Use Of Pharmacological Agents Research Articles

TLR4-dependent neuroinflammation mediates LPS-driven food-reward alterations during high-fat exposure

BackgroundObesity has become a global pandemic, marked by significant shifts in both the homeostatic and hedonic/reward aspects of food consumption. While the precise causes are still under investigation, recent studies have identified the role of gut microbes in dysregulating the reward system within the context of obesity. Unravelling these gut–brain connections is crucial for developing effective interventions against eating and metabolic disorders, particularly in the context of obesity. This study explores the causal role of LPS, as a key relay of microbiota component-induced neuroinflammation in the dysregulation of the reward system following exposure to high-fat diet (HFD).MethodsThrough a series of behavioural paradigms related to food-reward events and the use of pharmacological agents targeting the dopamine circuit, we investigated the mechanisms associated with the development of reward dysregulation during HFD-feeding in male mice. A Toll-like receptor 4 (TLR4) full knockout model and intraventricular lipopolysaccharide (LPS) diffusion at low doses, which mimics the obesity-associated neuroinflammatory phenotype, were used to investigate the causal roles of gut microbiota-derived components in neuroinflammation and reward dysregulation.ResultsOur study revealed that short term exposure to HFD (24 h) tended to affect food-seeking behaviour, and this effect became significant after 1 week of HFD. Moreover, we found that deletion of TLR4 induced a partial protection against HFD-induced neuroinflammation and reward dysregulation. Finally, chronic brain diffusion of LPS recapitulated, at least in part, HFD-induced molecular and behavioural dysfunctions within the reward system.ConclusionsThese findings highlight a link between the neuroinflammatory processes triggered by the gut microbiota components LPS and the dysregulation of the reward system during HFD-induced obesity through the TLR4 pathway, thus paving the way for future therapeutic approaches.Graphical abstract

Abstract A035: Infection of primary mammary fibroblasts with cytomegalovirus coordinately increases autotaxin-lysophosphatidate-inflammatory signaling, which could increase breast cancer metastasis

Abstract Background: Metastatic breast cancer is the most prevalent cause of mortality by cancer-related deaths in women. Our group showed that the 63% of Canadian breast cancer patients who were infected with CMV were 5.6-times more likely to develop Stage IV cancers with reduced relapse-free survival. Also, the metastatic phenotype of breast tumors and the number and sizes of lung metastases were increased in mice with latent infections. Fibroblasts are important sites of CMV infection. Cancer-associated fibroblasts (CAFs) are also major sites of autotaxin (ATX) secretion in breast tumors, whereas ATX production and CMV infection in breast cancer cells is negligible. ATX produces lysophosphatidate (LPA), which increases inflammatory cytokine production that stimulates further ATX secretion in a feedforward cycle. LPA promotes breast tumor growth and metastasis by signaling through six G protein-coupled receptors. Signaling is terminated by lipid phosphate phosphatases (LPPs)-1 and -3, which degrade LPA and are decreased in breast tumors. Hypothesis: Breast cancer metastasis could be increased by active CMV infection of CAFs through increased inflammation and LPA signaling. Results: Quiescent fibroblasts isolated and cultured from mammary tissue of non-tumor bearing mice (n>3) produced negligible quantities of ATX. LPA signaling was coordinately promoted in these primary fibroblasts infected for 48 h with 1 MOI of mouse CMV (n=3) with a 5-fold increase in mRNA for ATX (p=0.008), increased mRNAs for LPA2,3,4 receptors (p<0.05) and decreased mRNA expressions for LPP1 and LPP3 (p<0.05). An increase in the secretion of granulocyte monocyte-colony stimulating factor of 548 pg/ml (p=0.01) and Interleukin-6 by 8307 pg/ml (p=0.03) was observed post infection (n=5), thus creating a pro-inflammatory environment. Increased mRNA expression of fibroblast markers, including alpha-smooth muscle actin (p=0.005), fibroblast-associated protein (p=0.007), epidermal growth factor receptor (EGFR) (p=0.001) and transforming growth factor- ß receptor 1 (TGF-ßR1) (p=0.03) was also observed post-infection (n=3). The results were analyzed by student’s t-test. Assessment of these factors in breast cancer patients (n=1100) using the Tumor Immune Estimation Resource Analysis showed a positive correlation in the expression of EGFR and TGF-ßR1 with the LPA3,4 receptors (p<0.05). Conclusion: The changes in expression of ATX, LPA receptors and LPPs in CMV- infected fibroblasts are consistent with increased metastasis. Our results show that mCMV infection of primary mammary fibroblasts dramatically reprograms them to express CAF-like properties and promotes ATX-LPA-inflammatory signaling. CAFs are a major constituent of the tumor stroma. They promote tumor progression by secreting factors such as ATX, which increases metastasis, fibrosis and favors immunosuppression. Our results support the use of pharmacological agents to block signaling by the ATX-LPA-inflammatory cycle to treat breast and other cancers, especially for the majority of patients who are infected with CMV. Citation Format: Humayara Khan, Xiaoyun Tang, Frank Wuest, David N. Brindley, Denise G. Hemmings. Infection of primary mammary fibroblasts with cytomegalovirus coordinately increases autotaxin-lysophosphatidate-inflammatory signaling, which could increase breast cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A035.

Investigating the Transfer of Lisinopril into Human Milk: A Quantitative Analysis.

Lisinopril is commonly prescribed to manage conditions such as hypertension and heart failure. While concerns about fetal toxicity have traditionally limited the use of lisinopril in women of reproductive age, recent ACOG guidelines promote aggressive treatment of hypertension, which may require the use of pharmacologic agents not previously considered in the postpartum period. We aimed to estimate infant exposure to maternal lisinopril via breastmilk and report the tolerance of the breastfed infant. Five volunteers taking lisinopril provided samples of their human milk and their associated health information for research through the InfantRisk Center Human Milk Biorepository. The milk pharmacokinetics of lisinopril were measured using liquid chromatography-mass spectrometry. The mean milk concentration of lisinopril was 0.49 ng/mL per 10 mg daily dose. The Relative Infant Dose (RID) was 0.06% for lisinopril, more than 100 times lower than the standard 10% safety threshold. The minimal transfer of lisinopril into human milk in this study suggests the drug is unlikely to pose a clinically significant risk to healthy breastfed infants.

Kindling Models of Epileptogenesis for Developing Disease-Modifying Drugs for Epilepsy.

Kindling models are widely used animal models to study the pathobiology of epilepsy and epileptogenesis. These models exhibit distinctive features whereby sub-threshold stimuli instigate the initial induction of brief focal seizures. Over time, the severity and duration of these seizures progressively increase, leading to a fully epileptic state, which is marked by consistent development of generalized tonic-clonic seizures. Kindling involves focal stimulation via implanted depth electrodes or repeated administration of chemoconvulsants such as pentylenetetrazol. Comparative analysis of preclinical and clinical findings has confirmed a high predictive validity of fully kindled animals for testing novel antiseizure medications. Thus, kindling models remain an essential component of anticonvulsant drug development programs. This article provides a comprehensive guide to working protocols, testing of therapeutic drugs, outcome parameters, troubleshooting, and data analysis for various electrical and chemical kindling epileptogenesis models for new therapeutic development and optimization. The use of pharmacological agents or genetically modified mice in kindling experiments is valuable, offering insights into the impact of a specific target on various aspects of seizures, including thresholds, initiation, spread, termination, and the generation of a hyperexcitable network. These kindling epileptogenesis paradigms are helpful in identifying mechanisms and disease-modifying interventions for epilepsy. © 2024 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Hippocampal kindling Basic Protocol 2: Amygdala kindling Basic Protocol 3: Rapid hippocampal kindling Basic Protocol 4: Chemical kindling.

APITHERAPY AND APPLICATIONS IN VETERINARY MEDICINE

The use of bees and bee products for therapeutic purposes in human and veterinary medicine is called apitherapy. Natural products have been used throughout human history to protect against and treat diseases. In recent years, the emergence of drug resistance and the occurrence of adverse effects associated with the indiscriminate and irregular use of pharmacological agents have prompted humanity to pursue alternative solutions. One of the most significant solutions is the administration of bee products. The use of bee products in apitherapy applications includes honey, bee venom, pollen, propolis, beeswax, royal jelly, perga and apilarnil (bee larvae). In general, apitherapy products with a wide range of indications are widely used in various system diseases and some dermatologic problems and various effects of these products such as antibacterial, antifungal, antiviral, antioxidant, anticarcinogenic, anti-inflammatory, antidiabetic and immunomodulatory effects in vitro and in vivo have been investigated in many different studies. Apitherapy is less common in veterinary practice than in human medicine. Additionally, bee products are employed in the treatment of other animal diseases, including gastrointestinal disorders, otitis, sinusitis, ophthalmic conditions, dermatological disorders, and skin care. Additionally, bee products are employed as food supplements for animals. The most prevalent additive in animal food is bee pollen. It has been demonstrated to promote growth, reduce mortality and prevent morbidity. Apitherapy has gained importance in the field of veterinary medicine in recent years in order to prevent both human health and economic losses, especially in the treatment of animals consumed as food.

Utility of rest magnetocardiography in patients presenting to the emergency department with chest pain: A case series on the CardioFlux MCG

BackgroundMagnetocardiography (MCG) may provide a rapid diagnostic option for patients presenting with chest pain in the emergency department (ED). Case summariesThis case series presents two instances from a multicenter study, where MCG could have served as a rapid, non-invasive diagnostic tool for chest pain patients. In both cases, multiple high-sensitivity troponin (hsTn) tests yielded incorrect evidence of ischemia. In the first case, multiple positive hsTn tests led to the patient requiring 23 h of observation care, while MCG rapidly ruled out acute coronary syndrome (ACS). In the second case, MCG revealed findings indicative of cardiac ischemia where serial ECGs did not indicate ischemia and serial hsTns were normal. Subsequent cardiac catheterization confirmed 99 % stenosis in the patient's left main and left anterior descending arteries, necessitating coronary artery bypass grafting (CABG). ConclusionMCG offers a rapid, painless, non-invasive, radiation free assessment for patients presenting with acute chest pain. Integrating MCG into ED workflows has the potential to improve throughput, reduce the need for subsequent patient observation or inpatient admission, and minimize or eliminate the need for other more expensive non-invasive cardiac testing. MCG avoids some of the problems associated with other methods for diagnosing ischemia. MCG does not involve radiation or the use of pharmacologic agents which have a risk for allergic reactions and anaphylaxis, or the need for an intravenous line. Stress tests are frequently contraindicated or unable to be performed in patients on various medications, may require patient cooperation and in the case of exercise stress tests, the patient's capability to exercise. MCG requires no special patient preparation.

KAT2A and KAT2B prevent double-stranded RNA accumulation and interferon signaling to maintain intestinal stem cell renewal.

Histone acetyltransferases KAT2A and KAT2B are paralogs highly expressed in the intestinal epithelium, but their functions are not well understood. In this study, double knockout of murine Kat2 genes in the intestinal epithelium was lethal, resulting in robust activation of interferon signaling and interferon-associated phenotypes including the loss of intestinal stem cells. Use of pharmacological agents and sterile organoid cultures indicated a cell-intrinsic double-stranded RNA trigger for interferon signaling. Acetyl-proteomics and sequencing of immunoprecipitated double-stranded RNA were used to interrogate the mechanism behind this response, which identified mitochondria-encoded double-stranded RNA as the source of intrinsic interferon signaling. Kat2a and Kat2b therefore play an essential role in regulating mitochondrial functions and maintaining intestinal health.

Pharmacological and non-pharmacological prevention and management of delirium in critically ill and palliative patients in the inpatient setting: a review.

This review explores delirium in critically ill patients in the inpatient setting, focusing on its prevention and management. It evaluates the efficacy of both current pharmacological and non-pharmacological interventions, aiming to provide a comprehensive overview. A systematic literature search was conducted to identify relevant studies investigating the prevention and management of delirium resulting in a final sample of 26 articles for analysis. Of the 26 articles analyzed for this review (N = 8,831 participants) of controlled trials, 16 studies examined the prevention of delirium, 9 explored the treatment of delirium, and 1 investigated both prevention and treatment of delirium. Among the reviewed studies, there is evidence that non-pharmacologic methods are effective in the prevention of delirium. Evidence regarding pharmacological interventions for delirium prevention is varied and inconclusive, with some indication that atypical antipsychotics like aripiprazole and quetiapine may reduce the incidence of delirium. Regarding the treatment of delirium, there is limited evidence supporting the use of pharmacological agents. Additional double-blinded, randomized, placebo-controlled clinical trials are needed to investigate the efficacy of pharmacologic agents for diverse hospitalized populations.

Comparison of intranasal ketamine with intranasal midazolam and dexmedetomidine combination in pediatric dental patients for procedural sedation: A crossover study.

The main goal of the pediatric dentist is to address and reduce children's fear and anxiety during the dental treatment, especially when conventional behavior-guiding strategies fail. In such cases, the use of pharmacological agents becomes an essential factor to consider. The objective of the study was to compare the efficacy, safety, and acceptability of intranasal ketamine (INK) with the combination of intranasal midazolam and dexmedetomidine (INMzD) in pediatric dental patients for the procedural sedation. Forty-seven children aged 3-9 years who required dental procedures such as extractions, pulpectomy, and restorations were randomly distributed into two groups using the envelope drawing method. Group INK received 7 mg/kg INK, whereas Group INMzD received a combination of midazolam spray (0.3 mg/kg) and atomized dexmedetomidine (3 μg/kg). INK showed faster onset, faster recovery, and shorter discharge time than INMzD. Both groups had acceptable physiological parameters and no postoperative complications. INK was more accepted by the patients than INMzD. In terms of efficacy, safety, and acceptability, INK outperformed the combination of INMzD for the procedural sedation.

Phospholipid Signaling in Crop Plants: A Field to Explore.

In plant models such as Arabidopsis thaliana, phosphatidic acid (PA), a key molecule of lipid signaling, was shown not only to be involved in stress responses, but also in plant development and nutrition. In this article, we highlight lipid signaling existing in crop species. Based on open access databases, we update the list of sequences encoding phospholipases D, phosphoinositide-dependent phospholipases C, and diacylglycerol-kinases, enzymes that lead to the production of PA. We show that structural features of these enzymes from model plants are conserved in equivalent proteins from selected crop species. We then present an in-depth discussion of the structural characteristics of these proteins before focusing on PA binding proteins. For the purpose of this article, we consider RESPIRATORY BURST OXIDASE HOMOLOGUEs (RBOHs), the most documented PA target proteins. Finally, we present pioneering experiments that show, by different approaches such as monitoring of gene expression, use of pharmacological agents, ectopic over-expression of genes, and the creation of silenced mutants, that lipid signaling plays major roles in crop species. Finally, we present major open questions that require attention since we have only a perception of the peak of the iceberg when it comes to the exciting field of phospholipid signaling in plants.

Effectiveness of cannabis use and cannabis use disorder interventions: a European and international data synthesis.

This data synthesis examined the effectiveness of behavioural and pharmacological approaches for cannabis treatment. We integrated findings from high level evidence studies and prioritised data from Europe when available. The synthesis found that only a relatively small number of published behavioural and pharmacological studies on cannabis interventions have been conducted in Europe. Applying both European and non-European data, it was found that Cognitive Behavioural Therapy (CBT) and/or Motivational Enhancement Therapy (MET) improved short-term outcomes in the frequency of cannabis use and dependency severity, although abstinence outcomes were less consistent. These improvements were typically not maintained nine months after treatment. CBT and MET (or combined CBT + MET) treatments that extend beyond four sessions were more effective than fewer sessions over a shorter duration. Combining CBT or MET (or combined CBT + MET) with adjunctive Contingency Management (CM) improved therapeutic outcomes. No pharmacotherapies have been approved for the management of cannabis use, cannabis use disorders or cannabis withdrawal. Despite only weak evidence to support the use of pharmacological agents, some are used 'off-label' to manage withdrawal symptoms outside clinical trials.

Intractable Singultus: Causes, diagnosis and treatment. A case report

IntroductionHiccups are involuntary, spasmodic contractions of the diaphragm and intercostal muscles that cause inspiration and are interrupted by closure of the glottis. Most sources define the term “persistent hiccups” as lasting more than 2 days and “intractable” as lasting more than 1 month. Both are most likely associated with a pathologic process. “Intractable hiccups” should lead to investigation of organic pathology. If it does not improve, it can interfere with the patient’s ability to eat, socialize and sleep, leading to a significant worsening of quality of life. “Intractable hiccups” are more frequent in men (91%), over 50 years of age. Women suffer from psychogenic hiccups more frequently than men. Anxiety or stress can trigger hiccups. Multiple neurotransmitters are involved.ObjectivesWe present a theoretical review on the topic.MethodsA bibliographic review on the topic.ResultsIn recent years, new trials and case series have been published, and regulatory agencies have issued new recommendations on the use of pharmacologic agents for this indication. The literature has described the efficacy of several pharmacologic agents in the empiric treatment of persistent and intractable hiccups. Most of these target dopaminergic and GABAergic receptors.Based on limited efficacy and safety data, Baclofen and Gabapentin can be considered as first-line treatment for intractable and persistent hiccups, as they suggest efficacy and are less likely to cause long-term side effects than standard neuroleptic agents. Dopamine blocking agents such as Metoclopramide, Chlorpromazine, and Haloperidol, could be used as second line. In one study, withdrawal of Benzodiazepines or addition of Pregabalin was found to help reduce hiccups.The patient we consulted came for persistent hiccups or singultus of 2 years of evolution. Organic pathology was ruled out. She related the onset of the symptoms to different stressors that had caused her anxiety. We administered Escitalopram and Gabapentin and indicated withdrawal of Bromazepam, which she started taking months ago. In follow-up appointments she reported a decrease in the intensity and frequency of the symptoms, with a notable improvement in her quality of life.ConclusionsConsidering all available evidence, a treatment algorithm with Baclofen is recommended as first-line therapy for persistent and intractable hiccups. Gabapentin may also be safe and effective in the long-term treatment of this condition, especially for patients with CNS disease. Metoclopramide is no longer recommended for long-term treatment of hiccups. Clinical experience also supports the use of Chlorpromazine and other neuroleptics for acute, but not long-term, treatment. Going forward, large multicenter studies will be needed to create an adequate evidence base for the treatment of persistent and intractable hiccups. Until then, guidelines will continue to be based on unreliable data and clinical experience.Disclosure of InterestNone Declared

Targeting epigenetic mechanisms in amyloid-β-mediated Alzheimer's pathophysiology: unveiling therapeutic potential.

Alzheimer's disease is a prominent chronic neurodegenerative condition characterized by a gradual decline in memory leading to dementia. Growing evidence suggests that Alzheimer's disease is associated with accumulating various amyloid-β oligomers in the brain, influenced by complex genetic and environmental factors. The memory and cognitive deficits observed during the prodromal and mild cognitive impairment phases of Alzheimer's disease are believed to primarily result from synaptic dysfunction. Throughout life, environmental factors can lead to enduring changes in gene expression and the emergence of brain disorders. These changes, known as epigenetic modifications, also play a crucial role in regulating the formation of synapses and their adaptability in response to neuronal activity. In this context, we highlight recent advances in understanding the roles played by key components of the epigenetic machinery, specifically DNA methylation, histone modification, and microRNAs, in the development of Alzheimer's disease, synaptic function, and activity-dependent synaptic plasticity. Moreover, we explore various strategies, including enriched environments, exposure to non-invasive brain stimulation, and the use of pharmacological agents, aimed at improving synaptic function and enhancing long-term potentiation, a process integral to epigenetic mechanisms. Lastly, we deliberate on the development of effective epigenetic agents and safe therapeutic approaches for managing Alzheimer's disease. We suggest that addressing Alzheimer's disease may require distinct tailored epigenetic drugs targeting different disease stages or pathways rather than relying on a single drug.

Phitosomin drug and its use in poultry farming

Solving the problem of normalizing metabolic processes and the morphological and functional state of the liver in poultry through the use of pharmacological agents seems to be an important reserve for increasing the effi ciency of industrial poultry farming and food production. Promising in this regard are studies on the development of medicines based on plant resources, which are characterized by structural diversity, multifunctionality of pharmacological action and low toxicity. The purpose of the research was to develop the liposomal drug Phitosomin, study its pharmacological and toxicological properties and substantiate the eff ectiveness of its use in poultry farming. Biopharmaceutical research has been carried out to develop a liposomal drug for veterinary use with a multifunctional pharmacological eff ect. The component composition of the drug Phitosomin represented by lecithin, dihydroquercetin, extracts of milk thistle, common agrimony and hare’s-ear, has been substantiated. A liposomal dosage form of the drug has been developed. Its physicochemical properties and shelf life have been established. The toxicological characteristics of the drug Phitosomin were studied, which made it possible to determine the degree of safety of its use in rearing of broiler chickens. Data were obtained experimentally on the pharmacological eff ects of Phitosomin on laboratory animals and broiler chickens when modeling various pathologies. The pharmacodynamic eff ect of the drug on blood parameters and productive traits of broiler chickens has been established, and the eff ective dose of its use in rearing broiler chickens has been determined. It was established as a result of the production inspection that when Phitosomin was introduced into the main diet of poultry of the experimental group at a dose of 5 g/kg of feed during the growth and finishing periods of feeding, there was an increase in the live weight of broiler chickens by 12,6 % and the livability of livestock by 1,6 abs.% compare with the control group.

Targeting SWI/SNF Complexes in Cancer: Pharmacological Approaches and Implications.

SWI/SNF enzymes are heterogeneous multi-subunit complexes that utilize the energy from ATP hydrolysis to remodel chromatin structure, facilitating transcription, DNA replication, and repair. In mammalian cells, distinct sub-complexes, including cBAF, ncBAF, and PBAF exhibit varying subunit compositions and have different genomic functions. Alterations in the SWI/SNF complex and sub-complex functions are a prominent feature in cancer, making them attractive targets for therapeutic intervention. Current strategies in cancer therapeutics involve the use of pharmacological agents designed to bind and disrupt the activity of SWI/SNF complexes or specific sub-complexes. Inhibitors targeting the catalytic subunits, SMARCA4/2, and small molecules binding SWI/SNF bromodomains are the primary approaches for suppressing SWI/SNF function. Proteolysis-targeting chimeras (PROTACs) were generated by the covalent linkage of the bromodomain or ATPase-binding ligand to an E3 ligase-binding moiety. This engineered connection promotes the degradation of specific SWI/SNF subunits, enhancing and extending the impact of this pharmacological intervention in some cases. Extensive preclinical studies have underscored the therapeutic potential of these drugs across diverse cancer types. Encouragingly, some of these agents have progressed from preclinical research to clinical trials, indicating a promising stride toward the development of effective cancer therapeutics targeting SWI/SNF complex and sub-complex functions.

Influence of new dimethylaminoethanol derivatives, butanoic and trans-butenedioic acids, on the tolerability of hypoxia, hyperthermia, and hypothermia

BACKGROUND: The need to increase the tolerance of various extreme effects is associated not only with the expansion of human professional activity regions but also with the need to assist victims of natural and man-made disasters. The use of pharmacological agents for individual adverse effects is a well-known method; however, considering the combined effects of several physical or chemical factors, only a few references are found in the literature.
 AIM: This preclinical study aimed to examine the effectiveness of a new derivative of aminoethanol and intermediates of the Krebs cycle in relation to the isolated and combined effects of hypoxia and temperature (hyperthermia and hypothermia).
 MATERIALS AND METHODS: The fumaric salt of the amber ether of diethylaminoethanol was synthesized at St. Petersburg State University of Chemistry and Pharmacy, Department of Organic Chemistry (Head Professor I.P. Yakovlev). The study was conducted on small laboratory animals. Resistance to hypoxia was assessed by the dynamics of the altitude threshold of animals, tolerance to hyperthermia by survival in a thermal chamber at 40°C, and tolerance to hypothermia by the time of maximum swimming in water at 10–12°C. Under combined exposure, the condition of the animals was assessed by the dynamics of physical performance, hypoxia was induced by preliminary administration of the methemoglobin former sodium nitrite at a dose of 50 mg/kg, and thermal exposure was induced by placing the animal in water at 40°C (hyperthermia) or 9–11°C (hypothermia).
 RESULTS: After a single intragastric administration in a wide range of doses, the test compound stimulated the physical performance of animals and exhibited a protective effect under the isolated effects of hypobaric hypoxia, hyperthermia, and hypothermia. With combined exposure to hemic hypoxia and hyperthermia, the compound was effective at a dose of 250 mg/kg. With combined exposure to hemic hypoxia and hypothermia, efficiency was also noted at lower doses (25 and 50 mg/kg).
 CONCLUSION: Fumaric salt of dimethylaminoethanol amber ether, a new derivative of dimethylaminoethanol, butenedioic, and trans-butenedioic acids, is promising for further study as a means of increasing the body’s resistance to extreme influences.

Efficacy of COVID-19 Treatments in Intensive Care Unit: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Objectives: Examining the cumulative evidence from randomized controlled trials (RCTs), evaluating the use of pharmacological agents for the treatment of COVID-19 infections in patients with critical illness. Data Sources: Databases Medline, Embase, Web of Science, Scopus, CINAHL, and Cochrane. Study Selection: Inclusion criteria were RCTs that enrolled patients with confirmed or suspected COVID-19 infection who are critically ill. Only RCTs that examined therapeutic agents against one another or no intervention, placebo, or standard of care, were included. Data Extraction: Pairs of reviewers extracted data independently. Outcomes of interest included the overall reported mortality defined as either the ICU mortality, hospital mortality, mortality within 28 days or mortality within 90 days. Data Synthesis: A total of 40 studies (11,613 patients) evaluated 50 therapeutic intervention arms divided into five main therapy categories; steroids, antiviral medications, immunomodulators, plasma therapies [intravenous immunoglobulins (IVIG), convalescent plasma and/or, therapeutic plasma exchange], and therapeutic anticoagulation. Immunomodulators was the only group with possible mortality benefit, risk ratio (RR) 0.83 (95% CI 0.73; 0.95), with nonsignificant heterogeneity (I 2 = 8%, p=0.36). In contrast, the other therapy groups showed no significant impact on mortality, as indicated by their respective pooled RRs: steroids [RR 0.91 (95% CI 0.82; 1.01), I 2 = 31%], antiviral medications [RR 1.11 (95% CI 0.82; 1.49), I 2 = 57%], plasma therapies [RR 0.77 (95% CI 0.58; 1.01), I 2 = 36%], and anticoagulation [RR 1.06 (95% CI 0.95; 1.18), I 2 = 0%]. Conclusions: This meta-analysis highlights both the heterogeneity and a lack of benefit from therapies evaluated during the COVID-19 pandemic. Many of the RCTs were developed based on limited observational data. Future RCTs investigating pharmaceutical interventions in critically ill patients during pandemics need to be designed based on better evidence.

Clinical and treatment profiles of arterial hypertension in Mexico during the COVID-19 pandemic: a cross-sectional survey endorsed by the "Collaborative Group on Arterial Hypertension".

Arterial hypertension is highly prevalent in Mexico; nevertheless, there are limited insights regarding its management during the COVID-19 pandemic. Here, we estimate the prevalence of clinical and treatment profiles of arterial hypertension and explore associated factors for undiagnosed and uncontrolled hypertension using a cross-sectional survey endorsed by the Collaborative Group on Arterial Hypertension from the Mexican Institute of Social Security. Our survey was conducted from May to November 2021 using the May-Measurement Month 2021 protocols of the International Society of Hypertension. Arterial hypertension (defined as: blood pressure [BP] ≥140/90 mmHg, previous diagnosis, or taking antihypertensives) and its clinical and treatment profiles were classified according to the World Hypertension League Expert Committee. Mixed-effects logistic regression models were used to explore associated factors for undiagnosed and uncontrolled hypertension. Among 77,145 screened participants (women: 62.4%; median age: 46 [IQR: 32-59] years), the prevalence of arterial hypertension was 35.7% (95% CI: 35.3-36.0, n = 27,540). Among participants with arterial hypertension, 30.9% (95% CI: 30.4-31.5, n = 8,533) were undiagnosed, 6.6% (95% CI: 6.3%-6.9%, n = 1,806) were diagnosed but untreated, 43.4% (95% CI: 42.9-44.0, n = 11,965) had uncontrolled hypertension, and only 19% (95% CI: 18.6%-19.5%, n = 5,236) achieved hypertension control (BP < 130/80 mmHg). Explored associated factors for undiagnosed and uncontrolled hypertension include being men, living in the central and southern regions, lower educational attainments, higher use of pharmacological agents, and previous COVID-19 infection. Our findings suggest that adverse arterial hypertension profiles, mainly undiagnosed and uncontrolled hypertension, were highly prevalent during the context of the COVID-19 pandemic in Mexico.

Factors of the aging process and longevity—selected data

Abstract The article presents endogenous and exogenous factors affecting the aging process and longevity, indicating their influence on the epigenome and genome. While discussing endogenous factors, we described genes and protein complexes, metabolic and signaling pathways [IIS (insulin and insulin-like growth factor 1/IGF-1 signaling), ARE/Nrf2 (antioxidant response elements/nuclear factor erythroid-related factor 2), kynurenine/NAD+ (nicotinamide adenine dinucleotide and kynurenine signaling)], and the sirtuin enzyme group and antioxidant enzymes (e.g., SOD1). While characterizing exogenous factors, we indicated the role of nutrition, including the effect of a diet balanced in terms of the number of calories and the effect of consuming polyphenols, including resveratrol, curcumin, or epigallocatechin-3-gallate, and vitamins C and E, as well as the impact of microclimate, stress, the role of physical exercise, and the use of pharmacological agents. Analysis of these data showed that the factors related to the aging process have an influence on longevity and age-related diseases.

Thymoquinone: A comprehensive review of its potential role as a monotherapy for metabolic syndrome.

Metabolic syndrome (MetS) is a widespread global epidemic that affects individuals across all age groups and presents a significant public health challenge. Comprising various cardio-metabolic risk factors, MetS contributes to morbidity and, when inadequately addressed, can lead to mortality. Current therapeutic approaches involve lifestyle changes and the prolonged use of pharmacological agents targeting the individual components of MetS, posing challenges related to cost, compliance with medications, and cumulative side effects. To overcome the challenges associated with these conventional treatments, herbal medicines and phytochemicals have been explored and proven to be holistic complements/alternatives in the management of MetS. Thymoquinone (TQ), a prominent bicyclic aromatic compound derived from Nigella sativa emerges as a promising candidate that has demonstrated beneficial effects in the treatment of the different components of MetS, with a good safety profile. For methodology, literature searches were conducted using PubMed and Google Scholar for relevant studies until December 2023. Using Boolean Operators, TQ and the individual components of MetS were queried against the databases. The retrieved articles were screened for eligibility. As a result, we provide a comprehensive overview of the anti-obesity, anti-dyslipidaemic, anti-hypertensive, and anti-diabetic effects of TQ including some underlying mechanisms of action such as modulating the expression of several metabolic target genes to promote metabolic health. The review advocates for a paradigm shift in MetS management, it contributes valuable insights into the multifaceted aspects of the application of TQ, fostering an understanding of its role in mitigating the global burden of MetS.