude that more study is needed to determine the ideal therapeutic approach to treating antihistamine overdoses.

Lung cancer is the leading cause of cancer death, with non-small cell lung cancer (NSCLC) accounting for approximately 85 % of all lung cancers and having a poor treatment and prognosis. Conventional clinical chemotherapy and immunotherapy are challenged by systemic toxicity and drug resistance, so researchers are increasingly focusing on antibody-drug conjugate (ADC), an innovative concept combining chemotherapy and targeted therapy, in which a drug selectively binds to antigens on the surface of a tumor cell via antibodies, which internalize the ADC, and then transfers the ADC to the lysosome via the endosomes to degrade the drug and kill the tumor cell. Despite the promising nature of ADCs, no ADC product for any indication including NSCLC has been approved for marketing by the FDA to date. In this review, we summarize the main advantages of ADCs and discuss in depth the design of the most desirable ADCs for NSCLC therapy. In addition to preclinical studies, we focus on the current state of clinical research on ADCs as interventions for the treatment of NSCLC by summarizing real-time clinical trial data from ClinicalTrials.gov, and reasonably speculate on the direction of the design of future generations of ADCs.

This study reports the first application of in silico methods to assess the toxicity of 4-chloromethcathinone (4-CMC), a novel psychoactive substance (NPS). Employing advanced toxicology in silico tools, it was possible to predict crucial aspects of the toxicological profile of 4-CMC, including acute toxicity (LD50), genotoxicity, cardiotoxicity, and its potential for endocrine disruption. The obtained results indicate significant acute toxicity with species-specific variability, moderate genotoxic potential suggesting the risk of DNA damage, and a notable cardiotoxicity risk associated with hERG channel inhibition. Endocrine disruption assessment revealed a low probability of 4-CMC interacting with estrogen receptor alpha (ER-α), suggesting minimal estrogenic activity. These insights, derived from in silico studies, are critical in advancing the understanding of 4-CMC properties in forensic and clinical toxicology. These initial toxicological findings provide a foundation for future research and aid in the formulation of risk assessment and management strategies in the context of the use and abuse of NPSs.

UNASSIGNED: Mitogen-activated protein kinase kinase (MEK) inhibitors are targeted anticancer agents that are prescribed to treat a broad range of cancers. Despite their strong efficacy profile, MEK inhibitors have been associated with ocular toxicities, most notably, self-limited serous detachments of the neurosensory retina. In this report, we outline 3 cases of a rarely documented toxicity, MEK inhibitor-associated ocular hypertension.
UNASSIGNED: In the first case, a 69-year-old female with metastatic cholangiocarcinoma presented with an intraocular pressure (IOP) of 25 mm Hg right eye (OD) and 27 mm Hg left eye (OS) 2 months after starting trametinib therapy. Similarly, in the second case, a 26-year-old female with Langerhans cell histiocytosis presented with an elevated IOP of 24 mm Hg bilaterally (OU) 13 months after beginning treatment with an investigational MEK inhibitor. In the third case, a 46-year-old male with Langerhans cell histiocytosis presented with a new onset of elevated IOP of 24 mm Hg 21 days after initiating treatment with cobimetinib. All 3 patients\' IOP returned to normal following dorzolamide/timolol administration and continued their cancer therapy.
UNASSIGNED: This report presents 3 cases of elevated IOP in patients taking three distinct MEK inhibitors which would suggest that IOP-elevating effects exist across the class of MEK inhibitors. All 3 patients had a satisfactory response to topical pressure-lowering drops while continuing their life-preserving MEK inhibitor drug dose, indicating that discontinuation of therapy may not be necessary. Due to the increasing use of MEK inhibitors, it is important that ophthalmologists familiarize themselves with the broad range of potential adverse ocular effects of MEK inhibitors.

Tyrosine kinase inhibitors (TKIs) have greatly improved chronic myeloid leukemia (CML) treatments, with survival rates close to the general population. Yet, for the very elderly, robust data remains limited. This study focused on assessing comorbidities, treatment approaches, responses, and survival for elderly CML patients. Our study was conducted on 123 elderly (≥ 75 years) CML patients across four centers in Israel and Moffitt Cancer Center, USA. The median age at diagnosis was 79.1 years, with 44.7% being octogenarians. Comorbidities were very common; cardiovascular risk factors (60%), cardiovascular diseases (42%), with a median age-adjusted Charlson Comorbidity Index (aaCCI) of 5. Imatinib was the leading first-line therapy (69%), while the use of second-generation TKIs increased post-2010. Most patients achieved a major molecular response (MMR, 66.7%), and half achieved a deep molecular response (DMR, 50.4%). Over half (52.8%) of patients moved to second-line, and nearly a quarter (23.5%) to third-line treatments, primarily due to intolerance. Overall survival (OS) was notably longer in patients with an aaCCI score below 5, and in patients who attained DMR. Contrary to expectations, the Israeli cohort showed a shorter actual life expectancy than projected, suggesting a larger impact of CML on elderly survival. In summary, imatinib remains the main initial treatment, but second-generation TKIs are on the rise among elderly CML patients. Outcomes in elderly CML patients depend on comorbidities, TKI type, response, and age, underscoring the need for personalized therapy and additional research on TKI effectiveness and safety.

Methemoglobinemia secondary to administration of hydroxyurea is only reported in veterinary medicine as a result of accidental ingestion of high doses, and once at therapeutic dose in human medicine. A 2.5-year-old female spayed mixed breed dog was presented for acute signs of neurologic disease and diagnosed with severe erythrocytosis without an identified underlying cause, leading to suspicion of polycythemia vera. The dog was managed with phlebotomies, supportive care, and administration of hydroxyurea. Within 2 h of administration of hydroxyurea (37 mg/kg) administration, respiratory distress with cyanosis, and methemoglobinemia developed. Signs resolved within 24 h but recurred after a second administration of lower dosage of hydroxyurea (17 mg/kg) 20 days later. The dog remained asymptomatic except for mild cyanosis but was humanely euthanized for lack of relevant improvement of signs of neurologic disease. This case report documents the repeated occurrence of methemoglobinemia in a dog after administration of hydroxyurea at therapeutic doses.