Stannous fluoride forms aggregates between outer and inner membranes leading to membrane rupture of Porphyromonas gingivalis and Prevotella pallens.

Objective: Stannous has been shown to bind to free lipopolysaccharides, thus preventing them from binding to TLR receptors. This study was undertaken to determine the histomorphological mechanism of stannous binding to anaerobic bacteria. Methods: Two bacteria associated with gingivitis and advanced periodontal disease, Porphyromonas gingivalis (P. gingivalis) and Prevotella pallens (P. pallens), were cultured in 25-1,000 µM of stannous fluoride and stannous chloride for 48 h. The growth rate was estimated using absorbance OD600. Bacterial cells were then fixed and processed for transmission electron microscopy (TEM) analysis. Results: Stannous fluoride inhibited proliferation of both P. gingivalis and P. pallens in a dose-dependent manner. There was a statistically significant suppression of the growth curve starting at 100 µM for P. pallens (P = 0.050) and 200 µM for P. gingivalis (P = 0.039). TEM analysis revealed a thick layer of polysaccharides (19.8 nm) in P. gingivalis. The outer and inner membranes were clearly visible with low electron densities in both bacteria. Stannous diffused into bacterial membranes and formed precipitates in the areas spanning outer and inner membranes and below inner membranes. Precipitates varied in size ranging from 46.4 to 84.5 nm in length, and 18.4 to 35.9 nm in width. The membranes were disintegrated in the region where stannous formed precipitates. Cytosolic contents were leaked out, and in several cases, small vesicles were formed. Stannous precipitates were more abundant in numbers and larger in size in bacteria treated with high concentrations (100-300 µM) than in low concentrations (25-50 µM) of stannous fluoride. Furthermore, most of the bacteria were disintegrated in the groups treated with 100-300 µM stannous fluoride. At low concentrations (25 µM), stannous fluoride formed complexes primarily around outer membranes, to which lipopolysaccharides are anchored. Stannous chloride results showed similar trends, but it was less potent than stannous fluoride. Conclusion: Stannous fluoride can penetrate bacteria, bind to the constituents of the membrane and form precipitates between outer and inner membranes and beneath inner membranes. These large precipitates damaged the integrity of membranes and allowed cytosolic contents to be leaked out. Stannous complexes formed at the outer membranes, even at low concentrations (25 µM).

Acute Motor Conduction Block Neuropathy After Initiation of Omalizumab: Case Report and Literature Review for Possible Causality.

Background: Omalizumab is an established therapy for allergic conditions, yet its neurological effects remain underexplored compared to other biological agents. Case description: A 45-year-old male with asthma developed acute quadriparesis one week after receiving the first dose of omalizumab. Electrophysiological studies have shown partial motor conduction block in multiple nerves, with reduced CMAP amplitudes and absent F-waves in others. CSF showed cyto-albuminous dissociation. The diagnosis was a variant of Guillain-Barré syndrome. Despite intravenous immunoglobulin (IVIG) therapy, the patient experienced persistent neuropathic symptoms. Discussion: The patient presented with acute quadriparesis devoid of sensory or cranial nerve involvement, suggestive of a variant of Guillain-Barré syndrome (GBS) known as acute motor conduction block neuropathy (AMCBN). Electrophysiological studies have indicated conduction block without demyelination, implicating axonal degeneration. Despite negative findings for common etiologies, the temporal association between omalizumab administration and symptom onset suggests a potential link, supported by criteria for drug-induced illness. Conflicting evidence exists regarding omalizumab's neurological effects, with proposed mechanisms including autoimmune reactions and mast cell dysfunction. Comparisons to TNF-α antagonists highlight similar neuropathy patterns, indicating a need for further research to clarify omalizumab's neurotoxicity. Conclusion: In conclusion, while omalizumab holds promise for allergic conditions, including chronic urticaria, its potential impact on peripheral nerves necessitates vigilance among clinicians. Further studies are imperative to ascertain the risk-benefit profile and elucidate underlying mechanisms and risk factors of neurological complications associated with omalizumab therapy.

Oral Lipid Nanocrystal Amphotericin B (MAT2203) for the Treatment of Invasive Fungal Infections.

Amphotericin B (AmB) has broad fungicidal activity against many fungi, but the high incidence of adverse events, particularly nephrotoxicity, and the need for intravenous administration restrict its use for many patients. MAT2203, an investigational oral AmB formulation available under a compassionate use program, uses a lipid nanocrystal bilayer structure to deliver AmB with lower toxicity. We present a synopsis of clinical characteristics, treatment course, and outcomes for 5 patients who were treated with MAT2203. Outcomes were positive, with cure of infection noted in 4 patients and improvement in 1 patient who remains on therapy. MAT2203 was well tolerated with only modest gastrointestinal adverse effects. This new oral formulation might provide a safer treatment option for patients requiring extended courses of AmB.

Assessing GPT-4's Performance in Delivering Medical Advice: Comparative Analysis With Human Experts.

Background: Accurate medical advice is paramount in ensuring optimal patient care, and misinformation can lead to misguided decisions with potentially detrimental health outcomes. The emergence of large language models (LLMs) such as OpenAI's GPT-4 has spurred interest in their potential health care applications, particularly in automated medical consultation. Yet, rigorous investigations comparing their performance to human experts remain sparse. Objective: This study aims to compare the medical accuracy of GPT-4 with human experts in providing medical advice using real-world user-generated queries, with a specific focus on cardiology. It also sought to analyze the performance of GPT-4 and human experts in specific question categories, including drug or medication information and preliminary diagnoses. Methods: We collected 251 pairs of cardiology-specific questions from general users and answers from human experts via an internet portal. GPT-4 was tasked with generating responses to the same questions. Three independent cardiologists (SL, JHK, and JJC) evaluated the answers provided by both human experts and GPT-4. Using a computer interface, each evaluator compared the pairs and determined which answer was superior, and they quantitatively measured the clarity and complexity of the questions as well as the accuracy and appropriateness of the responses, applying a 3-tiered grading scale (low, medium, and high). Furthermore, a linguistic analysis was conducted to compare the length and vocabulary diversity of the responses using word count and type-token ratio. Results: GPT-4 and human experts displayed comparable efficacy in medical accuracy ("GPT-4 is better" at 132/251, 52.6% vs "Human expert is better" at 119/251, 47.4%). In accuracy level categorization, humans had more high-accuracy responses than GPT-4 (50/237, 21.1% vs 30/238, 12.6%) but also a greater proportion of low-accuracy responses (11/237, 4.6% vs 1/238, 0.4%; P=.001). GPT-4 responses were generally longer and used a less diverse vocabulary than those of human experts, potentially enhancing their comprehensibility for general users (sentence count: mean 10.9, SD 4.2 vs mean 5.9, SD 3.7; P<.001; type-token ratio: mean 0.69, SD 0.07 vs mean 0.79, SD 0.09; P<.001). Nevertheless, human experts outperformed GPT-4 in specific question categories, notably those related to drug or medication information and preliminary diagnoses. These findings highlight the limitations of GPT-4 in providing advice based on clinical experience. Conclusions: GPT-4 has shown promising potential in automated medical consultation, with comparable medical accuracy to human experts. However, challenges remain particularly in the realm of nuanced clinical judgment. Future improvements in LLMs may require the integration of specific clinical reasoning pathways and regulatory oversight for safe use. Further research is needed to understand the full potential of LLMs across various medical specialties and conditions.

Development of 5-hydroxybenzothiophene derivatives as multi-kinase inhibitors with potential anti-cancer activity.

Aim: Chemoresistance in cancer challenges the classical therapeutic strategy of 'one molecule-one target'. To combat this, multi-target therapies that inhibit various cancer-relevant targets simultaneously are proposed. Methods & results: We introduce 5-hydroxybenzothiophene derivatives as effective multi-target kinase inhibitors, showing notable growth inhibitory activity across different cancer cell lines. Specifically, compound 16b, featuring a 5-hydroxybenzothiophene hydrazide scaffold, emerged as a potent inhibitor, displaying low IC50 values against key kinases and demonstrating significant anti-cancer effects, particularly against U87MG glioblastoma cells. It induced G2/M cell cycle arrest, apoptosis and inhibited cell migration by modulating apoptotic markers. Conclusion: 16b represents a promising lead for developing new anti-cancer agents targeting multiple kinases with affinity to the hydroxybenzothiophene core.

[Box: see text].

Assessing genotoxic effects of chemotherapy agents by a robust in vitro assay based on mass spectrometric quantification of γ-H2AX in HepG2 cells.

Chemotherapy has already proven widely effective in treating cancer. Chemotherapeutic agents usually include DNA damaging agents and non-DNA damaging agents. Assessing genotoxic effect is significant during chemotherapy drug development, since the ability to attack DNA is the major concern for DNA damaging agents which relates to the therapeutic effect, meanwhile genotoxicity should also be evaluated for chemotherapy agents' safety especially for non-DNA damaging agents. However, currently applicability of in vitro genotoxicity assays is hampered by the fact that genotoxicity results have comparatively high false positive rates. γ-H2AX has been shown to be a bifunctional biomarker reflecting both DNA damage response and repair. Previously, we developed an in vitro genotoxicity assay based on γ-H2AX quantification using mass spectrometry. Here, we employed the assay to quantitatively assess the genotoxic effects of 34 classic chemotherapy agents in HepG2 cells. Results demonstrated that the evaluation of cellular γ-H2AX could be an effective approach to screen and distinguish types of action of different classes of chemotherapy agents. In addition, two crucial indexes of DNA repair kinetic curve, i.e., k (speed of γ-H2AX descending) and t50 (time required for γ-H2AX to drop to half of the maximum value) estimated by our developed online tools were employed to further evaluate nine representative chemotherapy agents, which showed a close association with therapeutic index or carcinogenic level. The present study demonstrated that mass spectrometric quantification of γ-H2AX may be an appropriate tool to preliminarily evaluate genotoxic effects of chemotherapy agents.

Assessment of the safety of Roxadustat for cardiovascular events in chronic kidney disease-related anemia using meta-analysis and bioinformatics.

Objective: This study compares the cardiovascular risk in anemic chronic kidney disease patients treated with Roxadustat versus erythropoietin stimulating agents (ESAs). It also explores the cardiovascular impact of Roxadustat. Methods: We searched PubMed, EMBASE, Cochrane, Scopus, and Web of Science databases up to 13 August 2023, using terms such as "ESA," "Roxadustat," "MACE," "stroke," "death," "myocardial infarction," and "heart failure." Two researchers independently selected and extracted data based on predefined criteria. We assessed the risk of bias with the Cochrane tool and analyzed statistical heterogeneity using the Q and I2 tests. We conducted subgroup analyses by geographical region and performed data analysis with Stata 14.0 and RevMan 5.4 software. Data were sourced from the NCBI database by filtering for "Roxadustat" and "human," and differentially expressed genes were identified using R software, setting the significance at p < 0.01 and a 2-fold logFC, followed by GO enrichment analysis, KEGG pathway analysis, and protein interaction network analysis. Results: A total of 15 articles encompassing 1,43,065 patients were analyzed, including 1,38,739 patients treated with ESA and 4,326 patients treated with Roxadustat. In the overall population meta-analysis, the incidences of Major Adverse Cardiovascular Events (MACE), death, and heart failure (HF) were 13%, 8%, and 4% in the Roxadustat group, compared to 17%, 12%, and 6% in the ESA group, respectively, with P-values greater than 0.05. In the subgroup analysis, the incidences were 13%, 11%, and 4% for the Roxadustat group versus 17%, 15%, and 5% for the ESA group, also with p-values greater than 0.05. Bioinformatics analysis identified 59 differentially expressed genes, mainly involved in the inflammatory response. GO enrichment analysis revealed that these genes are primarily related to integrin binding. The main pathways identified were the TNF signaling pathway, NF-κB signaling pathway, and lipid metabolism related to atherosclerosis. The protein interaction network highlighted IL1B, CXCL8, ICAM1, CCL2, and CCL5 as the top five significantly different genes, all involved in the inflammatory response and downregulated by Roxadustat, suggesting a potential role in reducing inflammation. Conclusion: The meta-analysis suggests that the use of Roxadustat and ESA in treating anemia associated with chronic kidney disease does not significantly alter the likelihood of cardiovascular events in the overall and American populations. However, Roxadustat exhibited a safer profile with respect to MACE, death, and heart failure. The bioinformatics findings suggest that Roxadustat may influence integrin adhesion and affect the TNF and NF-κB signaling pathways, along with lipid and atherosclerosis pathways, potentially reducing inflammation.

Controversies in the management of community-acquired pneumonia in adults.

Community-acquired pneumonia (CAP) is a common infectious syndrome in Australia and a leading global cause of morbidity and mortality. It drives a significant amount of antimicrobial prescribing in Australia. Accurate assessment and stratification of CAP severity is important. However, adequate evaluation is challenging and controversy remains about the optimal method. Streptococcus pneumoniae is the most commonly identified bacterial pathogen causing CAP. As such, oral amoxicillin monotherapy is the mainstay of empirical therapy for low-severity CAP. The need to start empirical therapy for pathogens such as Mycoplasma pneumoniae and Legionella species in low-severity CAP remains controversial; evaluating the causative pathogen on clinical grounds alone is difficult. Oral antibiotics recommended for CAP (e.g. amoxicillin, doxycycline) have excellent bioavailability and may be used instead of intravenous therapy in some hospitalised patients. A duration of 5 days of antibiotic therapy is recommended in clinical practice guidelines for patients with uncomplicated CAP who meet stability criteria at follow-up.

One Year of Long-Acting Cabotegravir and Rilpivirine in People With Human Immunodeficiency Virus and Long Exposure to Antiretroviral Therapy: Data From the SCohoLART Study.

Background: The aim of the study was to evaluate the 12-month cumulative probability of treatment discontinuation (TD) in people with human immunodeficiency virus (HIV; PWH) and a long exposure to antiretroviral therapy (ART) switching to long-acting cabotegravir and rilpivirine (CAB/RPV). Methods: SCohoLART is a single-center, prospective, cohort study designed to collect both samples and clinical data from PWH with virological suppression who switched to bimonthly long-acting CAB/RPV. TD occurred at switch to another regimen for any reason including virological failure (VF); VF was defined as HIV RNA levels ≥50 copies/mL at 2 consecutive measurements or a single HIV RNA level ≥1000 copies/mL. Results were reported as median (interquartile range [IQR]) or frequency (percentage). Cumulative probabilities of TD were estimated using Kaplan-Meier curves. Results: We evaluated 514 participants; 467 (90.9%) were male, and their median age (IQR) was 49 (40-56) years. At the time of switching, the median time from HIV diagnosis and the median duration of ART were 14.0 (IQR, 8.8-20.5) and 11.4 (7.9-17.4) years, respectively; before starting CAB/RPV, the median number of antiretroviral regimens was 3 (2-4). During a median study follow-up (IQR) of 13.1 (9.1-15.5) months, 52 PWH (10.1%) experienced TD, including 4 (0.8%) for VF. The 12-month cumulative probability of TD was 11% (95% confidence interval, 8%-14%). The main cause of TD was injection site reaction (15 participants [28.8%]). Conclusions: The 1-year cumulative probability of TD with long-acting CAB/RPV was quite low in this cohort of people with a median exposure to ART of 10 years, in whom injection site reaction was the leading cause of TD. VFs were rare during study follow-up.

Less is more: An analysis of venetoclax and hypomethylating agent post-induction treatment modifications in AML.

Venetoclax (Ven) combined with a hypomethylating agent (HMA) enhances survival in elderly/unfit acute myeloid leukemia (AML) patients, yet often necessitates regimen modifications due to intolerance. However, it is unclear how these modifications affect patient outcome. This retrospective cohort study evaluates the impact of post-induction HMA/Ven regimen modifications on disease progression and survival. This study reviewed 142 AML patients treated with HMA/Ven within the Northwell Health System from January 2019 to December 2022. To assess the impact of post-induction regimen modifications, patients were grouped according to median days between cycles (≤34 or ≥35 days cycle intervals) and median Ven days per cycle (≤14 or ≥15 days/cycle) based on only cycle 3 and beyond. Kaplan-Meier and Cox proportional hazard regression analyses were employed for univariate and multivariate assessments, respectively. There was no significant difference in median progression-free survival (mPFS)(11.6 vs 11.8 months, p = 0.73) or median overall survival (mOS)(15.1 vs 21.8 months, p = 0.16) between cycle interval groups. However, there was a clinically and statistically significant advantage in mPFS (15.8 vs 8.7 months, p = 0.01) and mOS (24.7 vs 11.3 months, p = 0.006) for patients with a median of ≤14 Ven days/cycle compared to ≥15 Ven days/cycle. Multivariate analysis demonstrated that ≤14 days of Ven for cycle 3 and beyond was an independent predictor of decreased mortality (HR 0.18, CI 0.07-0.48, p = 0.0007). Extended cycle intervals did not adversely affect mortality while reduced Ven duration per cycle post-induction was associated with improved survival in elderly AML patients.

Synthesis and activity of benzimidazole N-Acylhydrazones against Trypanosoma cruzi, Leishmania amazonensis and Leishmania infantum.

In this study, we present the design, synthesis, and cytotoxic evaluation of a series of benzimidazole N-acylhydrazones against strains of T. cruzi (Y and Tulahuen) and Leishmania species (L. amazonensis and L. infantum). Compound (E)-N'-((5-Nitrofuran-2-yl)methylene)-1H-benzo[d]imidazole-2-carbohydrazide demonstrated significant activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC50/120 h of 0.033 µM and a selectivity index (SI) of 7680. This represents a potency 46 times greater than that of benznidazole (IC50/120 h = 1.520 µM, SI = 1390). Another compound (E)-N'-(2-Hydroxybenzylidene)-1H-benzo[d]imidazole-2-carbohydrazide showed promising activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC50/120 h of 3.600 µM and an SI of 14.70. However, its efficacy against L. infantum and L. amazonensis was comparatively lower. These findings provide valuable insights for the development of more effective treatments against Trypanosoma cruzi.

Pityriasis Rubra Pilaris: A Multicentric Case Series of 65 Spanish Patients.

INTRODUCTION: PRP is a rare entity of unknown etiopathogenesis. Lack of clinical practice guidelines makes management challenging for clinicians. OBJECTIVE: To add our experience to the corpus evidence on PRP. METHODS: This was a retrospective, descriptive, and multicentric study of 65 patients with PRP, the largest European case series of patients with PRP ever reported. RESULTS: PRP was more prevalent in men with a mean age of 51 years, yet erythrodermic forms presented in older patients (mean age, 61 years).Six (75%) pediatric patients and 10 (60%) non-erythrodermic adults controlled their disease with topical corticosteroids. However, 26 (68%) erythrodermic patients required biologic therapy as the last and effective therapy for a mean 6.5 months to achieve complete response. CONCLUSION: Our study showed a statistical difference in terms of outcome and response to treatment between children, or patients with limited disease and patients who develop erythroderma.

B/F/TAF forgiveness to non-adherence.

BACKGROUND: ART forgiveness is the ability of a regimen to maintain HIV-RNA suppression despite a documented imperfect adherence. We explored forgiveness of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF). METHODS: In this retrospective cohort study pharmacy drug refills were used to calculate the proportion of days covered (PDC) as a proxy of adherence. Forgiveness was defined as the possibility to achieve a selected HIV-RNA threshold by a given level of imperfect adherence. A logistic model was applied to verify the impact of baseline variables and adherence on the virologic outcomes. RESULTS: We enrolled 420 adults. From them, 787 one-year time-periods were derived for a median cohort follow-up of 873 person/years.Most of them were males (73.1%); the most frequent risk factor for HIV infection was heterosexual contacts (49.5% of cases), followed by 22.5% MSM and 22.5% intravenous drug users. The median age of enrolled persons with HIV was 51 years (IQR 45-57 years); the median duration of HIV infection was 7.9 years (IQR 4-18 years) and the median nadir of CD4 cells was 277 cells/mcL (IQR 100-513 cells/mcL).Adherence showed a median of 0.97 (IQR 0.91-1.00), consequently only 17 time-periods (2.2%) in 17 different individuals (4.0%) showed HIV-RNA blood levels above 200 copies/ml.A PDC of 0.75 was sufficient to obtain in > 90% of cases the virologic outcome for both 200 copies/ml or 50 copies/ml. An adherence value of 0.85 obtained a positive response in virtually all subjects either for a cut-off of 50 or 200 copies/ml. CONCLUSIONS: Long-term success of ART needs effective, well tolerated, friendly regimens. Adherence remains a crucial determinant of long-term success, but suboptimal adherence levels are relatively common. Given this, an elevated forgiveness plays a relevant role to further improve long-term outcomes and should be considered a fundamental characteristic of any antiretroviral regimen. B/F/TAF has been proved to have all of these characteristics.

Benefits of Hepatitis C Viral Eradication: A Real-World Nationwide Cohort Study in Taiwan.

BACKGROUND: Chronic hepatitis C (CHC) increases the risk of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). This nationwide cohort study assessed the effectiveness of viral eradication of CHC. METHODS: The Taiwanese chronic hepatitis C cohort and Taiwan hepatitis C virus (HCV) registry are nationwide HCV registry cohorts incorporating data from 23 and 53 hospitals in Taiwan, respectively. This study included 27,577 individuals from these cohorts that were given a diagnosis of CHC and with data linked to the Taiwan National Health Insurance Research Database. Patients received either pegylated interferon and ribavirin or direct-acting antiviral agent therapy for > 4 weeks for new-onset LC and liver-related events. RESULTS: Among the 27,577 analyzed patients, 25,461 (92.3%) achieved sustained virologic response (SVR). The mean follow-up duration was 51.2 ± 48.4 months, totaling 118,567 person-years. In the multivariable Cox proportional hazard analysis, the hazard ratio (HR) for incident HCC was 1.39 (95% confidence interval [CI]: 1.00-1.95, p = 0.052) among noncirrhotic patients without SVR compared with those with SVR and 1.82 (95% CI 1.34-2.48) among cirrhotic patients without SVR. The HR for liver-related events, including HCC and decompensated LC, was 1.70 (95% CI 1.30-2.24) among cirrhotic patients without SVR. Patients with SVR had a lower 10-year cumulative incidence of new-onset HCC than those without SVR did (21.7 vs. 38.7% in patients with LC, p < 0.001; 6.0 vs. 18.4% in patients without LC, p < 0.001). CONCLUSION: HCV eradication reduced the incidence of HCC in patients with and without LC and reduced the incidence of liver-related events in patients with LC.

Classification of anticancer drugs: an update with FDA- and EMA-approved drugs.

Anticancer systemic therapy comprises a complex and growing group of drugs. Some of the new agents with novel mechanisms of action that have appeared are difficult to fit in the groups of classical chemotherapy, hormones, tyrosine-kinase inhibitors, and monoclonal antibodies. We propose a classification based on two levels of information: the site of action and the mechanism of action. Regarding the former, drugs can exert their action in the tumor cell, the tumor vasculature, the immune system, or the endocrine system. The mechanism of action refers to the molecular target.

Advancements in inhibitors of crucial enzymes in the cysteine biosynthetic pathway: Serine acetyltransferase and O-acetylserine sulfhydrylase.

Infectious diseases have been jeopardized problem that threaten public health over a long period of time. The growing prevalence of drug-resistant pathogens and infectious cases have led to a decrease in the number of effective antibiotics, which highlights the urgent need for the development of new antibacterial agents. Serine acetyltransferase (SAT), also known as CysE in certain bacterial species, and O-acetylserine sulfhydrylase (OASS), also known as CysK in select bacteria, are indispensable enzymes within the cysteine biosynthesis pathway of various pathogenic microorganisms. These enzymes play a crucial role in the survival of these pathogens, making SAT and OASS promising targets for the development of novel anti-infective agents. In this comprehensive review, we present an introduction to the structure and function of SAT and OASS, along with an overview of existing inhibitors for SAT and OASS as potential antibacterial agents. Our primary focus is on elucidating the inhibitory activities, structure-activity relationships, and mechanisms of action of these inhibitors. Through this exploration, we aim to provide insights into promising strategies and prospects in the development of antibacterial agents that target these essential enzymes.

Perioperative hypotension and use of vasoactive agents in non-cardiac surgery: A scoping review.

BACKGROUND: Perioperative hypotension is common and associated with adverse patient outcomes. Vasoactive agents are often used to manage hypotension, but the ideal drug, dose and duration of treatment has not been established. With this scoping review, we aim to provide an overview of the current body of evidence regarding the vasoactive agents used to treat perioperative hypotension in non-cardiac surgery. METHODS: We included all studies describing the use of vasoactive agents for the treatment of perioperative hypotension in non-cardiac surgery. We excluded literature reviews, case studies, and studies on animals and healthy subjects. We posed the following research questions: (1) in which surgical populations have vasoactive agents been studied? (2) which agents have been studied? (3) what doses have been assessed? (4) what is the duration of treatment? and (5) which desirable and undesirable outcomes have been assessed? RESULTS: We included 124 studies representing 10 surgical specialties. Eighteen different agents were evaluated, predominantly phenylephrine, ephedrine, and noradrenaline. The agents were administered through six different routes, and numerous comparisons between agents, dosages and routes were included. Then, 88 distinct outcome measures were assessed, of which 54 were judged to be non-patient-centred. CONCLUSIONS: We found that studies concerning vasoactive agents for the treatment of perioperative hypotension varied considerably in all aspects. Populations were heterogeneous, interventions and exposures included multiple agents compared against themselves, each other, fluids or placebo, and studies reported primarily non-patient-centred outcomes.

Antidepressants and fetal death: A systematic review and disproportionality analysis in the WHO safety database (VigiBaseⓇ).

Recent research suggests that fetal exposure to antidepressants (ADs) is significantly associated with fetal death, including stillbirth. However, there has been limited investigation into the timing of AD exposure during pregnancy, the specific effect of each drug, and the possibility of indication bias. To address these gaps in knowledge, we conducted a systematic review of literature and disproportionality analyses using the WHO Safety Database (VigiBaseⓇ). The systematic review provided evidence for increased risks of fetal death with exposure to any selective serotonin reuptake inhibitor (SSRI) at any time of pregnancy, stillbirth with exposure to any AD during the first trimester, and stillbirth with exposure to any SSRI during the first trimester. Disproportionality analyses revealed significant associations with citalopram, clomipramine, paroxetine, sertraline, and venlafaxine. Combining both sets of results, we conclude that exposure to ADs, especially during the first trimester of pregnancy, seems to be associated with fetal mortality, and that ADs with highest placental transfer may be particularly involved. Further research should investigate the links between ADs during early pregnancy and fetal mortality.

Silvestrol, a potent anticancer agent with unfavourable pharmacokinetics: Current knowledge on its pharmacological properties and future directions for the development of novel drugs.

Cancer remains a leading cause of death, with increasing incidence. Conventional treatments offer limited efficacy and cause significant side effects, hence novel drugs with improved pharmacological properties and safety are required. Silvestrol (SLV) is a flavagline derived from some plants of the Aglaia genus that has shown potent anticancer effects, warranting further study. Despite its efficacy in inhibiting the growth of several types of cancer cells, SLV is characterized by an unfavorable pharmacokinetics that hamper its use as a drug. A consistent research over the recent years has led to develop novel SLV derivatives with comparable pharmacodynamics and an ameliorated pharmacokinetic profile, demonstrating potential applications in the clinical management of cancer. This comprehensive review aims to highlight the most recent data available on SLV and its synthetic derivatives, addressing their pharmacological profile and therapeutic potential in cancer treatment. A systematic literature review of both in vitro and in vivo studies focusing on anticancer effects, pharmacodynamics, and pharmacokinetics of these compounds is presented. Overall, literature data highlight that rationale chemical modifications of SLV are critical for the development of novel drugs with high efficacy on a broad variety of cancers and improved bioavailability in vivo. Nevertheless, SLV analogues need to be further studied to better understand their mechanisms of action, which can be partially different to SLV. Furthermore, clinical research is still required to assess their efficacy in humans and their safety.

Synthesis, biological evaluation, theoretical calculations, QSAR and molecular docking studies of novel arylaminonaphthols as potent antioxidants and BChE inhibitors.

A completely green protocol was developed for the synthesis of a series of arylaminonaphthol derivatives in the presence of N-ethylethanolamine (NEEA) as a catalyst under ultrasonic irradiation and solventless conditions. The major assets of this methodology were the use of non-toxic organic medium, available catalyst, mild reaction condition, and good to excellent yield of desired products. All of the synthesized products were screened for their in vitro antioxidant activity using DPPH, ABTS, and Ferric-phenanthroline assays and it was found that most of them are potent antioxidant agents. Also, their butyrylcholinesterase inhibitory activity has been investigated in vitro. All tested compounds exhibited potential inhibitory activity toward BuChE when compared to standard reference drug galantamine, however, compounds 4r, 4u, 4 g and 4x gave higher butyrylcholinesterase inhibitory with IC50 values of 14.78 ± 0.65 µM, 16.18 ± 0.50 µM, 20.00 ± 0.50 µM, and 20.28 ± 0.08 µM respectively. On the other hand, we employed density functional theory (DFT), calculations to analyze molecular geometry and global reactivity descriptors, and MESP analysis to predict electrophilic and nucleophilic attacks. A quantitative structure-activity relationship (QSAR) investigation was conducted on the antioxidant and butyrylcholinesterase properties of 25 arylaminonaphthol derivatives, resulting in robust and satisfactory models. To evaluate their anti-Alzheimer's activity, compounds 4 g, 4q, 4r, 4u, and 4x underwent docking simulations at the active site of the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), revealing why these compounds displayed superior activity, consistent with the biological findings.