Add-on Agent Research Articles

Sodium-dependent glucose transporter 2 inhibitors effects on myocardial function in patients with type 2 diabetes and asymptomatic heart failure.

Sodium-dependent glucose transporter 2 inhibitors (SGLT2i) have shown efficacy in reducing heart failure (HF) burden in a very heterogeneous groups of patients, raising doubts about some contemporary assumptions of their mechanism of action. We previously published a prospective observational study that evaluated mechanisms of action of SGLT2i in patients with type 2 diabetes who were in HF stages A and B on dual hypoglycemic therapy. Two groups of patients were included in the study: the ones receiving SGLT2i as an add-on agent to metformin and the others on dipeptidyl peptidase-4 inhibitors as an add-on to metformin due to suboptimal glycemic control. To evaluate the outcomes regarding natriuretic peptide, oxidative stress, inflammation, blood pressure, heart rate, cardiac function, and body weight. The study outcomes were examined by dividing each treatment arm into two subgroups according to baseline parameters of global longitudinal strain (GLS), N-terminal pro-brain natriuretic peptide, myeloperoxidase (MPO), high-sensitivity C-reactive protein (hsCRP), and systolic and diastolic blood pressure. To evaluate the possible predictors of observed changes in the SGLT2i arm during follow-up, a rise in stroke volume index, body mass index (BMI) decrease, and lack of heart rate increase, linear regression analysis was performed. There was a greater reduction of MPO, hsCRP, GLS, and blood pressure in the groups with higher baseline values of mentioned parameters irrespective of the therapeutic arm after 6 months of follow-up. Significant independent predictors of heart rate decrease were a reduction in early mitral inflow velocity to early diastolic mitral annular velocity at the interventricular septal annulus ratio and BMI, while the predictor of stroke volume index increase was SGLT2i therapy itself. SGLT2i affect body composition, reduce cardiac load, improve diastolic/systolic function, and attenuate the sympathetic response. Glycemic control contributes to the improvement of heart function, blood pressure control, oxidative stress, and reduction in inflammation.

Comparative Efficacy and Acceptability of Treatment Strategies for Antipsychotic-Induced Akathisia: A Systematic Review and Network Meta-analysis.

Antipsychotics are the treatment of choice for schizophrenia, but they often induce akathisia. However, comparative efficacy of treatment strategies for akathisia remains unclear. We performed a systematic review and network meta-analyses (PROSPERO CRD42023450720). We searched multiple databases on July 24, 2023. We included randomized clinical trials comparing 1 or more treatment strategies for antipsychotic-induced akathisia against each other or control conditions. We included adults with schizophrenia or other psychiatric disorders treated with antipsychotics. The primary outcome was akathisia severity at posttreatment. Secondary outcomes included akathisia response, all-cause dropout, psychotic symptoms, and long-term akathisia severity. We synthesized data in random effects frequentist network meta-analyses and assessed confidence in the evidence using CINeMA. We identified 19 trials with 661 randomized participants (mean age 35.9 [standard deviation 12.0]; 36.7% [195 of 532] women). No trials examined dose reduction or switching of antipsychotics. Findings suggested 5-HT2A antagonists (k = 6, n = 108; standardized mean difference [SMD] -1.07 [95% confidence interval, -1.42; -0.71]) and beta-blockers (k = 8, n = 105; SMD -0.46 [-0.85; -0.07]) may improve akathisia severity, but confidence in the evidence was deemed low. We also found that benzodiazepines (k = 2, n = 13; SMD -1.62 [-2.64; -0.59]) and vitamin B6 (k = 3, n = 67; SMD -0.99 [-1.49; -0.50]) might also be beneficial, but confidence in the evidence was very low. Analyses of secondary outcomes did not provide additional insights. Our findings suggest that 5-HT2A antagonists, beta-blockers, and with a lesser certainty, benzodiazepines, and vitamin B6 might improve akathisia. Given the low to very low confidence in the evidence of add-on agents and the absence of evidence of their long-term efficacy, careful consideration of side effects is warranted. These recommendations are extremely preliminary and further trials are needed.

Real-world experience of commercial relmacabtagene autoleucel (relma-cel) for relapsed/refractory central nervous system lymphoma: a multicenter retrospective analysis of patients in China

BackgroundRelapsed/refractory (R/R) central nervous system lymphomas (CNSLs) are associated with a poor prognosis. Relmacabtagene autoleucel (relma-cel), expressing the same chimeric antigen receptor (CAR) as lisocabtagene maraleucel, with an optimized commercial-ready...

Abstract CT150: Trial in progress: A phase 1b single-arm, open-label, study of emavusertib (CA-4948) in combination with azacitidine and venetoclax in acute myeloid leukemia patients in complete response with measurable residual disease

Abstract Background: Emavusertib is a novel potent oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) with additional inhibitory activity against FMS-like tyrosine kinase 3 (FLT3) and CDC-like kinases (CLK1/2/4). Inhibition of these onco-proteins may induce remission thereby addressing a critical unmet need for novel therapies in acute myeloid leukemia (AML). Clinical studies with emavusertib monotherapy have demonstrated a significant reduction in AML blasts with clinical and molecular responses, including patients with relapsed or refractory AML, previously treated with an HMA and/or FLT3 inhibitors (Metzeler 2022). Azacitidine + venetoclax (aza+ven) has been approved in newly diagnosed, unfit patients with AML. In the VIALE-A study, composite complete response (CRc) (CR, CRh, or CRi) in the absence of measurable residual disease (MRD) of <1 residual blast/1000 leukocytes (MRD negative [MRD−]) resulted in longer duration of response (DOR), event-free survival, and overall survival (OS), and better HSCT outcome compared with patients who achieved CRc but were MRD+ (Pratz, 2022). In pre-clinical studies, emavusertib in combination with aza+ven demonstrated synergistic antileukemic effects in AML cell lines, including azacitidine- or venetoclax-resistant cell lines. Adding emavusertib to aza+ven in MRD+ patients at the time of CR may convert MRD status without adding significant toxicity and confirm that emavusertib can be safely added to aza+ven as a potential new regimen in front-line therapy. Study Design: This is a single-arm, open-label Phase 1b trial evaluating safety and tolerability, PK, and conversion of MRD status with emavusertib as an add-on agent to aza+ven in AML patients who achieved CR or CRh with MRD+ based on local testing (EU CT Number 2023-505828-58-00). The primary objective of the study is to determine a safe and tolerable dosing schedule for the triple combination. Secondary objectives include MRD conversion rate, DOR, OS, and pharmacokinetics. The study will enroll approximately 24 patients at 5 to 10 sites globally. Patients will have received azacitidine and venetoclax as first line therapy and achieved CR or CRh after 1-6 cycles of aza/ven. If MRD status remains positive, emavusertib will be added to the existing well tolerated aza+ven regimen. The starting emavusertib dose is 200 mg BID for 7 days per cycle of 28 days. If well tolerated, duration of emavusertib treatment will be extended to 14 and 21, respectively; no intra-patient change of emavusertib dosing duration is planned. The patients will continue triple treatment (emavusertib+aza+ven) until consent withdrawal, disease progression, intolerable toxicity, or not achieving MRD- within 6 cycles of triple treatment. In this Phase 1b trial, MRD can be evaluated by local testing of bone marrow. Key exclusion criteria include residual toxicities and significant comorbidities. Citation Format: Reinhard von Roemeling, Adolfo De La Fuente, Claudio Cerchione, Sebastian Scholl, Jan Moritz Middeke, Gaurav S. Choudhary, Maria Lamar, Steven Angelides, Uwe Platzbecker. Trial in progress: A phase 1b single-arm, open-label, study of emavusertib (CA-4948) in combination with azacitidine and venetoclax in acute myeloid leukemia patients in complete response with measurable residual disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT150.

Comparative efficacy and safety of stiripentol, cannabidiol and fenfluramine as first-line add-on therapies for seizures in Dravet syndrome: A network meta-analysis.

Stiripentol, fenfluramine, and cannabidiol are licensed add-on therapies to treat seizures in Dravet Syndrome (DS). There are no direct or indirect comparisons assessing their full licensed dose regimens, across different jurisdictions, as first-line add-on therapies in DS. We conducted a systematic review and frequentist network meta-analysis (NMA) of randomized controlled trial (RCT) data for licensed add-on DS therapies. We compared the proportions of patients experiencing: reductions from baseline in monthly convulsive seizure frequency (MCSF) of ≥50% (clinically meaningful), ≥75% (profound), and 100% (seizure-free); serious adverse events (SAEs); discontinuations due to AEs. We identified relevant data from two placebo-controlled RCTs for each drug. Stiripentol 50 mg/kg/day and fenfluramine 0.7 mg/kg/day had similar efficacy in achieving ≥50% (clinically meaningful) and ≥75% (profound) reductions from baseline in MCSF (absolute risk difference [RD] for stiripentol versus fenfluramine 1% [95% confidence interval: -20% to 22%; p = 0.93] and 6% [-15% to 27%; p = 0.59], respectively), and both were statistically superior (p < 0.05) to licensed dose regimens of cannabidiol (10 or 20 mg/kg/day, with/irrespective of clobazam) for these outcomes. Stiripentol was statistically superior in achieving seizure-free intervals compared to fenfluramine (RD = 26% [CI: 8% to 44%; p < 0.01]) and licensed dose regimens of cannabidiol. There were no significant differences in the proportions of patients experiencing SAEs. The risk of discontinuations due to AEs was lower for stiripentol, although the stiripentol trials were shorter. This NMA of RCT data indicates stiripentol, as a first-line add-on therapy in DS, is at least as effective as fenfluramine and both are more effective than cannabidiol in reducing convulsive seizures. No significant difference in the incidence of SAEs between the three add-on agents was observed, but stiripentol may have a lower risk of discontinuations due to AEs. These results may inform clinical decision-making and the continued development of guidelines for the treatment of people with DS. This study compared three drugs (stiripentol, fenfluramine, and cannabidiol) used alongside other medications for managing seizures in a severe type of epilepsy called DS. The study found that stiripentol and fenfluramine were similarly effective in reducing seizures and both were more effective than cannabidiol. Stiripentol was the best drug for stopping seizures completely based on the available clinical trial data. All three drugs had similar rates of serious side effects, but stiripentol had a lower chance of being stopped due to side effects. This information can help guide treatment choices for people with DS.

Approach to the Patient With Type 2 Diabetes Requiring Add-On Medication.

In the last 20 years, the number of approved agents and agent classes for management of type 2 diabetes has expanded significantly. This more robust armamentarium affords us the opportunity to utilize drugs with complementary modes of action to address progressive hyperglycemia as insulin secretion declines over time. Furthermore, some of these agents provide additional benefits, such as weight loss, prevention of major adverse cardiac events (MACE), and protection against declining renal function. This dramatic increase of treatment options has led to complex published treatment advice which may be challenging for the busy clinician. A critical element in medication selection is awareness of the hemoglobin A1c (HbA1c)-lowering potency of the agent being considered, and the distance of the patient's HbA1c level from the individualized goal. Other important factors in choosing medication as diabetes progresses include the recognition that there is a diminishing return of glucose-lowering efficacy as add-on agents are introduced, and that the extent of benefit for cardiac and renal protection is not fully understood. In addition, the availability of newer non-insulin agents may distract the clinician from utilizing insulin, the most potent agent available. The goal of this article is to provide a straightforward approach to add-on medication in the treatment of type 2 diabetes, recognizing the limits of polypharmacy and the importance of employing agents best suited to achieving treatment targets. Proposed is a practical tool which provides stepwise guidance, utilizing available data on medication efficacy, while allowing flexibility based on clinician and patient preference.

Intermediate and long-term residual cardiovascular risk in patients with established cardiovascular disease treated with statins.

Statins remain the first-line treatment for secondary prevention of cardiovascular (CV) events, with lowering of low-density lipoprotein cholesterol (LDL-C) being their therapeutic target. Although LDL-C reduction significantly lowers CV risk, residual risk persists, even in patients with well-controlled LDL-C; thus, statin add-on agents that target pathways other than LDL-C, such as the omega-3 fatty acid eicosapentaenoic acid, may help to further reduce persistent CV risk in patients with established CV disease. This narrative review examines the contemporary literature assessing intermediate- and long-term event rates in patients with established CV disease treated with statins. CV event rates among patients treated with statins who have established CV disease, including coronary artery disease, cerebrovascular disease, or peripheral arterial disease, accumulate over time, with a cumulative incidence of CV events reaching up to approximately 40% over 10 years. Recurrent stroke occurs in up to 19% of patients seven years after a first cerebrovascular event. Repeat revascularization and CV-related death occurs in up to 38% and 33% of patients with peripheral artery disease after three years, respectively. Additional treatment strategies, such as eicosapentaenoic acid, are needed to reduce persistent CV risk in patients with established CV disease treated with statins.

Glucagon-like peptide-1 receptor agonists and the risk of atrial fibrillation in adults with diabetes: a real-world study.

Glucagon-like peptide-1 receptor agonists (GLP-1RA) have cardiovascular benefits in type 2 diabetes, but none of the cardiovascular trials studied atrial fibrillation/atrial flutter (AF) as a primary endpoint. Data from post-marketing surveillance studies remains sparse. To examine the real-world risk of AF comparing GLP-1RA with other non-insulin glucose-lowering agents. Cohort study using de-identified electronic health record data from the Optum Labs Data Warehouse. Adult patients with diabetes who were newly prescribed add-on non-insulin glucose-lowering agents and were on metformin between 2005-2020. New users of GLP-1RA were separately compared with new users of dipeptidyl peptidase-4 inhibitors (DPP4i) and sodium-glucose cotransporter 2 inhibitors (SGLT2i), using 1:1 propensity score matching to adjust for differences in patient characteristics. The primary outcome was incident AF, defined and captured by diagnosis code for AF. Incidence rate difference (IRD) and hazard ratio (HR) were estimated in the matched cohorts. In the matched cohort of 14,566 pairs of GLP-1RA and DPP4i followed for a median of 3.8 years, GLP-1RA use was associated with a lower risk of AF (IRD, -1.0; 95% CI, -1.8 to -0.2 per 1000 person-years; HR, 0.82; 95% CI, 0.70 to 0.96). In the matched cohort of 9,424 pairs of patients on GLP-1RA and SGLT2i with a median follow-up of 2.9 years, there was no difference in the risk for AF (IRD, 0.4; 95% CI -0.7 to 1.5 per 1000 person-years; HR, 1.12; 95% CI, 0.89 to 1.42). In this real-word study, GLP-1RA was associated with a lower risk of AF compared with DPP4i, but no difference compared with SGLT2i, suggesting that cardiovascular benefits of GLP-1RA use may extend to prevention for AF in patients with diabetes. Our findings call for future randomized controlled trials to focus on the effects of GLP-1RA on AF prevention.

Trial in Progress: A Phase 1b Single-Arm, Open-Label Study of Emavusertib (CA-4948) in Combination with Azacitidine and Venetoclax in Acute Myeloid Leukemia Patients in Complete Response with Measurable Residual Disease

Background Emavusertib is a novel potent oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) with additional inhibitory activity against FMS-like tyrosine kinase 3 (FLT3) and CDC-like kinases (CLK1/2/4). Inhibition of these onco-proteins may induce remission thereby addressing a critical unmet need for novel therapies in acute myeloid leukemia (AML). Clinical studies with emavusertib monotherapy have demonstrated a significant reduction in AML blasts with clinical and molecular responses, including patients with relapsed or refractory AML, previously treated with an HMA and/or FLT3 inhibitors (Metzeler 2022). Azacitidine + venetoclax (aza+ven) has been approved in newly diagnosed, unfit patients with AML. In the VIALE-A study, composite complete response (CRc) (CR, CRh, or CRi) in the absence of measurable residual disease (MRD) of &amp;lt;1 residual blast/1000 leukocytes (MRD negative [MRD−]) resulted in longer duration of response (DOR), event-free survival, and overall survival (OS), and better HSCT outcome compared with patients who achieved CRc but were MRD+ (Pratz, 2022). In pre-clinical studies, emavusertib in combination with aza+ven demonstrated synergistic antileukemic effects in AML cell lines, including azacitidine- or venetoclax-resistant cell lines. Adding emavusertib to aza+ven in MRD+ patients at the time of CR may convert MRD status without adding significant toxicity and confirm that emavusertib can be safely added to aza+ven as a potential new regimen in front-line therapy. Study Design: This is a single-arm, open-label Phase 1b trial evaluating safety and tolerability, PK, and conversion of MRD status with emavusertib as an add-on agent to aza+ven in AML patients who achieved CR or CRh with MRD+ based on local testing (EU CT Number 2023-505828-58-00). The primary objective of the study is to determine a safe and tolerable dosing schedule for the triple combination. Secondary objectives include MRD conversion rate, DOR, OS, and pharmacokinetics. The study will enroll approximately 24 patients at 5 to 10 sites globally. Patients will have received azacitidine and venetoclax as first line therapy and achieved CR or CRh after 1-6 cycles of aza/ven. If MRD status remains positive, emavusertib will be added to the existing well tolerated aza+ven regimen. The starting emavusertib dose is 200 mg BID for 7 days per cycle of 28 days. If well tolerated, duration of emavusertib treatment will be extended to 14 and 21, respectively; no intra-patient change of emavusertib dosing duration is planned. The patients will continue triple treatment (emavusertib+aza+ven) until consent withdrawal, disease progression, intolerable toxicity, or not achieving MRD- within 6 cycles of triple treatment. In this Phase 1b trial, MRD can be evaluated by local testing of bone marrow. Key exclusion criteria include residual toxicities and significant comorbidities.

Effects of bumetanide on neonatal seizures: A systematic review of animal and human studies

BackgroundBumetanide, an inhibitor of the sodium-potassium-chloride cotransporter-1, has been suggested as an adjunct to phenobarbital for treating neonatal seizures. MethodsA systematic review of animal and human studies was conducted to evaluate the efficacy and safety of bumetanide for neonatal seizures. PubMed, Embase, CINAHL and Cochrane databases were searched in March 2023. Results26 animal (rat or mice) studies describing 38 experiments (28 in-vivo and ten in-vitro) and two human studies (one RCT and one open-label dose-finding) were included. The study designs, methods to induce seizures, bumetanide dose, and outcome measures were heterogeneous, with only 4/38 experiments being in animal hypoxia/ischaemia models. Among 38 animal experiments, bumetanide was reported to have antiseizure effects in 21, pro-seizure in six and ineffective in 11. The two human studies (n = 57) did not show the benefits of bumetanide as an add-on agent to phenobarbital in their primary analyses, but one study reported benefit on post-hoc analysis. Overall, hearing impairment was detected in 5/37 surviving infants in the bumetanide group vs. 0/13 in controls. Four of the five infants with hearing impairment had received aminoglycosides concurrently. Other adverse effects reported were diuresis, mild-to-moderate dehydration, hypotension, and electrolyte disturbances. The studies did not report on long-term neurodevelopment. The certainty of the evidence was very low. ConclusionAnimal data suggest that bumetanide has inconsistent effects as an antiseizure medication in neonates. Data from human studies are scarce and raise some concerns regarding ototoxicity when given with aminoglycosides. Well conducted studies in animal models of hypoxic-ischaemic encephalopathy are urgently needed. Future RCTs, if conducted in human neonates, should have an adequate sample size, assess neurodevelopment, minimize using aminoglycosides, be transparent about the potential ototoxicity in the parent information sheet, conduct early hearing tests and have trial-stopping rules that include hearing impairment as an outcome.

The Role of Long-Acting Antimuscarinic Agents in the Treatment of Asthma.

The journey of using anticholinergics in the treatment of asthma started with anticholinergic-containing plants such as Datura stramonium and Atropa belladonna, followed by ipratropium bromide and continued with tiotropium, glycopyrronium, and umeclidinium. Although antimuscarinics were used in the maintenance treatment of asthma over a century ago, after a long time (since 2014), it has been recommended to be used as an add-on long-acting antimuscarinic agent (LAMA) therapy in the maintenance treatment of asthma. The airway tone controlled by the vagus nerve is increased in asthma. Allergens, toxins, or viruses cause airway inflammation and inflammation-related epithelial damage, increased sensory nerve stimulation, ganglionic and postganglionic acetylcholine (ACh) release by inflammatory mediators, intensification of ACh signaling at M1 and M3 muscarinic ACh receptors (mAChRs), and dysfunction of M2 mAChR. Optimal anticholinergic drug for asthma should effectively block M3 and M1 receptors, but have minimal effect on M2 receptors. Tiotropium, umeclidinium, and glycopyrronium are anticholinergic agents with this feature. Tiotropium has been used in a separate inhaler as an add-on treatment to inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA), and glycopyrronium and umeclidinium have been used in a single inhaler as a combination of ICS/LABA/LAMA in asthma in recent years. Guidelines recommend this regimen as an optimization step for patients with severe asthma before initiating any biologic or systemic corticosteroid therapy. In this review, the history of antimuscarinic agents, their effectiveness and safety in line with randomized controlled trials, and real-life studies in asthma treatment will be discussed according to the current data.

Equipotency of lacosamide to levetiracetam in new onset focal epilepsy: A randomized controlled trial.

Levetiracetam (LEV) is a well-established broad spectrum antiseizure medication (ASM) effective in focal, generalized, and myoclonic seizures whereas lacosamide (LCM) is a comparatively newer ASM currently approved only as an add-on agent in focal seizures. The aim of the study was to assess the efficacy and the tolerability of oral LCM as monotherapy in adult people with epilepsy (PWE) with new onset focal onset epilepsy compared with those receiving LEV. In this open-label single-center non-inferiority trial, PWE aged between 16 and 65 years suffering from new onset focal seizures, with or without secondary generalization were put on LCM monotherapy or LEV monotherapy. Data regarding demographic characteristics, seizure type and etiology, LCM and LEV daily dose, seizure frequency at baseline and at 6 months of follow-up, and seizure freedom rates were recorded. Thirty-five PWE on LCM (24 males), their mean age: 38.20 ± 16.62 years and 35 PWE on LEV (25 males, mean age: 38.91 ± 17.13 years) were enrolled. The most common type of seizure observed was focal to bilateral tonic-clonic seizure >70% followed by focal impaired awareness seizure and focal awareness seizure. Structural epilepsy was found in 21 among LCM group and 22 of LEV group. In the LCM group, the seizure frequency decreased from 3.33 ± 1.88 to 0.85 ± 1.09 (P = 0.001) at 6 months and from 3.61 ± 3.12 to 0.94 ± 1.24 (P = 0.001) in LEV group, intergroup difference (P = 0.74). At 6-month follow-up period, 78.9% in LCM arm and 87.9% in the LEV arm had experienced a 50% of reduction in seizure frequency while seizure freedom was attained in 43.3% of PWE in both the arms (P = 1). The most common treatment emergent adverse effects in the LCM group were fatiguability, dyspepsia, headache, and dizziness, while in the LEV group; somnolence and behavioral abnormality. Treatment with LCM met the non-inferiority criteria when compared with LEV. Therefore, it might be useful as first-line monotherapy for adults with newly diagnosed focal epilepsy.

Nephroprotective effects of Acacia senegal against aflatoxicosis via targeting inflammatory and apoptotic signaling pathways

Aflatoxin B1 (AFB1) is a common environmental pollutant that poses a major hazard to both humans and animals. Acacia senegal (Gum) is well-known for having antioxidant and anti-inflammatory bioactive compounds. Our study aimed to scout the nephroprotective effects of Acacia gum (Gum) against AFB1-induced renal damage. Four groups of rats were designed: Control, Gum (7.5 mg/kg), AFB1 (200 µg/kg b.w) and AFB1-Gum, rats were co-treated with both Gum and AFB1. Gas chromatography-mass spectrometry (GC/MS) analysis was done to determine the phytochemical constituents in Gum. AFB1 triggered profound alterations in kidney function parameters (urea, creatinine, uric acid, and alkaline phosphatase) and renal histological architecture. Additionally, AFB1 exposure evoked up-regulation of mRNA expression levels of inflammatory cytokines, including interleukin-6 (IL-6), tumor necrosis factor α (TNFα), inducible nitric oxide synthase (iNOS), and nuclear factor kB p65 (NF-κB/P65) in renal tissue. The oxidative distress and apoptotic cascade are also instigated by AFB1 intoxication as depicted in down-regulated protein expression of the nuclear factor erythroid 2–related factor 2 (Nrf2) and superoxide dismutase type 1 (SOD1) along with upregulation of cytochrome c (Cyto c), and cleaved Caspase3 (Casp3–17 and 19) in renal tissue. In conclusion, current study obviously confirms the alleviating effects of Gum supplementation against AFB1-induced renal dysfunction, oxidative harm, inflammation, and cell death. These mitigating effects are suggested to be attributed to Gum's antioxidant and anti-inflammatory activities. Our results recommend Gum supplementation as add-on agents to food that might aid in protection from AFB1-induced nephrotoxicity.

Pharmacological treatment and vaccines in monkeypox virus: a narrative review and bibliometric analysis.

Mpox (earlier known as monkeypox) virus infection is a recognized public health emergency. There has been little research on the treatment options. This article reviews the specific drugs used to treat mpox virus infection and the vaccines used here. Instead of focusing on the mechanistic basis, this review narrates the practical, real-life experiences of individual patients of mpox virus disease being administered these medicines. We conducted a bibliometric analysis on the treatment of the mpox virus using data from several databases like PubMed, Scopus, and Embase. The research on this topic has grown tremendously recently but it is highly concentrated in a few countries. Cidofovir is the most studied drug. This is because it is indicated and also used off-label for several conditions. The drugs used for mpox virus infection include tecovirimat, cidofovir, brincidofovir, vaccinia immune globulin, and trifluridine. Tecovirimat is used most frequently. It is a promising option in progressive mpox disease in terms of both efficacy and safety. Brincidofovir has been associated with treatment discontinuation due to elevated hepatic enzymes. Cidofovir is also not the preferred drug, often used because of the unavailability of tecovirimat. Trifluridine is used topically as an add-on agent along with tecovirimat for ocular manifestations of mpox virus disease. No study reports individual patient data for vaccinia immune globulin. Though no vaccine is currently approved for mpox virus infection, ACAM 2000 and JYNNEOS are the vaccines being mainly considered. ACAM 2000 is capable of replicating and may cause severe adverse reactions. It is used when JYNNEOS is contraindicated. Several drugs and vaccines are under development and have been discussed alongside pragmatic aspects of mpox virus treatment and prevention. Further studies can provide more insight into the safety and efficacy of Tecovirimat in actively progressing mpox virus disease.

Combination Diuretic Therapy to Counter Renal Sodium Avidity in Acute Heart Failure: Trials and Tribulations.

In contrast to significant advances in the management of patients with chronic heart failure over the past few years, there has been little change in how patients with acute heart failure are treated. Symptoms and signs of fluid overload are the primary reason for hospitalization of patients who experience acute decompensation of heart failure. Intravenous loop diuretics remain the mainstay of therapy in this patient population, with a significant subset of them showing suboptimal response to these agents leading to incomplete decongestion at the time of discharge. Combination diuretic therapy, that is, using loop diuretics along with an add-on agent, is a widely applied strategy to counter renal sodium avidity through sequential blockade of sodium absorption within renal tubules. The choice of the second diuretic is affected by several factors, including the site of action, the anticipated secondary effects, and the available evidence on their efficacy and safety. While the current guidelines recommend combination diuretic therapy as a viable option to overcome suboptimal response to loop diuretics, it is also acknowledged that this strategy is not supported by strong evidence and remains an area of uncertainty. The recent publication of landmark studies has regenerated the interest in sequential nephron blockade. In this article, we provide an overview of the results of the key studies on combination diuretic therapy in the setting of acute heart failure and discuss their findings primarily with regard to the effect on renal sodium avidity and cardiorenal outcomes.

New Perspective on Anorexia Nervosa: Tryptophan-Kynurenine Pathway Hypothesis

Anorexia nervosa (AN), affecting up to 4% of all females and 0.3% of all males globally, remains the neuropsychiatric disorder with the highest mortality rate. However, the response to the current therapeutic options is rarely satisfactory. Considering the devastating prognosis of survival among patients with AN, further research aimed at developing novel, more effective therapies for AN is essential. Brain and serum tryptophan is mostly converted along the kynurenine pathway into multiple neuroactive derivatives, whereas only 1-2% is used for the synthesis of serotonin. This narrative review provides an update on the experimental and clinical research data concerning the metabolism of tryptophan along the kynurenine pathway in anorexia nervosa based on the available literature. We propose that in AN, lower levels of L-kynurenine and kynurenic acid result in diminished stimulation of the aryl hydrocarbon receptor, which could contribute to abnormally low body weight. The impact of L-kynurenine supplementation on anorexia in animal models and the effects of changes in tryptophan and downstream kynurenines on the clinical progression of AN require further investigation. Moreover, prospective clinical studies on larger cohorts of restrictive and binge-eating/purging AN patients and assessing the potential benefit of L-kynurenine as an add-on therapeutic agent, should follow.

A Proposed Association between Improving Energy Metabolism of HepG2 Cells by Plant Extracts and Increasing Their Sensitivity to Doxorubicin

Increasing cancer cell sensitivity to chemotherapy by amending aberrant metabolism using plant extracts represents a promising strategy to lower chemotherapy doses while retaining the same therapeutic outcome. Here, we incubated HepG2 cells with four plant extracts that were selected based on an earlier assessment of their cytotoxicity, viz asparagus, green tea, rue, and avocado, separately, before treatment with doxorubicin. MTT assays elucidated a significant decrease in doxorubicin-IC50 following HepG2 incubation with each extract, albeit to a variable extent. The investigated extract's ultra-performance liquid chromatography and gas chromatography coupled with mass spectrometry (UPLC/MS and GC/MS) revealed several constituents with anticancer activity. Biochemical investigation displayed several favorable effects, including the inhibition of hypoxia-inducible factor1α (HIF1α), c-Myc, pyruvate kinase-M2 (PKM2), lactate dehydrogenase-A (LDH-A), glucose-6-phosphate dehydrogenase (G6PD), and glutaminase by asparagus and rue extracts. To less extent, HIF1α, c-Myc, PKM2, and LDH-A were partially inhibited by green tea extract, and HIF1α and glutaminase activity was inhibited by avocado oil. Undesirably, green tea extract increased glutaminase; avocado oil rose c-Myc, and both increased G6PD. In conclusion, our study confirms the potential cytotoxic effects of these plant extracts. It highlights a strong association between the ability of asparagus, green tea, rue, and avocado to sensitize HepG2 cells to doxorubicin and their power to amend cell metabolism, suggesting their use as add-on agents that might aid in clinically lowering the doxorubicin dose.

PncA Large Deletion is the Characteristic of Pyrazinamide-Resistant Mycobacterium tuberculosis belonging to the East Asian Lineage.

Pyrazinamide (PZA) is often used as an add-on agent in the treatment of multidrug-resistant tuberculosis, regardless of phenotypic drug susceptibility testing (pDST) results. However, evaluating the effectiveness of PZA is challenging because of its low pH activity, which can result in unreliable pDST results. This study aimed to investigate the genomic characteristics associated with PZA resistance that can be used to develop genotypic DST. A publicly available whole genome sequencing (WGS) dataset of 10,725 Mycobacterium tuberculosis complex genomes (3,326 phenotypically PZA-resistant and 7,399 phenotypically PZA-susceptible isolates) were analyzed. In total, 2,934 pncA non-silent mutations were identified in 2,880 isolates (26.9%). Detected mutations were found throughout the entire coding region of pncA in a scattered pattern, of which the most frequent mutation was p.Q10P (n = 278), followed by p.H57D (n = 167) and c.-11A>G (n = 122). The sensitivity and specificity of the group 1 or 2 mutations reported by the World Health Organization (WHO) mutational catalogue were 73.0% and 98.9%, respectively. We further identified 18 novel pncA mutations that were significantly associated with phenotypically PZA-resistant. In addition to these mutations, we identified 102 large deletions in the pncA gene, and all but two isolates were phenotypically resistant to PZA isolates. Notably, pncA deletions were mutually exclusive to pncA mutations, and more than half of the isolates with pncA large deletions belonged to the East Asian lineage (67.6%). The sensitivity, specificity, positive predictive value, and negative predictive value of the pooled variants (group 1 or 2 mutations, novel resistance-associated mutations, and large deletions of the pncA gene) were 79.0%, 98.9%, 97.0%, and 91.3%, respectively. The area under the curve (AUC) value for the pooled variants was significantly higher than the AUC value for the group 1 or 2 mutations (P <0.001), indicating that the pooled variants have a better discriminative ability for predicting PZA resistance. Using WGS, we found that the pncA mutations are scattered without specific mutational hotspots, and large deletions associated with PZA resistance are more common in the East Asian lineage of M. tuberculosis isolates. Our data also demonstrated the reliability of group 1 or 2 mutations presented in the WHO mutation catalogue and the need for further investigation on group 3 mutations, contributing to the evaluation of the current knowledge base on mutations associated with the PZA-resistant M. tuberculosis complex.

1213: A COMPARISON OF CORTICOSTEROIDS VERSUS VASOPRESSIN AS A SECOND-LINE ADD-ON AGENT IN SEPTIC SHOCK

Introduction: First-line hemodynamic support and the vasopressor of choice for septic shock is norepinephrine. There is considerable variability in practice and a paucity of data regarding when to add vasopressin or corticosteroids, and in what sequence. Defining which agent to administer secondarily to norepinephrine for escalation of hemodynamic support could reduce unnecessary adverse events from central line utilization, decrease adverse drug events, and may result in more economic management of patients. Methods: This is a single-center, retrospective cohort study of patients admitted to the intensive care unit (ICU) between October 2020 and January 2021. Patients were included if > 18 years of age and received norepinephrine plus either vasopressin or corticosteroids as second-line support for septic shock. Patients were excluded if they were on corticosteroids prior to admission. The primary outcome was the percentage of patients who required escalation of hemodynamic support after receipt of a second-line agent within 2 hours. Secondary outcomes included ICU length of stay (LOS), hospital LOS, in-hospital mortality, total hours on vasopressors, acute kidney injury (AKI), need for dialysis and/or renal replacement therapy, superinfection > 48 hours from time zero, and central line utilization. Results: Of 1287 patients screened for inclusion, 142 patients were included in the primary analysis. Eighty-three patients received vasopressin first, 43 patients received corticosteroids first, and 13 patients received both vasopressin and corticosteroids at the same time. For the primary outcome, 15.7%, 32.6%, 7.7% required escalation of norepinephrine within 2 hours, respectively. Respectively, mortality rates were 62.7%, 65.1%, and 76.9%. Central line utilization was on average 12.5 days, 6.6 days, and 5 days among the respective groups. Conclusions: There exists a lack of data when examining the utilization of vasopressin and corticosteroids as second-line add-on agents in septic shock. There was a higher mortality rate than expected among the population who received both corticosteroids and vasopressin at the same time. Central line utilization was lower in those who received corticosteroids first and for those who received both at the same time.

Recent advances in use of bio-inspired jellyfish search algorithm for solving optimization problems

The complexity of engineering optimization problems is increasing. Classical gradient-based optimization algorithms are a mathematical means of solving complex problems whose ability to do so is limited. Metaheuristics have become more popular than exact methods for solving optimization problems because of their simplicity and the robustness of the results that they yield. Recently, population-based bio-inspired algorithms have been demonstrated to perform favorably in solving a wide range of optimization problems. The jellyfish search optimizer (JSO) is one such bio-inspired metaheuristic algorithm, which is based on the food-finding behavior of jellyfish in the ocean. According to the literature, JSO outperforms many well-known meta-heuristics in a wide range of benchmark functions and real-world applications. JSO can also be used in conjunction with other artificial intelligence-related techniques. The success of JSO in solving diverse optimization problems motivates the present comprehensive discussion of the latest findings related to JSO. This paper reviews various issues associated with JSO, such as its inspiration, variants, and applications, and will provide the latest developments and research findings concerning JSO. The systematic review contributes to the development of modified versions and the hybridization of JSO to improve upon the original JSO and present variants, and will help researchers to develop superior metaheuristic optimization algorithms with recommendations of add-on intelligent agents.