Capivasertib-Induced Diabetic Ketoacidosis in a Patient With Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative (ER+/HER2-) Metastatic Breast Cancer and No Prior History of Diabetes Mellitus: A Case Report.

Capivasertib, a pan-AKT inhibitor, has shown promising efficacy in treating metastatic tumors harboring the AKT1 E17K mutation. However, its use is associated with notable adverse events, including hyperglycemia, which may impact treatment outcomes. This case describes a patient with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) metastatic breast cancer and no prior history of diabetes who developed diabetic ketoacidosis (DKA) following capivasertib therapy.

Pneumonitis Incidence in Patients With Metastatic Non-small Cell Lung Cancer on Immunotherapy: A Systematic Review and Meta-Analysis.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, often diagnosed at the advanced stage (metastatic). Treatment options for metastatic NSCLC include radiotherapy, chemotherapy, target drug therapy, and immunotherapy. Immunotherapy (utilization of checkpoint inhibitors) boosts the immune system to recognize and destroy cancer cells. However, it is often associated with immune-related complications such as pneumonitis. This review aims to determine the incidence of pneumonitis in metastatic NSCLC patients treated with different immunotherapy drugs. PubMed, Cochrane Library, and Embase databases were scoured for randomized controlled trials (RCTs) until October 2023. Published RCTs with similar research objectives were included, while non-English articles, reviews, case reports, ongoing trials, non-randomized studies, conference abstracts, and studies on small cell lung cancer (SCLC) were excluded. The Cochrane risk-of-bias tool for randomized trials (RoB 2) was used to assess the risk of bias among the included studies. The statistical analyses were performed with the Comprehensive Meta-Analysis software. The subgroup analysis of the 16 included RCTs showed that metastatic NSCLC patients treated with nivolumab and pembrolizumab had a higher incidence of any grade pneumonitis than those treated with atezolizumab (4.5% and 5.1% vs. 1.6%, respectively). Similarly, the incidence of grade ≥3 pneumonitis was higher among patients receiving nivolumab (1.3%) and pembrolizumab (2.4%) than those receiving atezolizumab (0.7%). Furthermore, the subgroup analysis showed that patients with naive-treated NSCLC on immunotherapy had a higher incidence of any grade pneumonitis than those with previously treated NSCLC (6.5% vs. 3.9%). Treatment-naive patients recorded higher grade ≥3 pneumonitis incidences than those previously treated (3.1% vs. 1.3%). Programmed death 1 (PD-1) inhibitors (i.e., pembrolizumab and nivolumab) have higher incidences of pneumonitis than programmed death-ligand 1 inhibitors (atezolizumab).

Mutations Associated With High-Grade irAEs in NSCLC Patients Receiving Immunotherapies.

OBJECTIVES: Compared to low-grade irAEs, high-grade irAEs are more often dose-limiting and can alter the long-term treatment options for a patient. Predicting the incidence of high-grade irAEs would help with treatment selection and therapeutic drug monitoring. MATERIALS AND METHODS: We performed a retrospective study of 430 stage III and IV patients with non-small cell lung cancer (NSCLC) who received an immune checkpoint inhibitor (ICI), either with or without chemotherapy, at a single comprehensive cancer center from 2015 to 2022. The study team retrieved sequencing data and complete clinical information, including detailed irAEs medical records. Fisher's exact test was used to determine the association between mutations and the presence or absence of high-grade irAEs. Patients were analyzed separately based on tumor subtypes and sequencing platforms. RESULTS: High-grade and low-grade irAEs occurred in 15.2% and 46.2% of patients, respectively. Respiratory and gastrointestinal irAEs were the 2 most common irAEs. The distribution of patients with or without irAEs was similar between ICI and ICI+chemotherapy-treated patients. By analyzing the mutation data, we identified 5 genes (MYC, TEK, FANCA, FAM123B, and MET) with mutations that were correlated with an increased risk of high-grade irAEs. For the adenocarcinoma subtype, mutations in TEK, MYC, FGF19, RET, and MET were associated with high-grade irAEs; while for the squamous subtype, ERBB2 mutations were associated with high-grade irAEs. CONCLUSION: This study is the first to demonstrate that specific tumor mutations correlate with the incidence of high-grade irAEs in patients with NSCLC treated with an ICI, providing molecular guidance for treatment selection and drug monitoring.

Metformin-Induced Nightmares: An Uncommon Event.

Metformin is well-known in the treatment of type 2 diabetes mellitus (DM). Metformin has become a drug of choice due to its affordability, cost-effectiveness, and established safety record. It primarily works by inhibiting hepatic gluconeogenesis. Common side effects include gastrointestinal issues, with rare complications, such as lactic acidosis and vitamin B12 malabsorption. This study discussed a 72-year-old male with type 2 DM who experienced recurrent nightmares upon initiating metformin, which ceased after discontinuation. The mechanism of metformin-associated nightmares remains poorly understood. Despite metformin's benefits, this case highlights the importance of recognizing rare adverse effects like nightmares, which can significantly impact patients' quality of life.

Study on the acute and subchronic oral toxicity of Calculus Bovis Sativus in rats.

This study aims to assess the acute and subchronic toxicity of Calculus Bovis Sativus (CBS), which is an ideal substitute for natural Calculus Bovis. After conducting a test of acute toxicity with KM mice of both sexes, it was determined that oral CBS had a lethal dosage (LD50) of greater than 9.26 g/kg BW. For ninety days, Wistar rats were fed on CBS orally at dosages of 0, 167, 501, and 1503 mg/kg BW/day, respectively, as part of the subchronic investigation. A comparison of the controls with the 1503 mg/kg and 501 mg/kg dosage groups revealed significant differences in the hematological and serum biochemical parameters, such as RBC, HGB, MONO%, PLT, LYMPH% and GLU, TP, ALB, and Ca2+, were observed. However, values of the above parameters fell within our laboratory's normal range. In terms of body weight, food intake, urinalysis, clinical chemistry, and pathology, no other adverse effects were observed. After 90 days of exposure, the no observed adverse effect level (NOAEL) of CBS in rats was determined to be 1503 mg/kg BW/day.

Reversible Second-Degree Heart Block Attributed to Ondansetron: A Rare Side Effect.

A primigravida at 36 weeks with gestational diabetes mellitus and hypothyroidism and no prior chronic medical illness was admitted for safe confinement. A cesarean section was required to deliver the baby with breech presentation complicated by a slow progression of labor. Asymptomatic sinus bradycardia with a heart rate of 40 per minute was observed during the induction of anesthesia. Before bupivacaine administration for spinal anesthesia, she was administered pantoprazole 40 mg and ondansetron 4 mg intravenously. ECG recording showed a type 1 Mobitz second-degree heart block. Follow-up ECG showed progression of heart block to type 2 Mobitz second-degree heart block. The second-degree heart block persisted for 16 hours, during which the patient was asymptomatic, and the ventricular rate was maintained at a range of 60-80 per minute. After normalization of rhythm, the patient was observed in the ICU. She received another dose of ondansetron 4 mg intravenously for vomiting, and the heart block recurred. The rhythm disturbance was attributed to ondansetron. Her rhythm normalized after 36 hours, and she was subsequently discharged home three days later.

Gemcitabine-Induced Thrombotic Microangiopathy in a Patient With Cholangiocarcinoma: An Atypical Case.

Gemcitabine-induced thrombotic microangiopathy (GITMA) is a rare but severe complication seen in cancer patients on gemcitabine therapy. This case report describes a 45-year-old female with metastatic cholangiocarcinoma on gemcitabine-capecitabine who developed acute kidney injury and hypertension without typical hematologic signs of thrombotic microangiopathy (TMA). Despite initial management targeting hypertensive urgency and acute kidney injury, renal function continued to decline and progressed to end-stage renal disease requiring hemodialysis. Laboratory tests revealed TMA features such as elevated lactate dehydrogenase (LDH), decreased haptoglobin, and schistocytes. Renal biopsy confirmed TMA with chronic features. This case highlights the challenge of diagnosing drug-induced TMA without typical hematologic findings.

Analysis of antipsychotic drugs prescribing in incarcerated persons in a Serbian correctional facility.

PURPOSE: Prison settings have limited resources, and it is of particular interest to analyze which antipsychotics are commonly prescribed in these conditions and to determine the prevalence of the adverse effects. DESIGN/METHODOLOGY/APPROACH: A cross-sectional, epidemiological survey was used to measure the prevalence of antipsychotic prescribing among adult prisoners in Sremska Mitrovica Prison in 2020. FINDINGS: The prevalence of antipsychotic use was 7.58%. The most commonly prescribed antipsychotic was clozapine (45.36%), but also olanzapine, haloperidol and risperidone were prescribed. The incidence of extrapyramidal adverse effects was nonexistent and the metabolic parameters did not differ between participants using metabolic syndrome-inducing antipsychotics and those who were prescribed metabolically inert medications. The prescribed doses were lower compared with the recommended. RESEARCH LIMITATIONS/IMPLICATIONS: This research includes certain points that should be cautiously considered. First, the data were cross-sectional and the findings did not provide causal interpretations. Second, the data are from a single penitentiary institution, albeit the largest in the country; however, that may affect the generalizability of the findings. Third, because the included subjects were not hospitalized, some laboratory analyses were not available, according to the local regulations, and thus the prevalence of metabolic syndrome could not be precisely determined. PRACTICAL IMPLICATIONS: The prevalence of the antipsychotic use in prison environment is significantly higher than in general population. The most frequently prescribed antipsychotics are clozapine and olanzapine. The prevalence of adverse effects is rare, however, that is possibly due to low doses of the prescribed antipsychotics. The list of therapeutic options available to the incarcerated persons in this facility is also limited. The list of available antipsychotics does not include some atypical antipsychotics with more favorable safety and tolerability profile, such as aripiprazole or cariprazine. Long-acting antipsychotic injectables were also not available to these patients. Laboratory analyses are not regularly conducted and do not include some essential parameters such as lipid status or differential blood count. Low-dose antipsychotics for behavioral symptoms appears to be well tolerated under prison conditions where adherence is assured. It is effective during the prison stay but long-term effects, especially after release from prison, had not been studied. SOCIAL IMPLICATIONS: This paper advocates for better quality of health care in this correctional facility: more therapeutic options and better laboratory monitoring. The authors justify the use of clozapine in this settings due its benefits in reducing violence and aggression; however, further research would be necessary to clarify does the use of clozapine in incarcerated persons cause behavioral improvements that could result in shorter incarcerations, less recidivism and better quality of life. ORIGINALITY/VALUE: To the best of the authors' knowledge, this is the first insight of the antipsychotic prescribing practice in Serbia. There is very limited data on prisoners' health care, especially mental health care, in Balkan countries. The antipsychotic prescribing pattern in this sample is characterized with higher than expected clozapine use, but without expected adverse effects.

Deciphering the Causality between Gut Microbiota Dysbiosis and Poisoning by Narcotics and Psychodysleptics: A Mendelian Randomization Analysis.

BACKGROUND: This study investigates the connection between gut microbiota and poisoning caused by narcotics and psychodysleptics, using Mendelian randomization (MR) to explore possible causal relationships. METHODS: The study employed the MR analysis, leveraging genetic variants as instrumental variables to facilitate robust causal inference. Data for gut microbiota was extracted from the MiBioGen study, integrating genome-wide genotyping data with 16S fecal microbiota profiles. Outcome metrics were based on the Finngen study. Genetic instruments were meticulously extracted based on stringent criteria, and harmonized with SNP outcomes associated with "Poisoning by narcotics and psychodysleptics [hallucinogens]". The inverse-variance weighted (IVW) method was utilized for MR analysis, supplemented by sensitivity analyses including MR-Egger Regression, Weighted Median Approach, and Leave-One-Out Cross-Validation. RESULTS: Among various microbial groups, nine showed significant statistical links. Specifically, Class Negativicutes (OR 5.68, 95% CI 2.13-15.16, p = 0.0005) and Order Selenomonadales (OR 5.68, 95% CI 2.13-15.16, p = 0.0005) were notably associated. These findings were consistent across different sensitivity analyses. CONCLUSION: The relationship between gut microbiota and the adverse effects of narcotics and psychodysleptics is an emerging area of research. Our MR study identifies certain microbes that might influence the body's response to these substances. These insights could help in predicting and treating the effects of narcotics and psychodysleptics in the future.

Combined antiallodynic effects of Neurotropin®-tramadol and Neurotropin®-mirogabalin in rats with L5-spinal nerve ligation.

We aimed to examine the efficacy of combination therapies of Neurotropin® with tramadol and Neurotropin with mirogabalin for neuropathic pain management. A neuropathic pain model (L5 spinal nerve ligation model: L5-SNL) using male Wistar rats was generated through tight ligation of the left fifth lumbar nerve using silk sutures. Mechanical allodynia was assessed using the 50% paw withdrawal threshold. The combined antiallodynic effects were evaluated using isobolographic analyses. Small intestinal transit was evaluated using the charcoal meal test, and motor coordination using the rota-rod test. Neurotropin (50-200 NU/kg, p.o.), tramadol (7.5-60 mg/kg, p.o.), and mirogabalin (3-30 mg/kg, p.o.) showed a dose-dependent antiallodynic effect in L5-SNL rats. The combined antiallodynic effects of Neurotropin and tramadol were additive or synergistic, whereas those of Neurotropin and mirogabalin were additive. Neurotropin (100-400 NU/kg, p.o.) did not affect the small intestinal transit, whereas tramadol (30-100 mg/kg, p.o.) significantly inhibited it. Neurotropin (100-400 NU/kg, p.o.) did not affect the walking time, whereas mirogabalin (10-100 mg/kg, p.o.) significantly decreased it. Neurotropin dose-dependently ameliorated mechanical allodynia in rats, and combination therapy with Neurotropin-tramadol or Neurotropin-mirogabalin may alleviate neuropathic pain without aggravating the adverse effects of tramadol and mirogabalin.

Fluorescein Angiogram Causing Cutaneous Venous Staining: A Rare Self-Resolving Phenomenon.

Introduction: Fluorescein angiography (FA) is a useful investigation in the diagnosis and treatment of retinal and choroidal disease. FA has well-reported adverse effects, most being mild. Very few cases have reported cutaneous venous staining following FA. Case Presentation: Two cases are reported. Case 1 was a 90-year-old female with bilateral neovascular age-related macular degeneration. In the few minutes following her routine FA, she developed cutaneous fluorescein staining ascending along the superficial forearm veins proximal to the cannula in situ at the dorsal wrist. Case 2 was a 50-year-old male with diabetic macular oedema. In the minutes following his FA, he developed cutaneous fluorescein staining descending along the dorsal forearm veins distal to the cannula in situ at the cubital fossa. Both patients were managed conservatively with the stain resolving in the next few days. Conclusion: Cutaneous fluorescein staining around superficial vasculature is a rare phenomenon. Despite this, it seems to be self-limiting and does not require any treatment.

Blood pressure changes during ketamine infusion for the treatment of depression.

OBJECTIVE: This study aimed to examine blood pressure changes during ketamine infusion for depression and exploring the factors associated with these changes. METHOD: This study is a retrospective chart-review of patients with depression undergoing ketamine infusion at Yale Psychiatry Hospital during a 7-year period. Blood pressure (BP) was recorded every 10 min during the infusion. Surges in systolic and diastolic blood pressure (SBP, DBP), along with severe hypertension events, were analyzed in relation to patient demographics. RESULTS: A total of 138 patients received a total of 2342 infusions. SBP and DBP peaked at 40 min after the start of the infusion with a mean change of 16.0 (SD: 11.2) and 11.0 mmHg (SD: 8.45) respectively. Severe hypertension was observed in 17 patients (12.5%) and 23 infusion sessions (0.98%), occuring more frequently during the first three infusions (43.4%). Age (OR = 1.04 [1.02,1.05], p-value <0.001) was significantly associated with a surge in SBP and all patients with a past medical history of hypertension experienced a BP surge during their infusions. CONCLUSION: Ketamine infusions can cause significant blood pressure increases, particularly in older and hypertensive patients, highlighting the need for careful cardiovascular monitoring to mitigate risks during treatment.

A rare adverse effect in inebilizumab therapy for neuromyelitis optica spectrum disorder: a case report.

Inebilizumab is one of the monoclonal antibodies approved as maintenance therapy for aquaporin-4 immunoglobulin G-seropositive neuromyelitis optica spectrum disorder (NMOSD). It is a humanized monoclonal antibody targeting cluster of differentiation 19 (CD19). Common adverse reactions include urinary tract infections, nasopharyngitis, arthralgia, infusion reactions, headaches and a decrease in immunoglobulin levels. Here, we present a case of an NMOSD patient who experienced transient hyperCKaemia after the use of inebilizumab. The adverse reactions of this very rare monoclonal antibody drug improved after discontinuation.

Localized Colitis Associated With Cholecystectomy in Multiple Sclerosis Patient Treated With Ocrelizumab.

Our understanding of multiple sclerosis (MS) has led to the development of new therapeutic strategies, including ocrelizumab, a third-generation humanized anti-CD20 antibody. Ocrelizumab is largely well tolerated with favorable effectiveness, however, it has been associated with reports of colitis presenting weeks to months following infusion. We present a case of severe localized colitis in the setting of recent surgery and chronic ocrelizumab use. High-dose IV hydrocortisone was initiated, and the patient showed gradual improvement. Repeat imaging after discharge showed near-complete resolution of the patient's condition. This case aims to increase awareness of possible postoperative severe localized colitis in MS patients on Ocrevus.

Pityriasis Rosea-Like Eruption following anti-fatigue traditional herbs: Aconitum carmichaelii Debx and Panax Ginseng suspected.

Traditional herbs have a history of clinical use in anti-fatigue. However, several adverse effects of herbs have been identified. Pityriasis rosea-like eruption (PR-LE) is a rare cutaneous complication of herbs. To the best of our knowledge, there have been few reports of PR-LE following herbs. Here, we described a case of PR-LE that developed 6 days after taking anti-fatigue herbs. After the 17 days of stopping Aconitum carmichaelii Debx and Panax Ginseng, it notably faded. So, when anti-fatigue herbs being authorized for fatigue use, monitoring for potential adverse effects is necessary.

Review on personal protective equipment: Emerging concerns in micro(nano)plastic pollution and strategies for addressing environmental challenges.

The COVID-19 pandemic was caused by the SARS-CoV-2 virus, marking one of the most catastrophic global health crises of the 21st century. Throughout this period, widespread use and improper disposal of personal protective equipment (PPE) emerged as a pressing environmental issue, significantly impacting various life forms. During the COVID-19 pandemic, there was a high rate of PEP disposal. An alarming 1.6 × 106 tons of plastic waste each day has been generated since the onset of the outbreak, predominantly from the inadequate disposal of PPE. The mismanagement and subsequent degradation of discarded PPE significantly contribute to increased non-biodegradable micro(nano)plastic (MNP) waste. This pollution has had profound adverse effects on terrestrial, marine, and aquatic ecosystems, which have been extensively of concern recently. Accumulated MNPs within aquatic organisms could serve as a potential route for human exposure when consuming seafood. This review presents a novel aspect concerning the pollution caused by MNPs, particularly remarking on their role during the pandemic and their detrimental effects on human health. These microplastic particles, through the process of fragmentation, transform into nanoparticles, persisting in the environment and posing potential hazards. The prevalence of MNP from PPE, notably masks, raises concerns about their plausible health risks, warranting global attention and comprehensive exploration. Conducting a comprehensive evaluation of the long-term effects of these processes and implementing effective management strategies is essential.

Post-marketing Safety Concerns of Teprotumumab: A Real-World Pharmacovigilance Assessment.

PURPOSE: Teprotumumab is the only drug approval by The US Food and Drug Administration (FDA) for the treatment of thyroid eye disease (TED), which targets the insulin-like growth factor-1 receptor. This study aimed to identify potential safety signals of teprotumumab by analyzing post-marketing safety data from the FDA Adverse Event Reporting System (FAERS) database in 2023. METHODS: The case/non-case approach was used to estimate the reporting odds ratio (ROR) and information component (IC) with relevant confidence intervals (95% CI) for adverse events (AEs) that numbered three or more. RESULTS: Total of 2158 cases were included in the analysis. Main safety signals identified were ear and labyrinth disorders, reproductive system and breast disorders, metabolism and nutrition disorders and gastrointestinal disorders. Specifically, autophony (ROR [95% CI] = 4188.34 [1403.29-12500.8]), eyelid retraction (ROR [95% CI] = 2094.17 [850.69-5155.29]), deafness permanent (ROR [95% CI] = 1552.35 [789.07-3053.98]), deafness bilateral (ROR [95% CI] = 73.12 [41.14-129.97]), inflammatory bowel disease (ROR [95% CI] = 23.26 [13.46-40.19]), hyperglycaemic hyperosmolar nonketotic syndrome (ROR [95% CI] = 17.75 [5.70-55.28]) and amenorrhoea (ROR [95% CI] = 47.98 [36.22-63.54]) showed significant safety signals of teprotumumab. CONCLUSIONS: This study identified ear and labyrinth disorders, reproductive system and breast disorders, as specific safety signals of teprotumumab. Clinicians and pharmacists should be vigilant regarding these AEs. However, available data are currently insufficient, and further pharmacovigilance and surveillance are needed to fully understand this issue.

Development of a new hazard scoring system in primary neuronal cell cultures for drug-induced acute neuronal toxicity identification in early drug discovery.

We investigated drug-induced acute neuronal electrophysiological changes using Micro-Electrode arrays (MEA) to rat primary neuronal cell cultures. Data based on 6-key MEA parameters were analyzed for plate-to-plate vehicle variability, effects of positive and negative controls, as well as data from over 100 reference drugs, mostly known to have pharmacological phenotypic and clinical outcomes. A Least Absolute Shrinkage and Selection Operator (LASSO) regression, coupled with expert evaluation helped to identify the 6-key parameters from many other MEA parameters to evaluate the drug-induced acute neuronal changes. Calculating the statistical tolerance intervals for negative-positive control effects on those 4-key parameters helped us to develop a new weighted hazard scoring system on drug-induced potential central nervous system (CNS) adverse effects (AEs). The weighted total score, integrating the effects of a drug candidate on the identified six-pivotal parameters, simply determines if the testing compound/concentration induces potential CNS AEs. Hereto, it uses four different categories of hazard scores: non-neuroactive, neuroactive, hazard, or high hazard categories. This new scoring system was successfully applied to differentiate the new compounds with or without CNS AEs, and the results were correlated with the outcome of in vivo studies in mice for one internal program. Furthermore, the Random Forest classification method was used to obtain the probability that the effect of a compound is either inhibitory or excitatory. In conclusion, this new neuronal scoring system on the cell assay is actively applied in the early de-risking of drug development and reduces the use of animals and associated costs.