Nalmefene, an opioid receptor modulator, aggravates atherosclerotic plaque formation in apolipoprotein E knockout mice by enhancing oxidized low-density lipoprotein uptake in macrophages.

Nalmefene, an antagonist of mu- and delta-opioid receptors and a partial agonist of kappa-opioid receptors, has shown promise in reducing alcohol consumption among patients with alcohol dependence. Opioid receptors play pivotal roles in various physiological processes, including those related to peripheral inflammatory diseases such as colitis and arthritis, as well as functions in the immune system and phagocytosis. Atherosclerosis, a chronic inflammatory disease, progresses through the phagocytosis and uptake of oxidized low-density lipoprotein (oxLDL) by macrophages in atherosclerotic plaques. Despite this knowledge, it remains unclear whether nalmefene influences the formation of atherosclerotic plaques and increases the risk of serious cardiovascular events. This study aims to elucidate the impact of nalmefene on atherosclerosis in apolipoprotein E knockout (ApoE KO) mice and peritoneal macrophages in vitro. In this experiment, 8-week-old male ApoE KO mice were fed a high-fat diet intraperitoneally administered either vehicle (saline) or nalmefene (1 mg and 3 mg kg-1 day-1) for 21 days. Oil red O-staining and immunohistochemistry with an anti-MOMA2 (monocyte/macrophage) antibody showed that a dose-dependent increase in atherosclerotic plaque formation and augmentation of macrophage-rich plaque formation in ApoE-KO mice. Further investigations focused on the effects of nalmefene on the expression of scavenger receptor CD36 in RAW264.7 cells, conducted through western blotting analysis. Nalmefene demonstrated a significant increase in CD36 protein expression in RAW264.7 cells. To explore the impact on oxidized LDL uptake in peritoneal macrophages, cells were treated with nalmefene (300 µg/mL) for 24 h, followed by the addition of DiI-labeled oxLDL (DiI-oxLDL) for 4 h. Nalmefene significantly enhanced DiI-oxLDL uptake in macrophages. Additionally, treatment with nalmefene (300 µg/mL) for 24 h decreased the mRNA expression of mu-, delta-, and kappa-opioid receptors in RAW264.7 cells. In conclusion, nalmefene may augment oxLDL uptake by macrophages through increased CD36 expression and decreased opioid receptor, thereby contributing to atherosclerotic plaque formation and vulnerability. Consequently, the use of nalmefene may be associated with an elevated risk of cardiovascular events.

Super-refractory status epilepticus, rhabdomyolysis, central hyperthermia and cardiomyopathy attributable to spinal anesthesia: a case report and review of literature.

BACKGROUND: There are only six past reports of super-refractory status epilepticus induced by spinal anesthesia. None of those patients have died. Only < 15 mg of bupivacaine was administered to all six of them and to our case. Pathophysiology ensuing such cases remains unclear. CASE PRESENTATION: A 27 year old gravida 2, para 1, mother at 37 weeks of gestation came to the operating theater for an elective cesarean section. She had no significant medical history other than controlled hypothyroidism and one episode of food allergy. Her current pregnancy was uneventful. Her American Society of Anesthesiologists (ASA) grade was 2. She underwent spinal anesthesia and adequate anesthesia was achieved. After 5-7 min she developed a progressive myoclonus. After delivery of a healthy baby, she developed generalized tonic clonic seizures that continued despite the induction of general anesthesia. She had rhabdomyolysis, one brief cardiac arrest and resuscitation, followed by stress cardiomyopathy and central hyperthermia. She died on day four. There were no significant macroscopic or histopathological changes in her brain that explain her super refractory status epilepticus. Heavy bupivacaine samples of the same batch used for this patient were analyzed by two specialized laboratories. National Medicines Quality Assurance Laboratory of Sri Lanka reported that samples failed to confirm United States Pharmacopeia (USP) dextrose specifications and passed other tests. Subsequently, Therapeutic Goods Administration of Australia reported that the drug passed all standard USP quality tests applied to it. Nonetheless, they have detected an unidentified impurity in the medicine. CONCLUSIONS: After reviewing relevant literature, we believe that direct neurotoxicity by bupivacaine is the most probable cause of super-refractory status epilepticus. Super-refractory status epilepticus would have led to her other complications and death. We discuss probable patient factors that would have made her susceptible to neurotoxicity. The impurity in the drug detected by one laboratory also would have contributed to her status epilepticus. We propose several possible mechanisms that would have led to status epilepticus and her death. We discuss the factors that shall guide investigators on future such cases. We suggest ways to minimize similar future incidents. This is an idiosyncratic reaction as well.

[The on-line turnover of biologically active additives. Part I. Legal regulation of on-line market of imported biologically active additives in Russia].

The interest of population to biologically active additives drastically increased both due to consequences of the COVID-19 corona-virus infection and dynamic development of online trade and active propaganda of healthy lifestyle through mass media. Such production contains in its compound substances that are necessary for maintaining normal vital activity of organism and increasing human immunity. In other cases it can be used as additional and auxiliary agent of treatment of various diseases. In Russia, biologically active additives can be sold through three channels: pharmacies, on-line market and network marketing. In Russia, the results of monitoring of on-line market in 2021-2022 testifies that purchasing of such biologically active additives at on-line platforms turned out to be the riskiest action for human life and health. The biologically active additives were sold at on-line market with serious violations that confirms their danger to health and in some cases for human life. The study demonstrated that nowadays there is no clear-cut legal regulation of turn-over of imported biologically active additives at on-line market. The article presents detailed analysis of normative legal field that regulates in Russia on-line trade of imported biologically active additives and relevant conclusions and recommendations.

Case report: Incidental MALT lymphoma of the left adrenal gland mimicking a metastatic spread within durvalumab maintenance treatment in inoperable stage III non-small cell lung cancer.

Durvalumab after chemotherapy in non-operable stage III non-small cell lung cancer (NSCLC) is the standard of care worldwide. We present a patient with the incidental discovery of a unilateral MALT lymphoma of the adrenal gland and adrenalitis during durvalumab maintenance treatment detected by 18F-FDG-PET/CT. We assessed the clinical and histopathological findings, radiological examinations and overall treatment. Our work emphasizes the significance of considering other differential diagnoses and the importance of multidisciplinary treatment of the findings, especially within clinical trials.

A Prospective Evaluation of Tubarial Gland Doses With Acute Dysphagia and Treatment Tolerance in Head and Neck Cancer Patients.

Background This study prospectively analyzed the clinical significance of tubarial glands (TGs) doses in head and neck cancer (HNC) patients. Methods Patients diagnosed with HNC in Ankara Bilkent City Hospital, Turkey were analyzed. TGs volumes and doses were noted. The patients were evaluated in terms of acute dysphagia (AD) and radiation therapy (RT)-associated xerostomia. Results The median volume of the TGs was 3.5(2.1-5.9)cc. No increased standardized uptake values (SUV) were observed in the TGs. There was no significant relationship between TGs values and the third or sixth months of xerostomia after RT. There was a significant relationship between grade ≥2 AD and TGs-Dmean (p0.020); TGs-V25(%) (p0.007); TGs-V30(%) (p0.009); TGs-V40% (p0.011); TGs-V50% (p0.010), TGs-V60% (p0.045). In terms of the risk of grade ≥2 AD, the cut-off value of the TGs-Dmean was analyzed for 50 Gy, with 75% sensitivity and 73.3% specificity (p 0.020; AUC 0.746; 95% CI 0.561-0.929). Additionally for grade ≥2 AD, the cut-off value of the TGs-V25(%) was analyzed 78 with 81.3% sensitivity and 80.0% specificity (p 0.011; AUC 0.769; 95% CI 0.591-0.947). Conclusion A significant correlation was found between TGs doses and AD during RT. TGs-V25(%) value showed higher significance. In future studies, the clinical significance of TGs can be studied especially on this value. The relationship between TGs doses and xerostomia should be evaluated with a larger series.

Anisocoria in patients with hyperhidrosis: A case series for the primary care physician.

The differential diagnosis for anisocoria is broad and ranges from benign to life-threatening causes. Often, patients with new onset anisocoria present to their primary care physician, an urgent care center, or an emergency room. As such, it is important for non-ophthalmologist physicians to be familiar with its common causes. We present two cases of pharmacologic anisocoria from Qbrexza (glycopyronnium), a wipe used in the treatment of hyperhidrosis. Identifying this medication as a cause of anisocoria in patients with hyperhidrosis can reduce costs and unnecessary testing. Furthermore, physician education about safer usage can be provided.

Polymorphic ventricular tachycardia and cardiac arrest from abiraterone-induced hypokalemia: a case report.

BACKGROUND: Polymorphic ventricular tachycardia (PMVT) is an unstable and often fatal cardiac tachyarrhythmia. While there are many causes of this rhythm, including electrolyte imbalances, ischemia, and genetic disorders, iatrogenic etiologies are important to recognize. Abiraterone is an androgen synthesis antagonist effective in treating prostate cancer, but here we describe a case of severe hypokalemia secondary to abiraterone resulting in polymorphic ventricular tachycardia and cardiac arrest. While this is a potential adverse effect of the medication, severe hypokalemia causing polymorphic ventricular tachycardia and cardiac arrest, as seen in our patient's case, has not been described. CASE PRESENTATION: A 78-year-old African-American man with history of prostate cancer presents with polymorphic ventricular tachycardia and cardiac arrest. After resuscitation, he was found to be severely hypokalemic and refractory to large doses of repletion. Evaluation of secondary causes of hypokalemia identified the likely culprit to be adverse effects from prostate cancer treatment. CONCLUSION: A broad differential diagnosis for polymorphic ventricular tachycardia is essential in identifying and treating patients presenting in this rhythm. Here we present a case of iatrogenic polymorphic ventricular tachycardia secondary to oncologic treatment.

Skin Numbness after Total Knee Arthroplasty: Complication or Side-Effect?

BACKGROUND: Peri-incisional numbness occurs frequently after Total Knee Arthroplasty (TKA), yet its impact on clinical outcomes remains controversial. With some studies reporting 100% incidence and patients often perceiving it as a minor inconvenience, its categorisation as a complication is controversial. This study investigates the prevalence and temporal changes of numbness post-TKA to refine the informed consent process and improve patient satisfaction. MATERIAL AND METHODS: A convenience sample of patients who underwent primary cemented TKA was studied. Demographic data, scar length, tourniquet time, and WOMAC scores were collected. Patients were grouped based on time from surgery, and areas of numbness for light touch and pinprick sensations measured. RESULTS: The study included 49 patients with a mean age of 68.9 years. While all patients reported numbness, the area decreased for both pinprick and light touch sensations over time. No significant correlation was found between WOMAC scores and the area of numbness. DISCUSSION: Numbness post-TKA is common, and the affected area contracts over time, implying a natural healing process. The study's findings challenge the perception of numbness as a complication and emphasise the importance of informed consent in managing patient expectations. CONCLUSIONS: 1. Postoperative numbness around the incision site following TKA is a common occurrence with minimal clinical impact on patients. 2. It is important to inform patients that this numbness will improve, although some residual numbness may remain.

Adverse Event Signal Detection Using Patients' Concerns in Pharmaceutical Care Records: Evaluation of Deep Learning Models.

BACKGROUND: Early detection of adverse events and their management are crucial to improving anticancer treatment outcomes, and listening to patients' subjective opinions (patients' voices) can make a major contribution to improving safety management. Recent progress in deep learning technologies has enabled various new approaches for the evaluation of safety-related events based on patient-generated text data, but few studies have focused on the improvement of real-time safety monitoring for individual patients. In addition, no study has yet been performed to validate deep learning models for screening patients' narratives for clinically important adverse event signals that require medical intervention. In our previous work, novel deep learning models have been developed to detect adverse event signals for hand-foot syndrome or adverse events limiting patients' daily lives from the authored narratives of patients with cancer, aiming ultimately to use them as safety monitoring support tools for individual patients. OBJECTIVE: This study was designed to evaluate whether our deep learning models can screen clinically important adverse event signals that require intervention by health care professionals. The applicability of our deep learning models to data on patients' concerns at pharmacies was also assessed. METHODS: Pharmaceutical care records at community pharmacies were used for the evaluation of our deep learning models. The records followed the SOAP format, consisting of subjective (S), objective (O), assessment (A), and plan (P) columns. Because of the unique combination of patients' concerns in the S column and the professional records of the pharmacists, this was considered a suitable data for the present purpose. Our deep learning models were applied to the S records of patients with cancer, and the extracted adverse event signals were assessed in relation to medical actions and prescribed drugs. RESULTS: From 30,784 S records of 2479 patients with at least 1 prescription of anticancer drugs, our deep learning models extracted true adverse event signals with more than 80% accuracy for both hand-foot syndrome (n=152, 91%) and adverse events limiting patients' daily lives (n=157, 80.1%). The deep learning models were also able to screen adverse event signals that require medical intervention by health care providers. The extracted adverse event signals could reflect the side effects of anticancer drugs used by the patients based on analysis of prescribed anticancer drugs. "Pain or numbness" (n=57, 36.3%), "fever" (n=46, 29.3%), and "nausea" (n=40, 25.5%) were common symptoms out of the true adverse event signals identified by the model for adverse events limiting patients' daily lives. CONCLUSIONS: Our deep learning models were able to screen clinically important adverse event signals that require intervention for symptoms. It was also confirmed that these deep learning models could be applied to patients' subjective information recorded in pharmaceutical care records accumulated during pharmacists' daily work.

Acute Non-infectious Cystitis Secondary to Immune-Related Adverse Events in a Patient Receiving Pembrolizumab for Treatment of Non-small Cell Lung Cancer: A Case Report.

Immune-related adverse events (IrAEs) involving the bladder are seldom reported and tend to be overlooked by oncologists. Cystitis caused by immune checkpoint inhibitors (ICIs) is rarely reported, with only four documented instances in the literature, of which just one case is attributed to pembrolizumab. We present a rare occurrence of pembrolizumab-induced hemorrhagic cystitis in a 71-year-old male with stage II-b lung adenocarcinoma with an chronic indwelling Foley catheter. He presented with persistent hematuria despite the completion of a course of antibiotics for a urinary infection; a cystoscopic examination was also normal. Drug-induced cystitis was suspected and the patient was treated with prednisone as well as temporary discontinuation of pembrolizumab, which was followed by an improvement of symptoms.

Effect of rituximab on immune status in children with aggressive mature B-cell lymphoma/leukemia-a prospective study from CCCG-BNHL-2015.

Background: Limited research has been conducted on the impact of rituximab on immune function and the incidence of side effects in children undergoing combination chemotherapy for aggressive mature B-cell lymphoma/leukemia. Methods: Clinical data from 85 patients with primary pediatric aggressive mature B-cell lymphoma/leukemia, treated according to the Chinese Children's Cancer Group (CCCG)-mature B-cell non-Hodgkin lymphoma (BNHL)-2015 protocol from June 1, 2015, to December 1, 2022, were collected from three tertiary medical centers in China. Patients with pre-existing malignancies or primary immune deficiencies (PIDs) were excluded. Results: Between June 1, 2015, and December 1, 2022, 85 patients (65 [76.5%] boys and 20[23.5%] girls; mean age, 6.95 years) were enrolled, and immune data at baseline during follow-up were analyzed. At the end of chemotherapy, a higher proportion of patients in the R4 group exhibited a decrease in peripheral blood CD3- CD19+ B cells (20[100%] of 20 vs 13[47.8%] of 18, p = 0.04), CD3+ T cells (21[91.3%] of 23 vs 14[60.9%] of 23, p = 0.016), and serum IgM (14[60.9%] of 23 vs 4[17.4%] of 23, p = 0.003) compared to the R3 group. However, these differences were no longer statistically significant six months after chemotherapy administration. The combination of rituximab with AA was associated with a higher incidence of significant thrombocytopenia (49[81.7%] of 60 vs 29[52.7%] of 55, p = 0.001) and infection (35[58.3%] of 60 vs 17[30.9%] of 55, p = 0.003) compared to AA alone. Furthermore, the combination of rituximab with BB was linked to a higher incidence of significant thrombocytopenia (32[52.5%] of 61 vs 31[31.0%] of 100, p = 0.007) compared to BB alone. Conclusions: While the effects of rituximab in combination with intense chemotherapy for childhood aggressive mature B-cell lymphoma/leukemia on children's immune function generally recovers within six months it may still prolong the recovery from immunoglobulinemia, posing a risk of secondary infections. Further studies are required to identify children with potential primary immunodeficiencies.

Case Report: Neurological adverse events in subject with myasthenia gravis after PCSK9 inhibitor administration.

Background: Myasthenia gravis is a rare chronic autoimmune neuromuscular disorder mainly caused by autoantibodies to the nicotinic acetylcholine receptor. Cholesterol is an essential molecule that affects the distribution and proper functioning of this receptor. Several reports have described the potential worsening of myasthenia gravis in patients treated with statins. Case presentation: The patient was an obese 72 years old man, past smoker, diagnosed with ischaemic heart disease, type 2 diabetes mellitus and lipid metabolism disorder. Statin treatment was not implemented because of chronic myasthenia gravis and PCSK9i monotherapy [Repatha (evolucamab), 140 mg] was implemented to treat dyslipidaemia. Within 24 h after the first dose of PCSK9i the patient developed severe muscle weakness, joint pain, fever, and general discomfort, lasting for several days. Despite strong advice against the second dose administration, this was self-administered approximately 2 weeks later, leading to report significant worsening of the muscle problems, leading to the patient admittion to the neurology department where he was being treated for myasthenia gravis attack. Conclusion: Based on the neurologist's conclusion, it can be assumed that in this case, treatment with PCSK9i resulted in significant worsening of the patient's chronic disease.

The Safety Profile of Common COVID-19 Vaccines in Patients With Multiple Sclerosis.

Background and objective Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). In light of the COVID-19 pandemic that emerged in late 2019, the World Health Organization (WHO) has endorsed mass immunization to enhance the population's immunity against the virus. However, certain concerns have been raised about the safety of COVID-19 vaccines among patients with autoimmune disorders, including those with multiple sclerosis (MS). Further research is required to address these concerns and to gain deeper insights into the possible complications of COVID-19 vaccines among MS patients. This study aimed to assess the side effects of COVID-19 vaccines among MS patients. Methods An observational cross-sectional study was conducted between May and November 2023 at the National Guard Hospital, Jeddah, Saudi Arabia. All MS patients enrolled in our local registry system and provided phone numbers were included in the study. A total of 208 MS patients were surveyed via phone interviews, and data were collected regarding their demographics, MS history, COVID-19 history, SARS-CoV-2 vaccination status, and their exposure to disease-modifying therapies (DMTs). All results were analyzed using Stata software. Statistical significance was set at a CI of 95% and a p-value <0.05. Results In our cohort, 128 (61.5%) patients had received three doses of the COVID-19 vaccine, while 68 (32.7%) had received two doses; four patients (2.0%) had received only one dose, five (2.4%) had not received the vaccine, and the number of doses was unknown for the remaining three patients (1.4%). The BNT162b2 mRNA COVID-19 Vaccine from Pfizer-BioNTech was the most commonly administered (n=136 patients, 66.0%), followed byChAdOx1 nCoV-19 Vaccine from Oxford-AstraZeneca (n=47 patients, 22.8%), and mRNA-1273 SARS-CoV-2 Vaccine from Moderna (n=5 patients, 2.4%). Of note, 139 patients (69.5%) reported experiencing adverse events after receiving the vaccine, and the ChAdOx1 nCoV-19 Vaccine from Oxford-AstraZeneca was significantly associated with higher rates of side effects, in 87.8% of the patients. Conclusion A sizable proportion of MS patients experienced self-limiting side effects from exposure to the COVID-19 vaccine. The rates and incidence of side effects were similar to those encountered in the general population. None of the adverse effects recorded in our population of MS patients were serious or life-threatening. We recommend that physicians encourage patients with MS who have never received COVID-19 vaccination to get promptly vaccinated as the risks of COVID-19 infection far outweigh the minor risks associated with COVID-19 vaccination.

Microbial bile acid metabolite ameliorates mycophenolate mofetil-induced gastrointestinal toxicity through vitamin D3 receptor.

Mycophenolate mofetil (MMF) is one of the most used immunosuppressive drugs in organ transplantation, but frequent gastrointestinal (GI) side effects through unknown mechanisms limit its clinical use. Gut microbiota and its metabolites were recently reported to play a vital role in MMF-induced GI toxicity, but the specific mechanism of how they interact with the human body is still unclear. Here, we found that secondary bile acids (BAs), as bacterial metabolites, were significantly reduced by MMF administration in the gut of mice. Microbiome data and fecal microbiota transfer model supported a microbiota-dependent effect on the reduction of secondary BAs. Supplementation of the secondary BA lithocholic acid alleviated MMF-induced weight loss, colonic inflammation, and oxidative phosphorylation damage. Genetic deletion of the vitamin D3 receptor (VDR), which serves as a primary colonic BA receptor, in colonic epithelial cells (VDRΔIEC) abolished the therapeutic effect of lithocholic acid on MMF-induced GI toxicity. Impressively, we discovered that paricalcitol, a Food and Drug Administration-approved VDR agonist that has been used in clinics for years, could effectively alleviate MMF-induced GI toxicity. Our study reveals a previously unrecognized mechanism of gut microbiota, BAs, and VDR signaling in MMF-induced GI side effects, offering potential therapeutic strategies for clinics.

Novel Strategy in the Detection of Adverse Cutaneous Drug Reactions: A Case Series Study.

With multimorbidity on the rise, adverse cutaneous drug reactions are becoming a daily challenge in clinical practice. The objective evaluation of the skin lesion is crucial but hardly realized due to missing technology and guidelines. In this study, the novel Dermus SkinScanner-U, an optically guided high-frequency ultrasound imaging device, was evaluated regarding its comparability with the Dermatology Life Quality Index (DLQI) and the pharmacological analysis of the patients' drug therapy. A total of 40 adult patients were evaluated, all with chronic medication use and skin lesions that led to non-compliance toward the pharmacotherapy. With the ongoing aim of further improving the methodology, the first results, with two detailed patient cases, are presented here. It was concluded that in the cases evaluated, there was a significant correlation between the characteristics of the lesions observed on the optical and ultrasound image, the DLQI score, and the pharmacological analysis. The next steps include increasing the scale of the study to ultimately develop a quality-assured methodology for the correct diagnosis of skin-related adverse drug reactions and to prepare a database with the most frequently observed events.

An Unusual Case of Apixaban-Induced Small Vessel Vasculitis: Leukocytoclastic Vasculitis.

Apixaban is a rare cause of drug-induced leukocytoclastic vasculitis (LCV). We report a case of apixaban-induced LCV in a 55-year-old male with deep vein thrombosis who developed systemic symptoms and pruritic rash in the bilateral lower extremity after 17 days of apixaban therapy. A skin biopsy confirmed the LCV, and he was diagnosed with apixaban-induced LCV after ruling out all other possible causes. His condition improved after apixaban discontinuation, supportive management, and oral prednisone. Our case highlights the early diagnosis and management of drug-induced LCV and also describes the existing literature to highlight existing knowledge and potential mechanisms underlying anticoagulant-induced vasculitis.

Beyond the Benefits: A Case Study on the Complications of Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibitors (Euglycemic Diabetic Ketoacidosis (DKA) and Takotsubo Cardiomyopathy).

Sodium-glucose co-transporter-2 (SGLT2) inhibitors, integral in type 2 diabetes mellitus (T2DM) management, are not without risks, with reported adverse effects including euglycemic diabetic ketoacidosis (EDKA). We present a case of a 75-year-old female with T2DM on canagliflozin, who developed altered mental status (AMS), nausea, vomiting, and hypotension. The laboratory results revealed ketoacidosis, elevated troponins, and Takotsubo cardiomyopathy (TC), prompting the cessation of canagliflozin. This paradoxical EDKA case underscores the necessity for cautious prescribing. Additionally, our discussion delves into the risk factors, mechanisms, and epidemiology of EDKA associated with SGLT2 inhibitors (SGLT2i), emphasizing the importance of individualized medicine and shared decision-making in their use, despite their proven cardiovascular benefits.