Naproxen adjunct to fluoxetine for moderate-to-severe obsessive-compulsive disorder: A randomized, double-blind, placebo-controlled trial.

AIM: Current treatments for obsessive-compulsive disorder (OCD) encounter resistance and limiting adverse events, necessitating novel therapeutic strategies. This study aimed to investigate the benefits of naproxen, a medication with effects on inflammation and neuronal function, on OCD. METHODS: One hundred and four OCD outpatients with a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score of >21 were equally assigned to receive fluoxetine plus either naproxen 250 mg or matched placebo q12hr. Patients were assessed using the Y-BOCS by recording the subscale scores at baseline and weeks 5 and 10 to evaluate efficacy. They were also assessed in terms of tolerability. RESULTS: Data from 96 patients were analyzed. The baseline characteristics were comparable between the groups. There were significant time-treatment interaction effects on the obsession subscale ( η P 2 $$ {\eta}_P^2 $$ = 0.055) and total ( η P 2 $$ {\eta}_P^2 $$ = 0.043) scores of Y-BOCS. Reductions in the obsession subscale and total scores of Y-BOCS were significantly greater in the fluoxetine plus naproxen group until the endpoint (Cohen's d = 0.560 and Cohen's d = 0.477, respectively). However, the difference in compulsion subscale score changes between the groups was not significant. Respondents with a reduction of ≥35% in Y-BOCS total scores were significantly more in the fluoxetine plus naproxen group (80.0% versus 47.8%). The side effect frequencies were comparable between the groups. CONCLUSION: Naproxen, adjunct to fluoxetine, outperformed adjunctive placebo in treating obsession and total symptoms of OCD patients in a safe and tolerable manner. CLINICAL TRIAL REGISTRATION: The study protocol was registered and published in the Iranian Registry of Clinical Trials (http://www.irct.ir; registration number IRCT20090117001556N139).

Dysregulation of RAS proteostasis by autosomal-dominant LZTR1 mutation induces Noonan syndrome-like phenotypes in mice.

Leucine-zipper-like post translational regulator 1 (LZTR1) is a member of the BTB-Kelch superfamily, which regulates the RAS proteostasis. Autosomal dominant (AD) mutations in LZTR1 have been identified in patients with Noonan syndrome (NS), a congenital anomaly syndrome. However, it remains unclear whether LZTR1 AD mutations regulate the proteostasis of the RAS subfamily molecules or cause NS-like phenotypes in vivo. To elucidate the pathogenesis of LZTR1 mutations, we generated two novel LZTR1 mutation knock-in mice (Lztr1G245R/+ and Lztr1R409C/+), which correspond to the human p.G248R and p.R412C mutations, respectively. LZTR1-mutant male mice exhibit low birth weight, distinctive facial features, and cardiac hypertrophy. Cardiomyocyte size and the expression of RAS subfamily members, including MRAS and RIT1, were significantly increased in the left ventricles (LVs) of mutant male mice. LZTR1 AD mutants did not interact with RIT1 and functioned as dominant-negative forms of wild-type LZTR1. Multi-omics analysis revealed that the MAPK signaling pathway was activated in the LVs of mutant mice. Treatment with the MEK inhibitor trametinib ameliorated cardiac hypertrophy in mutant male mice. These results suggest that MEK/ERK pathway is a therapeutic target for NS-like phenotype resulting from dysfunction of RAS proteostasis by LZTR1 AD mutations.

Vitamin C, doxycycline, and azithromycin (VDA) targeted changes in cellular senescence-related genes in human adipose-derived mesenchymal stem cells.

Objectives: Adipose-derived Mesenchymal stem cells (ASCs) have garnered attention for their regenerative potential; therefore, their cellular senescence-related gene expression remains crucial in therapeutic contexts. Nowadays, combination therapies have shown promising results in reducing senescent cells. This study investigated the effects of vitamin C, doxycycline, and azithromycin co-treatment on the key cellular senescence-associated genes in ASCs. Materials and Methods: Human ASCs were cultured and treated for 24 hr with vitamin C, doxycycline, azithromycin, and a combination of three drugs. Total RNAs were extracted, and the expression of p21, p16, Nanog, Oct4, and Sox2 genes was assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Additionally, cell cycle alterations were analyzed via flow cytometry after treatment with these compounds. Results: Notably, vitamin C treatment resulted in a significant down-regulation of p21 gene expression (P<0.01), implicating the potential role of vitamin C in promoting cell cycle progression. Doxycycline treatment led to a significant up-regulation of p21 and p16 gene expression (P<0.05), as it has previously been shown to induce cell cycle arrest. Similarly, azithromycin treatment predominantly increased p21 expression (P<0.05). Besides, cell cycle analysis revealed that each compound had changed the distribution of cells across different phases of the cell cycle. Conclusion: The combined use of all three drugs yielded intricate interactions, suggesting a complex yet promising approach to future research. According to our findings, the major difference in the combination drug-treated group (VDA) can be explained by the neutralizing effect of these three components in the environment.

Engine of Innovation in Hospital Pharmacy: Applications and Reflections of ChatGPT.

Hospital pharmacy plays an important role in ensuring medical care quality and safety, especially in the area of drug information retrieval, therapy guidance, and drug-drug interaction management. ChatGPT is a powerful artificial intelligence language model that can generate natural-language texts. Here, we explored the applications and reflections of ChatGPT in hospital pharmacy, where it may enhance the quality and efficiency of pharmaceutical care. We also explored ChatGPT's prospects in hospital pharmacy and discussed its working principle, diverse applications, and practical cases in daily operations and scientific research. Meanwhile, the challenges and limitations of ChatGPT, such as data privacy, ethical issues, bias and discrimination, and human oversight, are discussed. ChatGPT is a promising tool for hospital pharmacy, but it requires careful evaluation and validation before it can be integrated into clinical practice. Some suggestions for future research and development of ChatGPT in hospital pharmacy are provided.

Corrigendum: Study on the effects of intestinal flora on gouty arthritis.

[This corrects the article DOI: 10.3389/fcimb.2024.1341953.].

Efficacy and safety in early-phase clinical trials for refractory colorectal cancer: A meta-analysis.

BACKGROUND: Despite recent metastatic colorectal cancer (mCRC) therapeutic innovations a comprehensive synthesis of patient outcome and risk-benefit assessment of phase 1/2 trials is missing. The aim of this meta-analysis is to assess efficacy, safety, and trends over time for phase 1 and 2 mCRC trials by examining clinical benefit rate (CBR), overall response rate (ORR), grade 3 or higher adverse events (AE), and discontinuation due to AE. METHODS: The PRISMA guidelines were followed. We searched PubMed and Embase for publications of phase 1/2 trials between 2010-2021. Trials reporting on new therapies for treatment-refractory mCRC were included. RESULTS: The search strategy yielded 4175 unique reports, of which 258 publications were eligible. These publications report data of 277 unique treatment arms. Overall ORR was 6 %, CBR was 27 % in phase 1 % and 36 % in phase 2 trials. CBR increased from 23 % in 2010-2012 to 42 % in 2019-2021. Compared to 2010-2012, trials in 2019-2021 more often tested immunomodulators (4 % vs 23 %), included molecularly preselected populations (4 % vs 38 %) and younger patients (median age<60 44 % vs 66 %). Grade 3 + AE occurred in 35 % of patients, most frequently in trials investigating targeted treatments. CONCLUSIONS: Treatment efficacy in phase 1/2 trials is modest but improved from 2010 to 2021. This improvement is accompanied by a shift towards testing in a younger, fitter, and more strictly molecularly preselected population, as well as an increased focus on targeted and immunotherapies.

Sublingual administration of atropine eye drops for treating sialorrhea after stroke: A randomized controlled trial.

BACKGROUND: Sialorrhea is a common concern in patients with swallowing disorders after stroke. Atropine sulfate blocks the muscarinic receptors in the salivary glands and leads to reduced saliva production. OBJECTIVE: The present study aimed to assess the safety, efficacy, and tolerability of sublingual administration of atropine eye drops for treating sialorrhea after stroke. DESIGN: This was a prospective cohort study. SETTING: This study was conducted at Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Hubei Province, China. POPULATION: Stroke patients with sialorrhea were analyzed. METHODS: One hundred stroke patients with sialorrhea were randomly assigned to the control group and the test group (n = 50 per group). The control group received routine swallowing rehabilitation training and neuromuscular electrical stimulation. The test group received therapy with 1% atropine eye drops, wherein one drop was administered sublingually 3 times per day. The Sialorrhea Scoring Scale and the incidence of adverse events were used to compare the severity of sialorrhea in the two groups. RESULTS: The mean (standard deviation) sialorrhea score improved from 5.12 for the control group with routine rehabilitation training to 3.94 for the test group with atropine eye drop administration (P < 0.01). No significant differences in the incidence of adverse events were observed between the two groups. CONCLUSIONS: The sublingual administration of 1% atropine eye drops three times per day can reduce the degree of sialorrhea to an extent more than that achieved with routine rehabilitation training; thus, this approach is effective, safe, and minimally invasive for treating sialorrhea after stroke.

Ileal perforation at the site of peritoneal metastasis with intestinal infiltration by dual EGFR-VEGF pathway inhibition in an EGFR-mutant non-small cell lung cancer patient.

Gastrointestinal (GI) perforation including ileal perforation is a rare complication of antivascular endothelial growth factor (anti-VEGF) therapy. Risk factors of GI perforation have not been fully understood. This report highlights the case of a patient who experienced GI perforation at the site of peritoneal metastasis with intestinal infiltration immediately after treatment with dual epidermal growth factor receptor (EGFR)-VEGF pathway inhibition agents for EGFR-mutant non-small cell lung cancer (NSCLC). The administration of dual EGFR-VEGF pathway inhibition agents in EGFR mutant NSCLC patients appears to elevate the risk of GI perforation. This report provides insights into the association between EGFR mutant NSCLC and the susceptibility to GI perforation following treatment with dual EGFR-VEGF pathway inhibition agents.

Nurses' Perceptions of Support in Cancer Pharmacotherapy at a University Hospital: A Descriptive Quantitative Study.

Introduction: Advances in treatment have transformed cancer from a fatal to a chronic illness. This requires healthcare professionals, particularly nurses, to have advanced knowledge and collaborative skills. However, challenges persist in implementing patient-centered care in the context of evolving treatment complexity. Objectives: This study aimed to clarify nurses' support practices in providing cancer pharmacotherapy at a university hospital in Japan and compare these practices based on nurses' years of experience. Methods: A questionnaire survey was conducted from February to April 2023 among 430 nurses involved in provision of cancer pharmacotherapy at a Japanese university hospital. Nurses were asked about the types of support they provided during care for patients undergoing cancer pharmacotherapy. Nurses' cancer pharmacotherapy support practices were extracted using factor analysis, and differences in support scores by years of experience were examined. Results: Responses were received from 184 nurses (42.8% response rate). Three support factors were identified: "Providing patient-centered cancer pharmacotherapy," "Management of continued cancer pharmacotherapy treatment," and "Assessment of and response to physical symptoms." Scores for "Providing patient-centered cancer pharmacotherapy" were significantly lower than those for the other two factors (p < .001). The group with ≥10 years of nursing experience had statistically significantly lower practice scores than those with 4-9 years of experience. Conclusions: Enhancing nursing education and interprofessional collaboration are crucial to overcome barriers to patient-centered cancer care. Continuous learning opportunities are essential to adapt to evolving cancer treatment protocols and ensure delivery of patient-centered care, particularly for experienced nurses.

Fatal Case of Immune-Related Myocarditis and Myositis Due to Treatment with Immune Checkpoint and Tyrosine Kinase Inhibitors.

Immune checkpoint inhibitor and tyrosine kinase inhibitor combinations have become the new standard of care in the first-line treatment of metastatic clear cell renal cell carcinoma. However, there is a growing concern regarding severe immune-related adverse events. A 78-year-old man with metastatic clear cell renal cell carcinoma, treated with pembrolizumab and axitinib, was admitted to the emergency department 30 days after initiating treatment due to rapidly progressive myositis. Myocarditis with severe ventricular dysfunction was identified. Muscular biopsy findings were compatible with inflammatory myopathy associated with immune checkpoint inhibitors. Initial treatment with high-dose corticosteroids showed an insufficient response. Therapeutic escalation on the third day with methylprednisolone, immunoglobulin, and abatacept resulted in clinical improvement. On the eleventh day, a sudden malignant arrhythmia occurred, followed by cardiac arrest. This represents one of the first case reports describing myocarditis and myositis during treatment with pembrolizumab-axitinib. While immune checkpoint inhibitor may play a major role, it is also possible that the tyrosine kinase inhibitor, while attempting to promote immune modulation, also increases severe toxicities.

Medication Dosing for Children With Overweight and Obesity.

Approximately 14.7 million US children aged 2 to 19 years are obese. This creates significant challenges to dosing medications that are primarily weight based (mg/kg) and in predicting pharmacokinetics parameters in pediatric patients. Obese individuals generally have a larger volume of distribution (Vd) for lipophilic medications. Conversely, the Vd of hydrophilic medications may be increased or decreased owing to increased lean body mass, blood volume, and decreased percentage of total body water. They may also experience decreased hepatic clearance secondary to fatty infiltrates of the liver. Hence, obesity may affect loading dose, dosage interval, plasma half-life, and time to reach steady-state concentration for various medications. Weight-based dosing is also a cause for potential medication errors. This position statement of the Pediatric Pharmacy Association recommends that weight-based dosing should be used in patients ages <18 years who weigh <40 kg; weight-based dosing should be used in patients ≥40 kg, unless the recommended adult dose for the specific indication is exceeded; clinicians should use pharmacokinetic analysis for adjusting medications in children diagnosed with overweight and obesity; and research efforts continue to evaluate dosing of medications in children diagnosed with overweight and obesity.

In Vivo Evaluation of Nose-to-Brain Delivery of Liposomal Donepezil, Memantine, and BACE-1 siRNA for Alzheimer's Disease Therapy.

Our study took an innovative approach by evaluating, in vivo, the efficacy of intranasal (IN) administration of liposomal formulations of donepezil, memantine, and beta-site amyloid precursor protein-cleaving enzyme (BACE-1) siRNA, and their combination as a "triple-drug therapy" in treating Alzheimer's disease (AD). Female APP/PS1 homozygous, transgenic mice were used as an AD model. The spatial short-term memory of the APP/PS1 mice was evaluated by a Y-maze behavioral test. IN-administered formulations demonstrated better short-term memory recovery than oral administration. Triple-drug therapy induced short-term memory recovery and lowered beta-amyloid (Aß) 40 and 42 peptide levels and BACE-1 mRNA expression. Additionally, inflammatory cytokine mRNA expression was downregulated. This innovative approach opens new possibilities for Alzheimer's disease treatment and nose-to-brain delivery.

Should Hypertonic Saline Be Considered for the Treatment of Intracranial Hypertension? A Review of Current Evidence and Clinical Practices.

Intracranial hypertension (IH) is a critical neurological emergency that requires prompt intervention because failure to treat it properly can lead to severe outcomes, including secondary brain injury. Traditionally, mannitol (MNT) has been the cornerstone of hyperosmolar therapy. However, the use of hypertonic saline (HTS) has become increasingly important because of its unique advantages. Both HTS and MNT effectively reduce intracranial pressure by creating an osmotic gradient that draws fluid from brain tissue. However, unlike MNT, HTS does not induce diuresis or significantly lower blood pressure, making it more favorable for maintaining cerebral perfusion. Additionally, HTS does not cause rebound edema and carries a lower risk of renal injury than MNT. However, it is important to note that the use of HTS comes with potential risks, such as hypernatremia, hyperchloremia, and fluid overload. Due to its unique properties, HTS is a crucial agent in the management of IH, and understanding its appropriate use is essential to optimize patient outcomes.

Non­obstructive mesenteric ischaemia during drug therapy for maxillary cancer: A case report.

Non-occlusive mesenteric ischaemia (NOMI) refers to irreversible intestinal ischaemia and necrosis in the absence of organic obstruction to the mesenteric blood vessels. In cases of delayed diagnosis, the prognosis is poor and the mortality rate is 58-70%, being the highest among patients with acute mesenteric ischaemia. The risk factors for this disease include heart disease, sepsis, and administration of catecholamines and digitalis; however, there are few reports of its onset during drug therapy for malignant tumours. The present study reported the case of an 85-year-old man who developed NOMI during drug therapy for maxillary cancer. The patient was diagnosed with right maxillary carcinoma, for which paclitaxel, carboplatin and cetuximab (PCE) therapy was administered. Four days after starting the second course of PCE therapy, the patient visited the emergency department of our hospital with chief complaints of melena and abdominal pain. Contrast-enhanced computed tomography revealed ischaemia from the transverse to the descending colon, leading to a diagnosis of NOMI. Colectomy and colostomy were performed during the emergency surgery on the same day. Although the patient's general condition improved, he was transferred to a recuperation facility for palliative care.

Safety profile of drugs used in non-cystic fibrosis bronchiectasis: a narrative review.

Non-cystic fibrosis bronchiectasis is a long-term lung disease characterised by abnormal dilatation of the bronchi, with patients experiencing chronic productive cough and recurrent exacerbations. Currently, there are no licensed drugs for use in bronchiectasis while clinical trials have been conducted to either test new drugs or repurpose existing ones. These drugs target the underlying pathophysiology of bronchiectasis which is known to include infection, inflammation, mucus hypersecretion and retention. Most of the drugs used in daily clinical practice for bronchiectasis are off-label with no randomised trials exploring their safety. This review aims at exploring the safety profile of drugs frequently used in clinical practice to manage bronchiectasis, including antibiotics (e.g. macrolides, aminoglycosides, polymyxins, fluoroquinolones, aztreonam), mucoactive therapy (e.g. hypertonic saline, mannitol, DNase and carbocisteine), anti-inflammatory therapy (inhaled corticosteroids) and drugs currently in development for use in bronchiectasis (e.g. brensocatib, benralizumab and itepekimab).

A review on the safety aspects of drugs currently being used in bronchiectasis This review aims to detail the safety aspects of drugs that are currently prescribed to patients with bronchiectasis. These drugs are used in bronchiectasis without some of the high quality trials seen for other lung conditions. The drugs used have shown clinical benefits in patients who are suffering from infective exacerbations or worsening of the disease. The idea behind the use of these drugs is that they target the pathological processes in bronchiectasis such as inflammation, infection and excess mucus production. In this review, we have included the results from clinical trials that assessed the use of antibiotics (both oral and inhaled) during pulmonary infections and long-term antibiotics to prevent infections. Mucus production is a major symptom of bronchiectasis, and hence the drugs that target mucus secretion and consistency are used in an attempt to improve the quality of life and prevent infections. Inflammation is a key component of bronchiectasis, and we report on the safety of inhaled steroids in bronchiectasis. Some new drugs are currently being tried in clinical trials worldwide and are discussed. The occurrence of multiple other medical problems are recognized in people living with bronchiectasis has been seen to increase symptoms and linked with higher infection rates and hospitalizations. This means patients are often on lots of different medications for multiple conditions; we highlight the importance of considering the fact these drugs in combination can lead to potential issues and side effects linked to polypharmacy.

Aspergillus niger as a rare cause of postarthroscopy knee septic arthritis in a healthy patient.

This case report outlines the diagnostic and therapeutic challenges encountered in a man in his 70s suffering from knee septic arthritis caused by Aspergillus niger It is the second published case in the literature with osteoarticular infection from A. niger and the first one in the last 40 years. Following knee arthroscopy, the patient experienced persistent pain, swelling and discomfort, prompting further investigation. Postoperative knee cultures were negative for infection, but symptoms were not ameliorated. Therefore, an arthroscopic debridement was performed that revealed severe joint inflammation and degeneration. Cultures from the synovial fluid and tissue samples identified infection from A. niger sp. Antimicrobial treatment with voriconazole finally led to significant clinical improvement and eradication of infection. This case highlights the intricacies involved in diagnosing and managing fungal osteoarticular infections in healthy patients without concomitant medical diseases or comorbidities.

Choice of compound, dosage, and management of side effects for long-term corticosteroid treatment in Duchenne muscular dystrophy: Guidelines from the Neuromuscular Commission of the French Society of Pediatric Neurology.

The French Society of Pediatric Neurology and the FILNEMUS network created a working group on corticosteroid therapy in children with Duchenne muscular dystrophy in order to analyze the literature review and current French practices. The aim of this work was to produce guidelines regarding treatment initiation, pre-therapeutic interventions, choice between available compounds, and treatment monitoring (dosage, duration, and discontinuation). The treatment side effects and their management are also detailed: osteoporosis, endocrinological anomaly (growth delay, weight gain, pubertal delay), cataract, arterial hypertension, behavioral disorders, management of immunosuppression and vaccines, and management of gastrointestinal and metabolic complications.

Current Treatment Methods for Charcot-Marie-Tooth Diseases.

Charcot-Marie-Tooth (CMT) disease, the most common inherited neuromuscular disorder, exhibits a wide phenotypic range, genetic heterogeneity, and a variable disease course. The diverse molecular genetic mechanisms of CMT were discovered over the past three decades with the development of molecular biology and gene sequencing technologies. These methods have brought new options for CMT reclassification and led to an exciting era of treatment target discovery for this incurable disease. Currently, there are no approved disease management methods that can fully cure patients with CMT, and rehabilitation, orthotics, and surgery are the only available treatments to ameliorate symptoms. Considerable research attention has been given to disease-modifying therapies, including gene silencing, gene addition, and gene editing, but most treatments that reach clinical trials are drug treatments, while currently, only gene therapies for CMT2S have reached the clinical trial stage. In this review, we highlight the pathogenic mechanisms and therapeutic investigations of different subtypes of CMT, and promising therapeutic approaches are also discussed.

Synergistic Effects of Artesunate in Combination with Amphotericin B and Miltefosine against Leishmania infantum: Potential for Dose Reduction and Enhanced Therapeutic Strategies.

Leishmaniasis is a tropical infectious disease caused by Leishmania parasites. The disease can be spread by the bite of an infected sand fly. Currently, five chemotherapeutic drugs are available in leishmaniasis treatment. However, these drugs exhibit toxicity and serious adverse effects on infected individuals, necessitating alternative treatment strategies. One such strategy involves using combinations of existing antileishmanial drugs. In this study, we evaluated the interaction between artesunate (AS) and three antileishmanial drugs-amphotericin B (AmB), miltefosine (MF), and paromomycin (PM) against Leishmania infantum. This evaluation marks the first time such an assessment has been conducted. The Chou-Talalay combination index method was employed to analyze the drug interaction. The findings revealed that the interaction between AS and AmB ranged from antagonistic to synergistic, while the interaction between AS and MF showed moderate to strong synergism. In contrast, the interaction between AS and PM resulted in an antagonistic interaction, which differs from the combinations with AmB or MF. This study provides valuable insights for developing novel drug regimens for leishmaniasis treatment, emphasizing the potential of AS and its combination with existing antileishmanial drugs. Further research is necessary to optimize drug combinations and minimize adverse effects, leading to more effective therapeutic outcomes.