First-line Therapeutic Agents Research Articles

Recommendations for the management of acute immune thrombocytopenia in children. A Consensus Conference from the Italian Association of Pediatric Hematology and Oncology.

Immune thrombocytopenia (ITP) is an acquired immune-mediated bleeding disorder characterized by isolated thrombocytopenia. Its estimated yearly incidence in the pediatric population is 1.9-6.4/100,000. ITP in children is usually a self-limiting and benign disorder. The clinical management of children with ITP often remains controversial, as robust randomized trials on the management of this disorder are lacking. Treatments vary widely in clinical practice and existing guidelines from hematology societies on clinical management offer indications based largely on expert opinion rather than strong evidence. The Coagulative Disorder Working Group of the Italian Association of Pediatric Hematology and Oncology (AIEOP) developed this document to collect shared expert opinions on the management of newly diagnosed ITP, updating previous guidelines and providing recommendations to pediatricians. Each statement has been given a score expressing the strength of evidence, appropriateness and agreement among participants. Clear-cut definitions of the clinical phases of the disease and clinical response are stated. Recommendations are given regarding the classification of bleeding symptoms, evaluation of bleeding risk, diagnosis, and prognostic factors. Specific recommendations for treatment include indications for first-line (intravenous immunoglobulins, steroids) and second-line (combined therapy, thrombopoietin receptor agonists, immunosuppressive drugs, rituximab) therapeutic agents, as well as hemorrhagic emergency and supportive treatment, including emergency splenectomy. The optimal follow-up schedule, the relation between ITP and vaccines and health-related quality-of-life issues are also discussed. The panel achieved broad consensus on issues related to how to treat children with newly diagnosed ITP, providing a comprehensive review of all relevant clinical aspects.

Insulin resistance and stroke: mechanisms and therapeutic approaches

The review analyzed literature data on the epidemio­logy, risk factors, and mechanisms of acute cerebrovascular accident (ACVA) in patients with diabetes mellitus. The role of insulin resistance and the effectiveness of therapeutic approaches to its correction in cerebral stroke are considered. Diabetes mellitus is recognized as an independent modifiable risk factor for ACVA. In people with diabetes of different age, the risk of stroke is increased by 2–6 times, and the indicators are especially high in patients of young working age. The presence of diabetes mellitus is associated with more severe symptoms, increased risk of complications, longer hospitalization, and higher mortality. Research results show that insulin resistance is one of the main triggers for the development of ischemic stroke due to embolism caused by oxidative stress, endothelial dysfunction and platelet hyperactivation, as well as due to atherosclerotic changes caused by inflammation, proliferation of smooth muscle cells of the vascular wall, dyslipidemia and hypertension on the background of hyperglycemia and hyperinsulinemia. It has been proven that insulin resistance not only provokes ACVA, but also negatively affects their prognosis. Metformin is a key drug for improving insulin sensitivity and is recognized as one of the most important first-line therapeutic agents to achieve and maintain treatment goals in patients with type 2 diabetes. The results of expe­rimental and clinical studies proved that this agent has a whole range of neuroprotective properties, which generally prevent the development of cerebral ischemia and reduce the negative consequences in case of its occurrence. Animals with experimental acute cerebral ischemia who have been treated with metformin had a better overall neurological score, significantly smaller infarct size, better coordination scores, and higher numbers of neurons and microglia. The neuroprotective effect of metformin in stroke is realized through the AMPK (5’AMP-activated protein kinase) signaling pathway with reduction of oxidative stress, neuroinflammation, stimulation of angiogenesis and neurogenesis, autophagy, and inhibition of apoptosis. According to data from cohort and randomized clinical trials, the use of metformin is associated with a significantly lower risk of developing ACVA. Long-term use of this drug in type 2 diabetes contributes to a milder course of stroke, is associated with better functional recovery, and a decrease in disability and mortality rates.

Safety and Effect on Intracranial Pressure of 3% Hypertonic Saline Bolus Via Peripheral Intravenous Catheter for Neurological Emergencies.

Elevated intracranial pressure (ICP) is a neurological emergency in patients with acute brain injuries. Such a state requires immediate and effective interventions to prevent potential neurological deterioration. Current clinical guidelines recommend hypertonic saline (HTS) and mannitol as first-line therapeutic agents. Notably, HTS is conventionally administered through central venous catheters (CVCs), which may introduce delays in treatment due to the complexities associated with CVC placement. These delays can critically affect patient outcomes, necessitating the exploration of more rapid therapeutic avenues. This study aimed to investigate the safety and effect on ICP of administering rapid boluses of 3% HTS via peripheral intravenous (PIV) catheters. A retrospective cohort study was performed on patients admitted to Sisters of Saint Mary Health Saint Louis University Hospital from March 2019 to September 2022 who received at least one 3% HTS bolus via PIV at a rate of 999mL/hour for neurological emergencies. Outcomes assessed included complications related to 3% HTS bolus and its effect on ICP. Of 216 3% HTS boluses administered in 124 patients, complications occurred in 8 administrations (3.7%). Pain at the injection site (4 administrations; 1.9%) and thrombophlebitis (3 administrations; 1.4%) were most common. The median ICP reduced by 6mm Hg after 3% HTS bolus administration (p < 0.001). Rapid bolus administration of 3% HTS via PIV catheters presents itself as a relatively safe approach to treat neurological emergencies. Its implementation could provide an invaluable alternative to the traditional CVC-based administration, potentially minimizing CVC-associated complications and expediting life-saving interventions for patients with neurological emergencies, especially in the field and emergency department settings.

Abstract 15597: Unlocking Rate Control in Atrial Fibrillation: A Closer Look at the Intravenous Diltiazem and Metoprolol Duel - An Updated Systematic Review and Meta-Analysis

Background: Intravenous beta-blockers and calcium channel blockers remain first-line therapeutic agents for hemodynamically stable atrial fibrillation patients with a rapid ventricular rate (AF-RVR) in emergency medical settings. Material and Methods: We conducted a thorough review of various sources, including PubMed, Embase, Cochrane databases, and clinicaltrials.gov registry. Our search covered the period from the inception of these databases up to May 20, 2023. We only selected studies that compared the effectiveness and safety of diltiazem and metoprolol in adult patients with AF-RVR who were in emergency medical settings or hospitalized. We focused on whether the drugs successfully controlled heart rate and if there were any cases of hypotension or bradycardia following drug administration. Results: Among the 150 identified studies, 19 were suitable. All these studies demonstrated a low to moderate risk of bias. The meta-analysis, using the Mantel-Haenszel random-effects model, revealed a higher success rate in achieving the rate control target with diltiazem compared to metoprolol [19 studies, n = 1732, Odds Ratio (OR): 1.65; 95% Confidence Intervals (CI):1.18 to 2.32; I^2 = 58%, P = 0.001]. In terms of safety, no significant difference was observed in the risk of hypotension with either drug [15 studies, n = 1477, OR: 1.12; 95% CI: 0.76 to 1.64; I^2 = 25%, P = 0.18]. However, an incidence of bradycardia was noticed with diltiazem [7 studies, n = 1203, OR: 2.85; 95% CI: 1.25 to 6.46; I^2 = 21%, P = 0.27]. Conclusions: For patients with AF-RVR, intravenous diltiazem was more successful in achieving the desired rate control than metoprolol. Both drugs had similar rates of hypotension, but diltiazem had a slightly higher risk of bradycardia. These results indicate that diltiazem may be a better option for rate control in AF-RVR patients. However, high-quality randomized studies are needed to assess both medication's long-term safety and effectiveness in this group.

BACTERIAL PROFILE AND ANTIBIOTIC SUSCEPTIBILITY PATTERN OF UROPATHOGENS CAUSING URINARY TRACT INFECTIONS: OBSERVATIONSINA NEW TERTIARY CARE INSTITUTE OF A RURAL AREA OF NORTHERN INDIA

Introduction: Urinary tract infections (UTIs) are among the most common and burdensome diseases affecting outpatients and hospitalized patients, Escherichia coli being the most commonly implicated bacterium. UTIs have been treated empirically in locations where microbiological facilities are either non-existent or too expensive. This study was conducted to fill in our lack of knowledge regarding the bacterial composition and antimicrobial susceptibility patterns of uropathogens in Raebareli (Uttar Pradesh), India, and to help formulate an antibiotic policy. Materials and Methods: This retrospective study was conducted at a 600-bed tertiary care hospital in rural India, from 11th August 2021 to 10th July 2022. The study excluded patients who were on antibiotic therapy and had been hospitalized a week before their OPD visit. Midstream urine samples collected aseptically were cultured semi-quantitatively. Organisms with significant colony counts were identified using routine biochemical techniques and antimicrobial susceptibility was tested against various antibiotics as per CLSI guidelines. The data was condensed and analyzed using SPSS version 23 softwares descriptive statistics feature. Results: A total of 5,982 urine samples were considered eligible during the study period. Most of the patients were 19-39 years old (40.67%), and the majority were females (55.25%). Most of the samples were received from General Medicine (32.77%). 056 (17.65%) samples showed significant bacterial growth. 258 (4.31%) samples were not considered for further analysis due to contamination during collection. E. coli was the most common organism isolated (53.5%), followed by Enterococcus faecalis (21.4%). E. coli isolates exhibited good sensitivity to Fosfomycin (90.97%), Gentamicin (80.71%), and Imipenem (80%). Vancomycin and Linezolid showed &gt;90% susceptibility to all the gram-positive isolates. 71.79% of the Staphylococcal isolates were MRSA. Discussion: This study marks the primary investigation into the susceptibility patterns displayed by bacterial strains causing urinary tract infections in Raebareli, Uttar Pradesh (UP) and enables a comparison with other areas of the nation. Age, sex and pyuria were all crucial factors in the incidence of UTI, and must be considered when assessing and managing UTI patients. There was no significant difference in the prevalence of UTI among various departments. E. coli is the leading cause of UTI worldwide, as in our study. The bacterial isolates exhibited noteworthy resistance to the first-line therapeutic agents which are commonly employed for treating UTIs. Our results indicate that fosfomycin, gentamicin, and nitrofurantoin are viable options for treating E. coli infections, while carbapenems and piperacillin-tazobactam can potentially manage other Gram-negatives. Vancomycin, linezolid and nitrofurantoin were the available options for Gram-positive isolates, Conclusion: Our study has revealed a significant number of Gram-negative bacterial isolates, with Escherichia coli being the main cause of UTIs. We have also conducted a comprehensive analysis of antibiogram data. Based on our findings, Nitrofurantoin and Fosfomycin are recommended to initially treat UTIs in our region. These results will apply to our inpatient and outpatient facilities and other departments within our organization.

Metformin: A Review of Potential Mechanism and Therapeutic Utility Beyond Diabetes.

Metformin has been designated as one of the most crucial first-line therapeutic agents in the management of type 2 diabetes mellitus. Primarily being an antihyperglycemic agent, metformin also has a plethora of pleiotropic effects on various systems and processes. It acts majorly by activating AMPK (Adenosine Monophosphate-Activated Protein Kinase) in the cells and reducing glucose output from the liver. It also decreases advanced glycation end products and reactive oxygen species production in the endothelium apart from regulating the glucose and lipid metabolism in the cardiomyocytes, hence minimizing the cardiovascular risks. Its anticancer, antiproliferative and apoptosis-inducing effects on malignant cells might prove instrumental in the malignancy of organs like the breast, kidney, brain, ovary, lung, and endometrium. Preclinical studies have also shown some evidence of metformin's neuroprotective role in Parkinson's disease, Alzheimer's disease, multiple sclerosis and Huntington's disease. Metformin exerts its pleiotropic effects through varied pathways of intracellular signalling and exact mechanism in the majority of them remains yet to be clearly defined. This article has extensively reviewed the therapeutic benefits of metformin and the details of its mechanism for a molecule of boon in various conditions like diabetes, prediabetes, obesity, polycystic ovarian disease, metabolic derangement in HIV, various cancers and aging.

Comprehensive profiling of clinical JAK inhibitors in myeloproliferative neoplasms.

Small molecule inhibitors targeting JAK2 provide symptomatic benefits for myeloproliferative neoplasm (MPN) patients and are among first-line therapeutic agents. However, despite all having potent capacity to suppress JAK-STAT signaling, they demonstrate distinct clinical profiles suggesting contributory effects in targeting other ancillary pathways. Here, we performed comprehensive profiling on four JAK2 inhibitors either FDA-approved (ruxolitinib, fedratinib, and pacritinib) or undergoing phase 3 studies (momelotinib) to better outline mechanistic and therapeutic efficacy. Across JAK2-mutant in vitro models, all four inhibitors demonstrated similar anti-proliferative phenotypes, whereas pacritinib yielded greatest potency on suppressing colony formation in primary samples, while momelotinib exhibited unique erythroid colony formation sparing. All inhibitors reduced leukemic engraftment, disease burden, and extended survival across patient-derived xenograft (PDX) models, with strongest effects elicited by pacritinib. Through RNA-sequencing and gene set enrichment analyses, differential suppressive degrees of JAK-STAT and inflammatory response signatures were revealed, which we validated with signaling and cytokine suspension mass cytometry across primary samples. Lastly, we assessed the capacity of JAK2 inhibitors to modulate iron regulation, uncovering potent suppression of hepcidin and SMAD signaling by pacritinib. These comparative findings provide insight into the differential and beneficial effects of ancillary targeting beyond JAK2 and may help guide the use of specific inhibitors in personalized therapy.

Natural essential oils derived from herbal medicines: A promising therapy strategy for treating cognitive impairment.

Cognitive impairment (CI), mainly Alzheimer's disease (AD), continues to increase in prevalence and is emerging as one of the major health problems in society. However, until now, there are no first-line therapeutic agents for the allopathic treatment or reversal of the disease course. Therefore, the development of therapeutic modalities or drugs that are effective, easy to use, and suitable for long-term administration is important for the treatment of CI such as AD. Essential oils (EOs) extracted from natural herbs have a wide range of pharmacological components, low toxicity, and wide sources, In this review, we list the history of using volatile oils against cognitive disorders in several countries, summarize EOs and monomeric components with cognitive improvement effects, and find that they mainly act by attenuating the neurotoxicity of amyloid beta, anti-oxidative stress, modulating the central cholinergic system, and improving microglia-mediated neuroinflammation. And combined with aromatherapy, the unique advantages and potential of natural EOs in the treatment of AD and other disorders were discussed. This review hopes to provide scientific basis and new ideas for the development and application of natural medicine EOs in the treatment of CI.

Diagnosis and Management of Neuropathic Pain in Spine Diseases

Neuropathic pain is generally defined as a non-physiological pain experience caused by damage to the nervous system. It can occur spontaneously, as a reaction to a given stimulus, or independently of its action, leading to unusual pain sensations usually referred to as firing, burning or throbbing. In the course of spine disorders, pain symptoms commonly occur. According to available epidemiological studies, a neuropathic component of pain is often present in patients with spinal diseases, with a frequency ranging from 36% to 55% of patients. Distinguishing between chronic nociceptive pain and neuropathic pain very often remains a challenge. Consequently, neuropathic pain is often underdiagnosed in patients with spinal diseases. In reference to current guidelines for the treatment of neuropathic pain, gabapentin, serotonin and norepinephrine reuptake inhibitors and tricyclic antidepressants constitute first-line therapeutic agents. However, long-term pharmacologic treatment often leads to developing tolerance and resistance to used medications. Therefore, in recent years, a plethora of therapeutic methods for neuropathic pain have been developed and investigated to improve clinical outcomes. In this review, we briefly summarized current knowledge about the pathophysiology and diagnosis of neuropathic pain. Moreover, we described the most effective treatment approaches for neuropathic pain and discussed their relevance in the treatment of spinal pain.

Susceptibility analysis of mutations that confer resistance to inhibitors of the SARS-CoV-2 main protease (Mpro) and RNA-dependent RNA polymerase (RdRp)

Enormous efforts have been made worldwide to generate therapeutic options to prevent the transmissibility of SARS-CoV-2 and reduce its replication in humans. Currently, the emergence of new variants of the virus is of great concern because the evolution of the viral genome and the inherent mutations introduced in the viral proteins could decrease the effectiveness of the first-line therapeutic agents used to prevent and treat COVID-19. The present study evaluated the susceptibility of two important pharmacological drug targets of SARS-CoV-2, the major protease (Mpro) and the RNA-dependent RNA polymerase (RdRp), to suffer point mutations that could produce resistance to inhibitors of these enzymes. The results showed that the residues that contour the inhibitor binding site in RdRp are extremely conserved between the different RNA virus species. This suggests the RdRp enzyme has a low probability to suffer mutation that could confer resistance to therapeutic drugs, such as Remdesivir, an FDA approved compound to treat COVID-19. In contrast, we observed that the Mpro enzyme could undergo up to ten-point mutations in the active site, which is the binding site of several experimental drugs under development, such as Carmofur and N3. Molecular docking analysis showed that the presence of single point mutations in the Mpro active site produces an increase in the binding affinity of carmofur, probably due to the small size and high flexibility of this molecule. However, the Pro168Ser and Ala191Val mutations significantly decrease the affinity of N3 binding to Mpro, suggesting the possible emergence of resistance to this drug. These results could help to anticipate the effect of different mutations on the way Mpro inhibitors bind to the enzyme, and design new inhibitors that address the effect of resistance.

LB1000 Potential role of cold atmospheric plasma in improving drug resistance of BRAFi/MEKi and immune checkpoint blockade agents in melanoma cells

Cold atmospheric plasma (CAP) has been found effective in tumor treatment and promises to be adjuvant agents for various tumors. In melanoma, it has been reported that CAP can alter metabolism, senescence, migration, apoptosis and autophagy, and improve efficacy of chemotherapeutic agents. Current first-line therapeutic agents of advanced melanoma are immune checkpoint blockade and BRAF inhibitor (BRAFi)/MEK inhibitor (MEKi). These agents have definite effects with fatal limitation, drug resistance.

Role of STK11 in ALK-positive non-small cell lung cancer.

Anaplastic lymphoma kinase (ALK) inhibitors have been shown to be effective in treating patients with ALK-positive non-small cell lung cancer (NSCLC), and crizotinib, ceritinib and alectinib have been approved as clinical first-line therapeutic agents. The availability of these inhibitors has also largely changed the treatment strategy for advanced ALK-positive NSCLC. However, patients still inevitably develop resistance to ALK inhibitors, leading to tumor recurrence or metastasis. The most critical issues that need to be addressed in the current treatment of ALK-positive NSCLC include the high cost of targeted inhibitors and the potential for increased toxicity and resistance to combination therapy. Recently, it has been suggested that the serine/threonine kinase 11 (STK11) mutation may serve as one of the biomarkers for immunotherapy in NSCLC. Therefore, the main purpose of this review was to summarize the role of STK11 in ALK-positive NSCLC. The present review also summarizes the treatment and drug resistance studies in ALK-positive NSCLC and the current status of STK11 research in NSCLC.

Unbiased Phosphoproteomics Reveals a Therapeutically Relevant Connection between Pre-mRNA Splicing and Proteasome Inhibition in Multiple Myeloma

Introduction: Proteasome inhibitors (PIs) are first-line therapeutic agents in multiple myeloma. While these small molecules have revolutionized myeloma therapy, nearly all myeloma patients treated with PIs eventually experience drug resistance and relapse. We have previously examined the global effects of PIs on the transcriptional and translational landscape of multiple myeloma plasma cells (Wiita et al, eLife (2013) 2:01236). Here, we hypothesized that investigation into the intracellular signaling response to PI-induced stress would help elucidate additional PI mechanisms of action in this cancer.Methods: We applied an unbiased phosphoproteomic screen to MM.1S myeloma cells treated with the PI carfilzomib across a 24-hour time course. We used trypsin digestion, FeCl2 enrichment, and a single-shot 4-hour LC method on each sample harvested at each time point on a Thermo Q-Exactive Plus mass spectrometer, with phosphopeptide identification and label-free quantification performed in MaxQuant. Targeted mass spec was then performed for validation on a subset of upregulated and downregulated phosphosites by parallel reaction monitoring (PRM) on SILAC-labeled, carfilzomib treated MM.1S cells, as well as another multiple myeloma cell line, AMO1, at 24 hr of treatment. MM.1S cells were also treated with another multiple myeloma therapeutic agent, melphalan, to compare the response to a non-PI drug. Analysis was carried out in Skyline. For paired-end mRNA-seq, we constructed sequencing libraries from the SILAC samples and sequenced on an Illumina HiSeq4000 and analyzed with JuncBASE software to correlate changes in splicing factor phosphorylation with alternative splicing events. In vitro viability studies of myeloma cell lines were carried out with Cell-titer-glo assay. For in vivo studies, we used disseminated murine xenograft models of luciferase-labeled MM.1S implanted intravenously into NSG mice, with tumor burden measured by bioluminescence. Mice (n=6 per arm) were treated with 3 mg/kg E7107 or DMSO IV 5d/wk for 2 wks.Results: Among the more than 5,000 phosphopeptides quantified in the phosphoproteomic screen, the most profoundly upregulated phosphosites mapped to numerous serine-and-arginine rich (“SR”) core components of the pre-mRNA spliceosome (Fig. 1A: upregulated phosphosites across time course in gold; downregulated in cyan. Red arrows indicate SR protein phosphosites; green arrows are positive control phosphosites on EIF4EBP1 and RPS6, known to decrease after PI treatment.). These targets were confirmed by targeted mass spec, while simultaneous mRNA-seq confirmed no change in splicing factor abundance in response to PI (Fig. 1A). Intriguingly, intron retention appeared to be a dominant signature in pre-mRNA splicing after PI treatment based on JuncBASE analysis. This connection led us to investigate whether induction of intron retention may be sufficient to lead to myeloma tumor cell death. We therefore obtained the clinical candidate E7107, a specific inhibitor of the core spliceosome factor SF3B1, known to strongly induce intron retention across the transcriptome. We found that a panel of myeloma cell lines were highly sensitive to E7107 at low nanomolar concentrations, which are easily achievable in patients based on prior Phase I studies. We further found evidence of synergy in vitro between E7107 and PI treatment, and E7107 was equally efficacious in naïve and PI-resistant AMO1 cells. Furthermore, pre-clinical experiments in murine xenograft models with a brief two-week treatment with E7107 significantly decreased tumor burden and significantly increased lifespan (Fig 1B).Conclusion: Our approaches here reveal a novel connection between PI-induced stress and modulation of the core spliceosome machinery not previously observed in any other system. By capitalizing on this vulnerability, we further propose that targeting the spliceosome machinery may be a novel therapeutic option for multiple myeloma patients, either in combination with PIs or in the PI-refractory setting, addressing a major clinical need. [Display omitted] DisclosuresWiita:Sutro Biopharma: Research Funding; TeneoBio, Inc.: Research Funding.

First-Line Sodium Glucose Co-transporter 2 Inhibitors: Physicochemical Properties and Measurement in Biological Fluids

Sodium glucose co-transporter 2 (SGLT 2) inhibitors represent a new class of glucose-lowering drugs that act through the inhibition of glucose reabsorption at the proximal tubular cells of the kidney. The objective of the study was to provide most current information on the physicochemical properties and analytical methods of determination in biological matrices of the first-line sodium glucose co-transporter 2 (SGLT 2) inhibitors. The methodology of literature search entailed obtaining information from published works in scientific journals, official books and the internet websites. The results of the study show that these first-line therapeutic agents selectively inhibit the reabsorption of glucose in the kidney by almost 30-50 percent. Apart from their effects on carbohydrate homeostasis, they also affect human metabolism by decreasing blood pressure, arterial stiffness, body weight, serum concentrations of insulin. They increase glucagon concentration thus shifting energy metabolism towards the utilization of fatty acids and ketone bodies. They have also been found to preserve renal function in patients with type 2 diabetes mellitus and established cardiovascular disease. In conclusion, these therapeutic agents exhibit significant cardio-protective and renoprotective effects by their mechanism of action.

Potential therapeutic target identification in the novel 2019 coronavirus: insight from homology modeling and blind docking study

BackgroundThe 2019-nCoV which is regarded as a novel coronavirus is a positive-sense single-stranded RNA virus. It is infectious to humans and is the cause of the ongoing coronavirus outbreak which has elicited an emergency in public health and a call for immediate international concern has been linked to it. The coronavirus main proteinase which is also known as the 3C-like protease (3CLpro) is a very important protein in all coronaviruses for the role it plays in the replication of the virus and the proteolytic processing of the viral polyproteins. The resultant cytotoxic effect which is a product of consistent viral replication and proteolytic processing of polyproteins can be greatly reduced through the inhibition of the viral main proteinase activities. This makes the 3C-like protease of the coronavirus a potential and promising target for therapeutic agents against the viral infection.ResultsThis study describes the detailed computational process by which the 2019-nCoV main proteinase coding sequence was mapped out from the viral full genome, translated and the resultant amino acid sequence used in modeling the protein 3D structure. Comparative physiochemical studies were carried out on the resultant target protein and its template while selected HIV protease inhibitors were docked against the protein binding sites which contained no co-crystallized ligand.ConclusionIn line with results from this study which has shown great consistency with other scientific findings on coronaviruses, we recommend the administration of the selected HIV protease inhibitors as first-line therapeutic agents for the treatment of the current coronavirus epidemic.

Review article: the management of heartburn during pregnancy and lactation

Gestational reflux is common, affecting up to 80% of pregnant women. Most symptoms will abate during lactation. During both of these periods, interventions used to relieve symptoms focus on a "step-up" methodology with progressive intensification of treatment. This begins with lifestyle modifications. To provide guidance in the treatment of reflux in pregnancy and lactation, as well as briefly summarising the pathogenesis, clinical presentation and diagnostic workup. A comprehensive search, using online databases PubMed and MEDLINE, along with relevant manuscripts published in English between 1966 and 2019 was used. All abstracts were screened, potentially relevant articles were researched, and bibliographies were reviewed. Only a small percentage of relevant drugs are contraindicated for use in pregnancy or while breastfeeding. However, not all drug agents have been extensively evaluated in pregnant women or during the breastfeeding period. Antacids, alginates, and sucralfate are the first-line therapeutic agents. If symptoms persist, any of the H2 RAs can be used except for nizatidine (due to foetal teratogenicity or harm in animal studies). PPIs are reserved for women with intractable symptoms or complicated GERD; all are FDA category B drugs, except for omeprazole, which is a category C drug. The management of heartburn during pregnancy and lactation begins with lifestyle modifications. In situations where disease severity increases, medical providers must discuss risks and benefits of these medicines with the patient in detail.

Vector-borne diseases in pregnancy.

Vector-borne infections cause a significant proportion of world-wide morbidity and mortality and many are increasing in incidence. This is due to a combination of factors, primarily environmental change, encroachment of human habitats from urban to peri-urban areas and rural to previously uninhabited areas, persistence of poverty, malnutrition and resource limitation in geographical areas where these diseases are endemic. Pregnant women represent the single largest ‘at risk’ group, due to immune-modulation and a unique physiological state. Many of these diseases have not benefitted from the same level of drug development as other infectious and medical domains, a factor attributing to the ‘neglected tropical disease’ title many vector-borne diseases hold. Pregnancy compounds this issue as data for safety and efficacy for many drugs is practically non-existent, precluding exposure in pregnancy to many first-line therapeutic agents for ‘fear of the unknown’ or overstated adverse pregnancy-foetal outcomes. In this review, major vector-borne diseases, their impact on pregnancy outcomes, current treatment, vaccination and short-comings of current medical practice for pregnant women will be discussed.

Myasthenia Gravis: Analytical Methods for the Determination in Biological Fluids of First-Line Therapeutic Agents Used in the Management of the Disease

Myasthenia Gravis (MG) an autoimmune disease is the prototype of neuromuscular junction disease caused by auto antibodies against the nicotinic Acetylcholine Receptor (AChR) located in the postsynaptic muscle endplate membrane [1,2]. The autoimmune disorder is characterized by weakness and fatigability of the voluntary muscle arising from the distortion and simplification of the postynaptic muscle membrane and consequent attachment of antibodies and complement to the membrane.

An update on allergy and anaphylaxis in pediatric anesthesia.

Childhood allergy is common, and increasing. Many children are incorrectly labeled as having allergy or adverse drug reactions. This can pose a dilemma for anesthetists and lead to a change in practice or drug selection. We review the pathophysiology of hypersensitivity reactions and the implications for anesthesia of food allergy, atopy, and family history of allergy in children. The epidemiology of anaphylaxis is discussed. We discuss the common triggers of perioperative anaphylaxis in children and explore emerging triggers including chlorhexidine and sugammadex. Accurate data on pediatric perioperative anaphylaxis is limited worldwide, with marked geographic variation. This highlights the need for accurate local, district and/or nationwide incident reporting. The clinical features, diagnosis, and management of anaphylaxis under anesthesia are discussed. We review the process of expert allergy testing following a suspected case of anaphylaxis to guide future safe anesthesia administration. The preoperative consultation is an opportunity for referral for allergy testing to allow de-labeling. This has the potential for improved antibiotic stewardship and more effective treatment with first-line therapeutic agents.

Mo1706 EFFECTS OF PREDNISALONE AND VEDOLIZUMAB ON A NEWLY DEVELOPED CHRONIC DEXTRAN SULFATE SODIUM-INDUCED COLITIS MODEL IN THE NONHUMAN PRIMATE

Dextran sulfate sodium (DSS)-induced colitis is frequently used as an animal model of inflammatory bowel disease (IBD). However, first-line therapeutic agents, such as the corticosteroid prednisolone (PSL), show poor efficacy or even worsen colitis in the rodent model. Species specific differences in inflammatory/immune mechanisms between humans and rodents could be potential sources of this issue. Nonhuman primates (NHP) are phylogenetically closer to humans than rodents and are useful in investigating mucosal immunity. In the present study, a NHP model of chronic colitis was developed and the effect of PSL and the alpha-integrin blocking antibody vedolizumab (VED) on remission was assessed in this model.