Enzyme Inhibitors Research Articles

Identification of antimycobacterial 8-hydroxyquinoline derivatives as in vitro enzymatic inhibitors of Mycobacterium tuberculosis enoyl-acyl carrier protein reductase

The increasing prevalence of drug-resistant Mycobacterium tuberculosis strains stimulates the discovery of new drug candidates. Among them are 8-hydroxyquinoline (8HQ) derivatives that exhibited antimicrobial properties. Unfortunately, there is a lack of data assessing possible targets for this class mainly against Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (MtInhA), a validated target in this field. Thus, the main purpose of this study was to identify 8HQ derivatives that are active against M. tuberculosis and MtInhA. Initially, the screening against the microorganism of a small antimicrobial library and its new derivatives that possess some structural similarity with MtInhA inhibitors identified four 7-substituted-8HQ (series 5 – 5a, 5c, 5d and 5i) and four 5-substituted-8HQ active derivatives (series 7 – 7a, 7c, 7d and 7j). In general, the 7-substituted 8-HQs were more potent and, in the enzymatic assay, were able to inhibit MtInhA at low micromolar range. However, the 5-substituted-8-HQs that presented antimycobacterial activity were not able to inhibit MtInhA. These findings indicate the non-promiscuous nature of 8-HQ derivatives and emphasize the significance of selecting appropriate substituents to achieve in vitro enzyme inhibition. Finally, 7-substituted-8HQ series are promising new derivatives for structure-based drug design and further development.

W(h)Ither Fullerenes in Medicine? Challenges and Opportunities in Industrial Translation

The fullerenes—C60 and its derivatives in particular—have been lauded for three decades now as having revolutionary potential for next-generation medical applications. These span therapeutics (e.g. enzyme inhibition and photodynamic therapy for treating cancers) and diagnostics (e.g. improved contrast agents for magnetic resonance imaging). But translating this potential beyond academic research studies and into scaled-up production and clinical practice has proved far more elusive than the much-sought-after widespread industrial adoption of graphene.In this talk I will first outline why the fullerenes do indeed offer such promise in these clinical application areas, before providing an exploration of many of the intersecting factors that have contributed to making the clinical translation of fullerene-based therapeutics and diagnostics such a seemingly insurmountable barrier up to this point. These factors include: A uniquely multi-dimensional chemical design space when considering fullerene size and both exohedral and endohedral functionalisation possibilities;The relationship of the above with understanding functionality and safety in vivo;Regulatory requirements pertaining to the above;The presence of unregulated fullerene-based products in the beauty and wellness sector;The fuzzy borderlands between science and pseudoscience that much of the narrative around fullerenes occupies;Loss of funding momentum;Lack of industrial bridges between materials manufacturers and technology developers. After characterising the state of affairs in this way, I will offer some specific suggestions for hope and opportunity as we move into a world where synthesis and testing bottlenecks can be overcome with the help of artificial intelligence and automation, and increased awareness of the diverse properties of different types of nanomaterials changes the regulatory and industrial landscapes. Thus, I hope to provide a case study of how one family of carbon nanomaterials could finally realise its promise of advancing medicine in the Industry 4.0 era.

Determination of in vitro Antioxidant, Anticholinergic and Antiepileptic Activities of Some Aromatic Plant Extracts

Medicinal and aromatic plants such as Crocus cancellatus, Scilla Siberica subsp. armena, Juniperus oxycedrus subsp. oxycedrus and Anthriscus nemorosa have many different biological activities. While antioxidants are significant in preventing many diseases, inhibition of metabolic enzymes is also important in preventing many significant diseases. In this study, antioxidant activities of water, ethanol, and dichloromethane extracts of four different medicinal and aromatic plant species were determined by 1,1-diphenyl-2-picrylhydrazyl (DPPH·) and 2,20-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS·+) radical scavenging and Cu2+, Fe+3, and Fe3+-2,4,6-tris(2-pyridyl)-S-triazine (TPTZ) reducing assays. Standard antioxidants (BHA, BHT, Trolox, α-Tocopherol) were used in antioxidant assays, and the results were evaluated according to these standards. Enzyme inhibition studies were performed with metabolic enzymes acetylcholinesterase, butyrylcholinesterase, carbonic anhydrase I and II isoenzymes. The ethanol extract of A. nemorosa showed the highest activity in DPPH assay (IC50: 17.36 µg mL-1). In the ABTS assay, the ethanol extract of A. nemorosa plant showed the highest activity (IC50: 7.02 µg mL-1). In the Fe3+ reducing assay, the dichloromethane extract of A. nemorosa showed the highest activity (1.96±0.060 µg mL-1). In the Cu2+ reducing assay, the dichloromethane extract of J. oxycedrus showed the highest activity (1.773±0.066 µg mL-1). In the Fe3+-TPTZ reducing assay, the ethanol extract of S. siberica showed the highest activity (1.256±0.011 µg mL-1). In the enzyme inhibition results, it was determined that all plants and all extracts inhibited the enzymes studied. As a result of this study, it was determined that these four medicinal and aromatic plants have high biological and antioxidant activities.

СПЕКТР КЛИНИЧЕСКИХ ПРОЯВЛЕНИЙ Х-СЦЕПЛЕННОГО СИНДРОМА АЛЬПОРТА У ДЕВОЧЕК: ОДНОЦЕНТРОЕ КОГОРТНОЕ ИССЛЕДОВАНИЕ

X-linked Alport syndrome (XLAS) is an inherited disorder caused by genetic variants in gene COL4A5. The frequency and the severity of clinical manifestations as well as the risk of glomerulopathy progression are variable in XLAS in females, and the disease course features have not been sufficiently studied as yet. Since patient management tactics is determined by the disease course nature, studying the spectrum of XLAS clinical manifestations and prognosis in girls remains relevant. The purpose of this research was to determine the spectrum and the features of clinical manifestations of XLAS in girls. Materials and methods used: a single-center cohort prospective study was carried out by the Authors that included 74 girls aged 2 to 17 y/o with genetically proven XLAS diagnosis. Authors have analyzed the patients’ medical records identifying sensorineural hearing loss (SNHL), arterial hypertension (AH; blood pressure (BP) over 95% than at the patient’s age/height), albuminuria (Alb; norm<30 mg/mmol of creatinine), proteinuria (Pr; norm<100 mg/sq m/day) - with its degree, decrease in estimated glomerular filtration rate (eGFR, ml/min/1.73 sq m; norm≥90 ml/min/1.73 sq m) and angiotensin-converting enzyme inhibitors (ACEIs) therapy data. Results: all patients had hematuria with episodical macrohematuria in 27% of cases, proteinuria in 40%, eGFR decrease in 15%, SNHL in 8% and peripheral retinopathy in 7%. Girls with missense v. those with non-missense variants of COL4A5 more often had macrohematuria (0.15 v. 0.05; p=0.015) and albuminuria (1 v. 0.5; p<0.001) whilst no statistically significant difference was showed in proteinuria frequency and age of onset (0.48 v. 0.5 and 6.5 [3; 11] v. 5 [5; 8] y/o), eGFR decrease (0.15 v. 0.15; 12.4±2.6 v. 13.2 ±2.8 y/o), SNHL (0.07 v. 0.1; 13±2.8 v. 14.4±3.1 y/o) and retinopathy (0.04 v. 0.15; 14.3±3.5 v. 12.6±2.9 y/o). ACEIs therapy did not show any statistically significant effect on the cumulative proportion of patients with both proteinuria and eGFR decrease (log-rank test=1.25, p=0.213 and log-rank test=0.66, p=0.512, respectively). Conclusion: the results obtained demonstrate the need for a dynamic follow-up of girls with XLAS with the purpose of earliest possible detection of proteinuria and timely prescribing with nephroprotective therapy as well as hearing loss diagnosing and timely audiological correction.

Ziziphus mauritiana Lam. Bark and Leaves: Extraction, Phytochemical Composition, In Vitro Bioassays and In Silico Studies.

In this work, homogenizer-assisted extraction (HAE) and maceration (MAE) were applied on leaves and bark of Ziziphus mauritiana using water and methanol (MeOH) as solvents. HAE and MAE extracts were compared through liquid chromatography coupled with mass spectrometry (LC-MS) and evaluating the antioxidant activity, and enzyme inhibition against acetylcholinesterase (AChE), butrylcholinesterase (BChE), tyrosinase, α-amylase, and α-glucosidase. Considering the phytochemical contents and the bioassays results, the HAE extracts resulted favorably with larger content of phenolics and higher antioxidant activity. The MeOH extracts displayed the highest α-amylase inhibitory activity, with HAE MeOH leaf extract leading at 0.78 mmol acarbose equivalent (ACAE)/g. In conclusion, the study highlights that HAE can increase the extraction of phenolic and flavonoid from Z. mauritiana plant materials compared to maceration. Further research could explore the potential therapeutic applications of Z. mauritiana extracts, especially HAE MeOH leaf extracts, for their notable antioxidant and enzyme inhibitory activities, facilitating the way for the development of novel pharmaceutical interventions.

Efficacy of ivermectin and its metabolites against Plasmodium falciparum liver stages in primary human hepatocytes.

Ivermectin, a broad-spectrum anti-parasitic drug, has been proposed as a novel vector control tool to reduce malaria transmission by mass drug administration. Ivermectin and some metabolites have mosquito-lethal effect, reducing Anopheles mosquito survival. Ivermectin inhibits liver stage development in a rodent malaria model, but no inhibition was observed in a primate malaria model or in a human malaria challenge trial. In the liver, cytochrome P450 3A4 and 3A5 enzymes metabolize ivermectin, which may impact drug efficacy. Thus, understanding ivermectin metabolism and assessing this impact on Plasmodium liver stage development is critical. Using primary human hepatocytes (PHHs), we characterized ivermectin metabolism and evaluated the efficacy of ivermectin and its primary metabolites M1 (3″-O-demethyl ivermectin) and M3 (4-hydroxymethyl ivermectin) against Plasmodium falciparum liver stages. Two different modes of ivermectin exposure were evaluated: prophylactic mode (days 0-3 post-infection) and curative mode (days 3-5 post-infection). We used two different PHH donors and modes to determine the inhibitory concentration (IC50) of ivermectin, M1, M3, and the known anti-malarial drug pyrimethamine, with IC50 values ranging from 1.391 to 14.44, 9.95-23.71, 4.767-8.384, and 0.9073-5.416 µM, respectively. In our PHH model, ivermectin and metabolites M1 and M3 demonstrated inhibitory activity against P. falciparum liver stages in curative treatment mode (days 3-5) and marginal activity in prophylactic treatment mode (days 0-3). Ivermectin had improved efficacy when co-administered with ketoconazole, a specific inhibitor of cytochrome P450 3A4 enzyme. Further studies should be performed to examine ivermectin liver stage efficacy when co-administered with CYP3A4 inhibitors and anti-malarial drugs to understand the pharmacokinetic and pharmacodynamic drug-drug interactions that enhance efficacy against human malaria parasites in vitro.

Discovery of a Highly Promising Disulfide Derivative Scaffold as Inhibitor of SARS-CoV-2 main protease.

The main protease (Mpro) of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) represents a promising target for antiviral drugs aimed at combating COVID-19. Consequently, the development of Mpro inhibitor is an ideal strategy for combating the virus. In this study, we identified twenty-two dithiocarbamates (1a-h), dithiocarbamate-Cu(II) complexes (2a-hCu) and disulfide derivatives (2a-e, 2i) as potent inhibitors of Mpro, with IC50 value range of 0.09-0.72, 0.9-24.7 and 15.1-111 µM, respectively, through FRET screening. The enzyme kinetics, inhibition mode, jump dilution, and DTT assay revealed that 1g may be a partial reversible inhibitor, while 2d and 2f-Cu are the irreversible and dose- and time-dependent inhibitors, potentially covalently binding to the target. Binding of 2d, 2f-Cu and 1g to Mpro was found to decrease the stability of the protein. Additionally, DTT assays and thermal shift assays indicated that 2f-Cu and 2d are the nonspecific and promiscuous cysteine protease inhibitor. ICP-MS implied that the inhibitory activity of 2f-Cu may stem from the uptake of Cu(II) by the enzyme. Cytotoxicity assays demonstrated that 2d and 1g exhibit low cytotoxicity, whereas 2f-Cu show certain cytotoxicity in L929 cells. Overall, this work presents two promising scaffolds for the development of Mpro inhibitors to combat COVID-19.

Sodium-glucose cotransporter 2 inhibitors reduce the risk of incident type 2 diabetes in people with heart failure without diabetes: An analysis of real-world, cohort data.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is), used as a glucose-lowering therapy in people with type 2 diabetes (T2D), have significant cardiorenal benefits, reducing hospitalization for heart failure (HF) and cardiovascular mortality in patients with and without T2D. Recent clinical trial evidence suggests their potential utility in preventing incident T2D among the high-risk HF populations. Therefore, we aimed to assess whether this finding was reproducible in a real-world setting. We performed a retrospective cohort analysis of 484 643 patients with HF, without baseline diabetes, prescribed either angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers with/without SGLT2is (treatment, n = 42 018; reference, n = 442 625) across 95 global health care organizations, using a large real-world ecosystem. Propensity score matching balanced arms 1:1 for confounders (n = 39 168 each arm). Subgroup analysis further evaluated the impact on patients with prediabetes and the efficacy of dapagliflozin/empagliflozin, specifically, on incident T2D and secondary outcomes, including all-cause mortality, acute pulmonary oedema and hospitalization. Treatment with SGLT2is significantly reduced incident T2D {hazard ratio (HR) 0.71 [95% confidence interval (CI) 0.63, 0.75]} in patients with HF. The analysis of patients with prediabetes found that SGLT2is further reduced incident T2D [HR 0.62 (95% CI 0.45, 0.80)]. The magnitude of reduction in incident T2D was higher in patients prescribed dapagliflozin [HR 0.47 (95% CI 0.39, 0.56)] versus empagliflozin [HR 0.81 (95% CI 0.70, 0.93)]. Treatment with SGLT2is in patients with HF was associated with a reduced risk of incident T2D, most strikingly in people with prediabetes.

Adenylyl Cyclase Isoform 6 in the Pulmonary Artery Is Inhibited by Hypoxia via Cysteine Nitrosylation.

Persistent pulmonary hypertension of the newborn (PPHN) is a hypoxic disorder of pulmonary vascular relaxation, mediated in part by adenylyl cyclase (AC). Neonatal pulmonary arteries (PA) express mainly AC6 isoform, followed by AC3, 7 and 9. AC6 expression is upregulated in hypoxia. We reported AC enzyme inhibition due to S-nitrosylation in PPHN PA, and in PA myocytes exposed to hypoxia. We hypothesize that hypoxia promotes cysteine thiol nitrosylation of AC6, impairing cAMP production. HEK293T cells stably expressing AC isoforms (AC3, 5, 6, 7, 9), or cysteine-to-alanine mutants AC6_C1004A, AC6_C1145A or AC6_C447A were cultured in normoxia (21% O2) or hypoxia (10% O2) for 72 hours, or challenged with nitroso donor S-nitrosocysteine (CysNO). AC activity was determined by real-time live-cell cAMP measurement (cADDis assay) or terbium-norfloxacin AC catalytic assay, with or without challenge by allosteric agonist forskolin; protein S-nitrosylation detected by biotin switch method and quantified by affinity precipitation. Only AC6 catalytic activity is inhibited in hypoxia or by S-nitrosylating agent, in presence or absence of forskolin; impaired cAMP production in hypoxia correlates with increased cysteine nitrosylation of AC6. Selective AC6 inhibition in pulmonary artery myocytes extinguishes AC sensitivity to inhibition by hypoxia. Alanine substitution of C1004, but not of other cysteines, decreases S-nitrosylation of AC6. AC activity is diminished in AC6_C1004A compared to AC6 wild type. Substitution of C1004 also extinguishes the inhibition of AC6 by hypoxia. We conclude AC6 is uniquely S-nitrosylated in hypoxia, inhibiting its activity and cAMP generation. We speculate that S-nitrosylation at C1004 may inhibit AC6 interaction with Gαs, playing a role in PPHN pathophysiology.

Discovery of 4-(Arylethynyl)piperidine Derivatives as Potent Nonsaccharide O-GlcNAcase Inhibitors for the Treatment of Alzheimer's Disease.

Inhibiting O-GlcNAcase and thereby up-regulation of the O-GlcNAc levels of tau was a potential approach for discovering AD treatments. Herein, a series of novel highly potent OGA inhibitors embracing a 4-(arylethynyl)piperidine moiety was achieved by capitalizing on the substrate recognition domain. Extensive structure-activity relationships resulted in compound 81 with significant enzymatic inhibition (IC50 = 4.93 ± 2.05 nM) and cellular potency (EC50 = 7.47 ± 3.96 nM in PC12 cells). It markedly increased the protein O-GlcNAcylation levels and reduced the phosphorylation on Ser199, Thr205, and Ser396 of tau in the OA-injured SH-SY5Y cell model, suggesting its potential role for AD treatment. In fact, an in vivo efficacy of ameliorating cognitive impairment was observed following treatment of APP/PS1 mice with compound 81 (100 mg/kg). Additionally, the appropriate plasma PK and beneficial BBB penetration properties were also observed. Compound 81 deserves to be further explored as an anti-AD agent.

Effects of Angiotensin-Converting Enzyme Inhibition on the Recurrence and Internal Structure of Chronic Subdural Hematomas.

Background/Objectives: Chronic subdural hematoma (cSDH) is a common disease of growing significance due to the increasing use of antithrombotic drugs and population aging. There exists conflicting observational evidence that previous treatment with angiotensin-converting enzyme (ACE) inhibitors reduces the rate of cSDH recurrence. This study assesses the hypothesis that ACE inhibitors may affect recurrence rates by altering hematoma membrane formation. Methods: All patients with chronic subdural hematoma who were operated upon in a single university hospital between 2015 and 2020 were considered for inclusion. Hematomas were classified according to their structural appearance in computed tomography (CT) imaging into one of eight subtypes. Patients' own medication, prior to hospitalization for cSDH treatment, was noted, and the use of ACI-inhibitors was identified. Results: Of the included 398 patients, 142 (35.9%) were treated with ACE inhibitors before admission for cSDH treatment. Of these, 115 patients (81.0%) received ramipril, 13 received patients lisinopril (11.3%), and 11 patients (9.6%) received enalapril. Reflecting cardiovascular comorbidity, patients on ACE inhibitors were more often simultaneously treated with antithrombotics (63.4% vs. 42.6%; p ≤ 0.001). Hematomas with homogenous hypodense (OR 11.739, 95%CI 2.570 to 53.612; p = 0.001), homogenous isodense (OR 12.204, 95%CI 2.669 to 55.798; p < 0.001), and homogenous hyperdense (OR 9.472, 95%CI 1.718 to 52.217; p < 0.001) architectures, as well as the prior use of ACE inhibitors (OR 2.026, 95%CI 1.214 to 3.384; p = 0.007), were independently associated with cSDH recurrence. Conclusions: Once corrected for hematoma architecture, type of surgery, and use of antithrombotic medication, preoperative use of ACE inhibitors was associated with a twofold increase in the likelihood of hematoma recurrence.

The Effect of Concomitant Administration of Proton Pump Inhibitors on the Pharmacokinetics of CDK4/6 Inhibitors in Rats: Implications for the Evaluation of Hepatic and Transporter-Mediated Drug-Drug Interactions.

Numerous clinical concerns have been expressed regarding the potential worsening of cyclin-dependent kinase 4/6 inhibitor effects in breast cancer patients because of co-administration of proton pump inhibitors. Hence, this study evaluated the effects of proton pump inhibitors on the pharmacokinetics of palbociclib and ribociclib in terms of cytochrome P450 (CYP)3A4 and P-glycoprotein involvement. The effects of omeprazole and rabeprazole on drug metabolism and efflux of these drugs were investigated using molecular docking, metabolic stability assay in rat liver microsomes, human recombinant CYP3A4(rCYP3A4) enzymes, and Caco-2 cell monolayers, and in vivo pharmacokinetics with omeprazole and rabeprazole in (5 and 10 mg/kg) 30 min and 7 days before orally dosing palbociclib and ribociclib (10 mg/kg). Omeprazole and rabeprazole inhibited CYP3A4 enzyme activity in rCYP3A4 baculosomes with a 50-60% inhibition at 30μM. Additionally, both omeprazole and rabeprazole (10µm) significantly reduced the P-glycoprotein-mediated drug efflux of palbociclib and ribociclib. The 7-day pretreatment of omeprazole at a dose of 10 mg/kg resulted in 24% and 26% reductions in palbociclib's mean maximum plasmaconcentration) Cmaxand area under the plasmaconcentration-time curve(AUC0-24 h), respectively. Palbociclib's pharmacokinetics were not significantly altered by the pretreatment with rabeprazole; however, ribociclib pharmacokinetics exhibited an 83.94% increase in AUC0-24 h. The findings indicate that long-term treatment with therapeutic doses of both omeprazole and rabeprazole can alter the pharmacokinetics of palbociclib and ribociclib. The co-administration of rabeprazole may alter the pharmacokinetics of palbociclib and ribociclib via CYP enzyme and P-glycoprotein inhibition.

Efficacy and safety of dapagliflozin in children with kidney disease: real-world data.

Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, has shown results in slowing estimated glomerular filtration rate (eGFR) decline and reducing proteinuria in adult patients with chronic kidney disease. This retrospective study examines dapagliflozin's effects in 22 children with kidney disease and proteinuria. Children with a median age of 15.6years were treated with dapagliflozin for > 3months between July 2022 and December 2023. All children had been treated with either an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for at least 1month before starting dapagliflozin. The most common kidney disease diagnoses in this study included Alport syndrome (n = 7) and medication-resistant nephrotic syndrome or focal segmental glomerulosclerosis (n = 7). After 6.1months of treatment, dapagliflozin treatment did not result in significant changes in eGFR or proteinuria. However, at the latest follow-up, a statistically significant decrease in eGFR was noted (65.5 compared to the baseline 71.1mL/min/1.73m2, P = 0.003). Proteinuria remained stable between baseline and the last follow-up (final spot urine protein/creatinine ratio (uPCR) 0.7 vs. baseline uPCR 0.6mg/mg, P = 0.489). In the subgroup analysis of children treated for > 8months, the eGFR decline post-treatment changed from - 0.5 to - 0.2ml/min/1.73m2 per month (P = 0.634). Only two children discontinued dapagliflozin due to suspected adverse events. Dapagliflozin has not been associated with serious side effects. Further prospective clinical trials are needed to confirm the efficacy and safety of dapagliflozin in children with kidney disease.

A retrospective analysis of e-prescriptions for non-communicable diseases on a telehealth platform in Malaysia

BackgroundThe management of non-communicable diseases (NCDs) has benefited from telehealth services. As these services which include teleconsultation services and e-prescriptions are relatively new in Malaysia, the data generated provide an unprecedented opportunity to study medication use patterns for the management of NCDs in the country. We analyze e-prescriptions from a local telehealth service to identify medication use patterns and potential areas to optimize medication use in relation to clinical practice guidelines.MethodsA cross sectional observational study was conducted by retrieving e-prescription records retrospectively from a telehealth service. 739,482 records from January 2019 to December 2021 were extracted using a designated data collection form. Data cleaning, standardization and data analysis were performed using Python version 3.11. The diagnoses were classified according to the International Classification of Disease 10 (ICD-10), while medications were classified using the Anatomical Therapeutic Chemical (ATC) system. Diagnoses, frequency of use for medication classes and individual medications were analyzed and compared to clinical practice guidelines.ResultsThe top five NCD diagnoses utilized by the service were hypertension (37.7%), diabetes mellitus (25.1%), ischemic heart disease (24.3%), asthma (14.4%), and dyslipidemia (11.7%). Medications were prescribed mostly in accordance with guideline recommendations. However, angiotensin receptor blockers (ARBs) were significantly more frequently prescribed compared to angiotensin converting enzyme inhibitors (ACEIs). Several medication classes appeared underutilized, including ACEIs in hypertensive patients with diabetes or ischemic heart disease, sodium glucose cotransporter 2 inhibitors in diabetic patients with ischemic heart disease, and metformin in patients with diabetes.ConclusionsTelehealth services are currently being utilized for the management of NCDs. Medication use for the management of NCDs through these services are mostly in accordance with guideline recommendations, but there exist areas that would warrant further investigation to ensure optimal clinical and economic outcomes are achieved.

Predictors of prolonged supratherapeutic serum lithium concentrations: a retrospective chart review

Introduction The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup suggests hemodialysis in severe lithium poisoning if specific criteria are met. One criterion is if the expected time to obtain a lithium concentration <1.0 mEq/L with optimal management is >36 h. There are a lack of data regarding which patient characteristics are associated with the rate at which patients achieve a lithium concentration <1.0 mEq/L. Methods We conducted a retrospective chart review analyzing hospital electronic medical records. Inclusion criteria consisted of a lithium concentration >1.2 mEq/L during hospitalization. We excluded patients who received extracorporeal treatment before 36 h elapsed from time of initial lithium concentration >1.2 mEq/L. The primary analysis consisted of a Cox regression and a secondary analysis evaluated the nomogram method described by Buckley and colleagues for predicting prolonged supratherapeutic lithium concentration. Results One hundred and one patients were included in the study. The median time to reach a lithium concentration <1.0 mEq/L was 42.5 h (IQR: 33.8–51.1). Older patients, patients taking a thiazide, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, patients with a higher initial lithium concentration, and patients with higher sodium concentrations achieved a lithium concentration <1 mEq/L at a slower rate. For the nomogram analysis, sensitivity (61.5%) and specificity (54.5%) were moderate, the positive predictive value (16.7%) was poor, and the negative predictive value (90.6%) was excellent. Discussion The results from our primary analysis suggest that identifying higher serum sodium concentration and use of certain antihypertensives that decrease glomerular filtration rate as predictors of an increased time to reach a therapeutic lithium concentration may help identify patients who meet the Extracorporeal Treatments in Poisoning criteria for hemodialysis. The nomogram method performed similarly to prior validation studies. Conclusions In this retrospective chart review of patients with supratherapeutic lithium concentrations, we identified several risk factors for prolonged supratherapeutic lithium concentrations.

Acute Declines in Estimated Glomerular Filtration Rate in Patients Treated With Benazepril and Hydrochlorothiazide Versus Amlodipine and Risk of Cardiovascular Outcomes.

Acute declines in estimated glomerular filtration rate (eGFR) occur commonly after starting angiotensin-converting enzyme inhibitors. Whether declines in eGFR that occur after simultaneously starting angiotensin-converting enzyme inhibitors with other antihypertensive agents modifies the benefits of these agents on cardiovascular outcomes is unclear. We identified predictors of acute declines in eGFR (>15% over 3 months) during randomization to benazepril plus amlodipine versus benazepril plus hydrochlorothiazide in the ACCOMPLISH (Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension) trial. We then determined the relation between declines in eGFR (treated as a binary variable, ≤15% versus >15% and separately, as a restricted spline variable) and the composite risk of fatal and nonfatal cardiovascular events using Cox proportional hazards models. We included 10 714 participants (median age 68 years [Q1 63, Q3 73]), of whom 1024 reached the trial end point over median follow-up of 2.8 years. Predictors of acute declines in eGFR>15% over 3 months included assignment to hydrochlorothiazide (versus amlodipine) and higher baseline albuminuria. Overall, declines in eGFR ≥15% (versus <15%) were associated with a 26% higher hazard of cardiovascular outcomes (95% CI, 1.07-1.48). In spline-based analysis, risk for cardiovascular outcomes was higher in the hydrochlorothiazide arm at every level of decline in eGFR compared with the same magnitude of eGFR decline in the amlodipine arm. Combined use of benazepril and amlodipine remains superior to benazepril and hydrochlorothiazide for cardiovascular outcomes, regardless of the magnitude of the decline in eGFR that occurred with initiation of therapy.

SYNTHESIS AND REACTIVITY OF CARBOHYDRATES CONTAINING 3‐MEMBERED HETEROCYCLES, KEY PRECURSORS OF MODIFIED SUGARS AND MIMETICS

Molecules containing three‐membered heterocycles, including oxiranes (epoxides), thiiranes (episulfides) and aziridines, are considered privileged structures as they serve as key precursors or intermediates for the synthesis of a varied range of organic compounds, such as natural products, mimetics and pharmaceuticals. The principal advantage of this type of heterocycles is their reactivity towards the nucleophilic ring‐opening, which usually occurs in a regioselective manner, resulting in the formation of 1,2‐disubstituted products. When attached to a chiral scaffold, such as a carbohydrate molecule, the ring‐opening process is usually highly diastereoselective. Therefore, these compounds have been extensively employed in the field of carbohydrates for the synthesis of enantiomerically pure modified sugars that are useful as glycobiology tools. This review presents an overview of the recent methodologies developed for the construction of epoxide, thiirane, and aziridine rings from common or modified sugars. Due to their structural similarity to carbohydrates, three‐membered heterocyclic derivatives of cyclitols and carbasugars have been included. All these compounds, and their ring‐opening derivatives have shown to be crucial in the synthesis of glycomimetics, which display diverse biological activities. These include enzyme inhibition, binding to lectin receptors, and more recently, the use as probes for the diagnosis and monitoring of diseases.

Evaluation of Antioxidant Potential, Enzyme Inhibition, and Chemical Profiling Through Mass Spectrometry on Bark Extract of Berberis aristata

Berberis aristata, a plant from the Berberidaceae family, is renowned for its medicinal properties. The presence of bioactive metabolites in its bark underscores its importance in traditional medicine and pharmacology. This study primarily focuses on the biological activities of the plant bark extract, specifically its antioxidant properties and alpha-glucosidase inhibition. In addition to these activities, mass spectrometry-based compound annotation was conducted to explore the metabolites present in the plant bark extract. In this study, the bark samples were collected and extracted using the cold percolation method with methanol. Subsequently, an ethyl acetate fraction was obtained from the methanol extract using a separating funnel. The methanol extract of the bark showed a total phenolic content (TPC) of 70.056 ± 2.52 mg GAE/g and a total flavonoid content (TFC) of 11.89 ± 0.16 mg QE/g. To determine the antioxidant activity of the samples, a DPPH assay was used. The ethyl acetate fraction of the bark showed potent antioxidant activity with an IC50 value of 188.93 ± 8.35 μg/mL, while the methanol extract of the bark showed radical scavenging activity with an IC50 value of 242.89 ± 4.62 μg/mL. In terms of alpha-glucosidase inhibition, the methanol extract of the bark had low enzyme inhibition activity, but the ethyl acetate fraction exhibited potential inhibition with an IC50 value of 112.99 ± 10.28 µg/mL. These results indicate that the plant bark extract is rich in phenolic content compared to flavonoid content. Additionally, the ethyl acetate fraction of the plant bark exhibits potent radical scavenging activity and inhibition of the digestive enzyme alpha-glucosidase. Mass spectrometric-based identification of metabolites revealed that the methanol extract of the bark contains compounds such as Palmatin, columbamine, and berberal. The presence of these metabolites further supports the medicinal use of this plant bark. These findings enhance the plant's potential in the drug discovery process in the future.

Electrochemical Synthesis of Isoquinoline Sulfone Compounds and Study of their Inhibition of Acetolactate Synthase Enzyme Activity

AbstractBoth of sulfone compounds and isoqunoline derivatives are important compounds. In this paper, Isoquinoline C1 and C3 Sulfone compounds have been synthesized by electrochemical means using isoquinoline N‐Oxides and some sodium benzenesulfinate as reactants, inexpensive and easily available sodium iodide as electrolytes, and a mixture of acetonitrile, water and acetic acid as reaction solvents. By using the method, a series of isoquinoline sulfone compounds have been synthesized in high yields. The reaction does not need oxidants and catalysts, and the reaction conditions are mild, environmentally friendly, efficient and suitable. In addition, we also carried out ALS enzyme inhibition experiments on the synthesized isoquinoline sulfone compounds, six of the isoquinoline sulfone compounds synthesized herein were found to inhibit ALS enzyme at a high rate, four of them inhibited ALS enzyme at a rate comparable to that of the commercialized herbicides Halosulfuron and Broadstrike, and the other two compounds also inhibited ALS enzyme at a rate higher than that of Halosulfuron and Broadstrike. Therefore, it is possible to find lead compounds with good herbicidal activity potential from these 6 compounds.

Bioactive profiling of two varieties of Indian legumes: adzuki and mung beans

SummaryNutritional benefits of legumes make them an important part of sustainable diets. They are rich not only in dietary fibres, proteins, and micronutrients but also in the bioactive compounds that can exhibit various biological activities. In the present study, we aimed to investigate the nutritional analysis, phytochemical composition, and in vitro anti‐obesity activity of two varieties of legumes indigenous to India namely, adzuki beans (Vigna angularis) and mung beans (Vigna radiata). GC–MS, UHPLC‐QTOF‐MS, ICP‐MS analyses were done for bioactive compounds, fatty acids, macro‐elements, micro‐elements, protein, and non‐proteinogenic amino acids. GC–MS analysis showed that the major constituents identified were hydrocarbons, fatty acids, and terpenes, while the presence of various secondary metabolites, macro‐ and micro‐nutrients were detected using UHPLC‐QTOF‐MS and ICP‐MS, respectively. FAME analysis revealed a higher concentration of linoleic acid in adzuki beans, which is nutritionally beneficial for human consumption. Amino acid profiling revealed the presence of essential, non‐essential, and non‐proteinogenic amino acids. Further, adzuki beans and mung beans were screened for cytotoxicity on 3T3‐cell line and it was observed that adzuki beans were less cytotoxic as compared to mung beans. Adzuki beans showed higher HMG‐Co‐A reductase enzyme inhibition activity (60%) as compared to mung beans (2.79%). The results indicate that these two legumes are a very good source of bioactive metabolites and can be developed into novel cholesterol‐lowering and anti‐obesity functional foods.