Enzyme Inhibitors Research Articles

From computational prediction to experimental validation: Hesperidin's anti-Urolithiatic activity in sodium oxalate-induced urolithiasis models in fruit flies and mice

Kidney stones have been a long-standing health issue, contributing to renal failure, especially in co-morbid patients. There is an increasing interest in exploring natural compounds with anti-urolithiatic properties. Our study utilized in-silico techniques followed by in vivo experiments to evaluate the anti-urolithiatic potential of selected phytoconstituents. Molecular docking studies were conducted on 11 different targets, including inhibitors of kidney stone formation, antioxidant enzymes, and biomarkers of kidney injury, to explore the potential of antiurolithiatic effects of 38 phytoconstituents from medicinal plants possessing diuretic activity. Further, the antiurolithiatic activity of the phytoconstituent was evaluated using a sodium oxalate-induced urolithiatic fruit fly and mouse model. Hesperidin emerged as a promising candidate, exhibiting binding interactions with a specific set of 11 target proteins involved in crystal formation with minimal free energy. Hesperidin demonstrated promising antiurolithiatic potential in mitigating urolithiasis as evidenced by reduced crystal covered area of Malpighian tubules of fruit fly and reduced blood urea nitrogen (BUN), serum creatinine and serum sodium, potassium levels in mice. Moreover, it increased urine volume, preventing crystal deposition, and reduced urine urea nitrogen, creatinine, sodium, and potassium levels, enhancing urine flow and preventing crystal accumulation. Histopathological analysis further supported its efficacy by showing minimal crystal deposition and reduced kidney damage. Hesperidin exhibited superior effectiveness in reducing various serum and urine parameters, making it promising alternatives for urolithiasis management warranting further investigation to determine its safety and optimal dosages in human.

Synthesis, antibacterial, anti-urease, DFT and molecular docking studies of novel bis-1,3,4-thiadiazoles

A series of 2-substitutedamino-1,3,4-thiadiazoles (4a-4j) were synthesized starting from various isothiocyanate derivatives. The newly synthesized compounds were characterized by 1H NMR, 13C NMR, and elemental analysis. All compounds were tested for antibacterial activity against Proteus vulgaris (ATCC 7829) via the microbroth dilution technique. Among them, compound 4h emerged as the most potent antibacterial agent with MIC value of 4.1 μM. All synthetic compounds were additionally evaluated for their urease inhibitory activity and exhibited good inhibitory potential against urease with IC50 values in the range of 1.732 ± 0.186 - 3.786 ± 0.300 μM as compared to the standard thiourea (IC50 = 11.008 ± 0.932 μM). Compounds 4d, 4h and 4i showed significant inhibitory effects with IC50 values of 1.981 ± 0.265, 1.732 ± 0.186 and 1.937 ± 0.173 μM, respectively. In silico molecular docking study showed the critical interactions of compound 4h with the active site of the urease. According to DFT, compounds 4j and 4d (with low ΔE=4.536 eV and 4.629 eV values, respectively) are more chemically reactive than the other molecules, in which consistent with their inhibitory potentials against the urease enzyme. Molecular Dynamics simulations also were performed to assess the energetic features of the urease in complex with compound 4h. Furthermore, the predicted ADMET characteristics of the compound 4h was calculated using QikProp to gain insights into its pharmacokinetic properties. These newly identified inhibitors of the urease enzyme can serve as leads for further antibacterial drug research and development.

Optimizing the dosing regimen of roxadustat in kidney transplant recipients with early post-transplant anemia

IntroductionRoxadustat, an oral inhibitor of hypoxia-inducible factor prolyl hydroxylase domain enzymes, has been approved for the treatment of renal anemia. However, there is a lack of study on its pharmacokinetics in kidney transplant recipients (KTRs) with early posttransplant anemia (PTA). Therefore, the aim of this study is to elucidate the pharmacokinetic characteristics of roxadustat in KTRs with early PTA and optimize the dosing regimen. MethodsA population pharmacokinetic (PopPK) analysis was performed based on 72-hour full concentration-time profiles collected from 52 Chinese KTRs. Covariates influencing exposure were assessed using stepwise covariate modelling. Monte Carlo simulations were conducted to recommend the dosing regimen for patients with different levels of covariates. ResultsPopPK analysis showed that the concentration-time data can be fully described by a two-compartment model. Body weight (BW) and direct bilirubin (DBIL) levels significant affected the apparent clearance of roxadustat. Based on the established model and the estimated exposures of roxadustat by Monte Carlo simulations, a recommended dosing regimen for KTRs with early PTA at varying BW and DBIL levels were developed. Roxadustat at 100 mg three times weekly were suitable for the majority of KTRs with a DBIL level around 3 μmol/L and BW between 50 and 75 kg. The required dose may need to be increased with higher BW and lower DBIL levels, while decreased with lower BW and higher DBIL levels. ConclusionsIt was the first PopPK analysis of roxadustat in KTRs with early PTA, which provide a research basis for optimizing the dosing regimen.

Evaluation of antioxidant, catalytic and antidiabetic activity of Phaseolus vulgaris (French green bean) mediated nickel oxide and copper doped nickel oxide bimetallic nanoparticles

In this study, nickel oxide nanoparticles (NPs) and copper doped NiO bimetallic nanoparticles (Cu@NiO BMNPs) were synthesized using Phaseolus vulgaris extracts as reducing and stabilizing agents by sol gel methods. The chemical and physical properties of synthesized NiO NPs and Cu@NiO BMNPs were confirmed by various techniques, like UV Visible spectrophotometer (UV–Vis), Fourier transform infrared spectroscopy (FTIR), Scanning Electron Microscope (SEM), Energy Dispersive X-ray (EDX), Transmission Electron Microscope (TEM) and X-ray diffraction (XRD) analysis. The optical properties of both NPs observed by UV–Vis analysis with well-defined peak and band gap value 3.2 eV & 2.62 eV. FTIR analysis confirmed the presence of functional group of NPs with fruits extract. The morphology of NPs was confirmed by SEM and TEM analysis as polygonal, rod and spherical shape. The elements present in NPs were confirmed by EDX analysis. The crystalline size calculated based on the XRD analysis was 49.78 nm and 53.66 nm for NiO and Cu@ NiO NPs respectively which were found to be slightly smaller than particle size determined from SEM and TEM micrograph. Antioxidant activity of NPs was examined using 2,2-Diphenyl-1-picrylhydrazyl (DPPH) scavenging radicals, Catalytic activities were screened by the degradation of Methylene blue (MB) and by the inhibition of alpha-amylase enzyme, antidiabetic activity of NPs were evaluated using acarbose as standard drug. The Cu@NiO BMNPs showed 77.60 % antioxidant, 76.98 % photocatalytic and 88.86 % antidiabetic activity, which were found to be more as compared to NiO NPs. The NiO and Cu@NiO BMNPs were synthesized for the first-time using P. vulgaris extracts. This study clearly showed that P. vulgaris extracts mediated mono- and bimetallic NPs were more stable and biocompatible than their respective bulk particles.

Biochemical and toxicological characteristics of polyphenol oxidase from red palm weevil Rhynchophorus ferrugineus (Olivier) (Coleoptera: Curculionidae)

Red palm weevil (RPW) Rhynchophorus ferrugineus is the most destructive insect pests of numerous palm species in the world. The introduction of botanical extract(s) as integral part of an integrated pest management (IPM) programs against RPW will reduce the use of chemical insecticides. Polyphenol oxidase (PPO) is one of the RPW innate immune mechanisms and inhibition of such enzyme could result in a disorder of the insect's immune system. A one single PO isoenzyme has been purified from the hemolymph of the 12th instar larvae of RPW. Using L-DOPA as substrate, R. ferrugineus PPO exhibited specific activity 428 Units/mg proteins with 8.3-fold purification, optimum pH and temperature for activity at 7.5 and 40 °C, respectively and is enhanced by Cu2+ with 1.76-fold. The rank order for oxidizing R. ferrugineus PPO different substrates is catechol > pyrogallol > L-DOPA > pyrocatechuic acid and not tyrosine. The kinetic parameters Km, Vmax and Vmax/Km for L-DOPA are 3.3 mM, 1.3 μmol/ml/min, and 0.39, respectively. The catalytic efficiency of the enzyme towards catechol is 5.3-fold higher than that for L-DOPA. The enzyme completely inhibited by thiourea, ascorbic acid, dithiothreitol, and SDS. R. ferrugineus PPO is a catechol oxidase di-phenol: O2 oxidoreductase. Based on the toxicological studies of various botanical extracts, the IC50 ranged from 20 to 90 mg/ml. The enzyme completely inhibited by 50 mg/ml Cinnamomum camphora. Gallic acid, the major phenolic compound, has IC50 0.8 mM and competitively inhibited the enzyme with Ki 0.54 mM. C. camphora could be a useful natural RPW-controlling agent and used as integral part in IPM programs. This interpretation can be validated in future through an in vivo investigation.

Experimental, Density Functional Theory, Molecular Docking and ADMET Analyses on the Role of Different Plant Extracts of Aronia melanocarpa (Michx) Elliot Species on Acetylcholinesterase Enzyme Activity

In the present study, different extracts obtained in different solvents from the fruits collected from the Aronia melanocarpa (Michx.) were prepared. The inhibition performances of these extracts on the inhibition of the acetylcholinesterase enzyme were checked via both theoretical and experimental analyses. Although all extracts used in experimental studies showed high inhibitory activity, it was observed that the extract obtained in methanol had higher inhibitory activity than the others. According to the enzyme activity results presented in the light of Ellman method, IC50 values were found between 0.0311-0.0857 mg/mL. Conceptual Density Functional Theory (CDFT) and Molecular Docking calculations were performed to identify the component or components of the extract with high inhibitory activity. Conceptual Density Functional Theoretical based data commented through popular electronic structure principles such as Maximum Hardness and Minimum Electrophilicity Principles showed that the most reactive one among studied dominant components of the extract is Malvin molecule. The interactions between studied molecules and AChE and mechanisms of these interactions were illuminated via Molecular Docking analyses and ADMET studies. As a result, it was shown that the most reactive molecule Malvin (with lowest hardness and the highest electrophilicity) interacts more powerful with AChE compared to other molecules. Within the framework of the theoretical analyses made, it was proposed that in the design and introduction of new AChE inhibitors, structures with low hardness and high electrophilicity values ​​should be preferred.

Pyrazole-based N-phenyl pyrazolines: Synthesis, docking, and pharmacological evaluation

A series of methoxy substituted pyrazole based pyrazoline derivatives (4a-j) were synthesized in good to excellent yield from corresponding pyrazole-chalcones (3a-j). All synthesized derivatives were characterized and screened for their in vitro anti-inflammatory, antioxidant, antidiabetic, and antibacterial activities. Among the series, compounds 4f, 4j, 4a, and 4i showed better anti-inflammatory activity as compared to diclofenac sodium. In DPPH free radical scavenging assay, all the compounds were shown excellent activity and moderate to good activity in SO and NO free radical scavenging assay as compared to standard ascorbic acid. Antibacterial screening of synthesized pyrazolines showed that compounds 4f and 4j have significant antibacterial activity. The compounds 4j, 4f, 4 h, 4a, and 4c have shown comparable inhibition of alpha-amylase enzyme leading to good antidiabetic activity as compared to standard acarbose. Molecular docking studies suggest that these compounds have strong binding with COX-2 and alpha-amylase enzyme due to significant capability of aromatic and hydrophobic interaction. The outstanding results of reported compounds in all biological screening will pave the way for the design of new drug candidate bearing pyrazole moiety.

P026 A PRESCRIPTION TREND ANALYSIS OF ANTIHYPERTENSIVE PHARMACOTHERAPY ACROSS DIFFERENT SPECIALTIES IN INDIA

Objective: To evaluate the temporal trends in the prescription patterns of antihypertensive medications among healthcare practitioners in India. Methods: The IQVIA (formerly Quintiles and IMS Health) prescription audit data came from prescriptions of a panel of 6000 private sector primary care clinicians for the different classes of antihypertensive drugs; beta-blockers(BB), calcium channel blockers(CCB), angiotensin receptor blockers(ARB), angiotensin-converting enzyme(ACE) inhibitors, and diuretics were examined. The analysis encompassed the period from 2014 to 2022. Additionally, combinations of these drug classes involving two or three medications were also subject to analysis. Results: Cardiologists’ prescription rates for antihypertensive medications stood at 21% in 2017 and decreased to 19% by 2023. In 2023, the highest rate of prescribing antihypertensive drugs was observed among consultant physicians, with a rate of 30%, followed by general practitioners at 27%. In addition, during COVID-19, the prescription share of general practitioners was highest (31%). Among antihypertensive medications, the prescription rates for BBs were highest (32%), followed by ARBs & CCBs (25% & 24% respectively). Single-drug formulation of anti-hypertensive medications was the most preferred (60%) among Indian clinicians. Prescription shares of fixed-dose combinations (FDC) of two antihypertensive drugs showed a slight decline (36% in 2017 to 34% in 2023) & FDCs of triple-drug exhibited an upward trend (3% in 2017 to 5% in 2023). Among the two drug FDCs, ARB & diuretics were most preferred (25% prescription share) & triple drug FDCs, CCB, ARB & diuretics were most preferred. Conclusions: Cardiovascular medications are prominent in the Indian pharmaceutical market, with antihypertensives standing out as one of the most frequently prescribed treatments. Consultant physicians and general practitioners manage the majority of hypertension cases. Notably, there has been an observed rise in preference for triple-drug combinations of antihypertensive medications, indicating a trend toward a more aggressive approach to hypertension management among Indian clinicians. The insights gleaned from this investigation can further assist healthcare professionals in crafting tailored treatment strategies for individuals grappling with hypertension. Such personalized approaches hold promise in enhancing treatment adherence and ultimately improving the QoL.

Comparative efficacy of amino acid availability and peptidomic analysis of alternative proteins from different sources under dynamic in vitro protein digestion

The increasing global demand for animal protein highlights the critical necessity of exploring alternative protein sources. Accessing the nutritional characteristics of emerging alternative proteins is vital for food processing and consumer acceptance. This study investigated the amino acid availability and peptidomics profiles of plant- (soy), fungal- (filamentous fungus Fusarium venenatum), microalgae- (Nannochloropsis oculata), and insect-based (black soldier fly) proteins using an advanced dynamic in vitro digestion system, with whey protein as a reference. After gastric digestion, soy and mycelial proteins, despite displaying distinct microstructures, exhibited slightly higher protein digestibility levels of 28.79% and 26.36%, respectively, compared to whey protein (22.39%). However, following small intestinal digestion, whey protein (61.31%) significantly outperformed alternative proteins. Mycelial protein (43.71%) exhibited digestibility similar to soy protein (46.12%), markedly surpassing both microalgae protein (33.35%) and insect protein (26.58%). Notably, insect protein achieved an amino acid availability nearly approaching that of whey protein, underscoring its substantial proteolysis capability. Furthermore, microalgae protein produced the highest percentage and number of bioactive peptides under simulated digestion, suggesting potential health benefits such as angiotensin I-converting enzyme (ACE) and dipeptidyl peptidase-IV (DPP-IV) inhibitor activities, which could mitigate the risk of hypertension and Type 2 diabetes. Alternative proteins from different sources demonstrate diverse digestive mechanisms and proteolysis profiles, thereby bolstering their potential applications as nutritious food ingredients in the future.

Trends in Drug Duplications in Swedish Older Adults: A Nationwide Register Study from 2006 to 2021.

Drug duplication (DD), the use of two identical drugs simultaneously, is a medication error increasing the risk of adverse drug events. We describe the trends and implicated drugs in potential DD in older adults in Sweden from 2006 to 2021. We conducted a register-based, repeated cross-sectional study of all older adults (aged ≥65years) dispensed drugs at a community pharmacy in 2006-2021. DD was defined as a ≥30-day overlap of two dispensations of drugs with the same 5th level (chemical substance) Anatomical Therapeutic Chemical (ATC) classification, but with different brand names, within a 3-month period each year. Among Swedish older adults with ordinary prescriptions (i.e. multidose excluded; n≈1,200,000-1,600,000 per year), the prevalence of potential DD increased from 5.2% to 10.6% in 65- to 79-year-olds and from 7.0% to 11.7% in those aged ≥80years. The drug groups (ATC level 3; pharmacological subgroup) most frequently implicated in DD in 2006 were β-blocking agents, angiotensin-converting enzyme (ACE) inhibitors, and calcium channel blockers, and in 2021Vitamin B12 and folic acid, β-blocking agents and angiotensin II receptor blockers. DD represents a common but unnecessary and potentially hazardous medication error. Our results indicate that during the last two decades, the prevalence has almost doubled in older adults with ordinary prescriptions, reaching 11% in 2021. More national efforts are needed to revert this trend, including a nationally available complete drug list for all patients, and prescriber support to detect DD.

Changes in the Use of Hydrochlorothiazide and Other Antihypertensive Drugs in Switzerland in Association With the Swissmedic Safety Alert Regarding Non-melanoma Skin Cancer: An Interrupted Time-Series Analysis Using Swiss Claims Data.

Long-term use of hydrochlorothiazide increases the risk of non-melanoma skin cancer. We aimed to evaluate potential changes in the use of hydrochlorothiazide in Switzerland after a direct healthcare professional communication (DHPC) in November 2018 by Swissmedic. We performed interrupted time-series analyses using a large Swiss healthcare claims database (2015-2021). Within monthly intervals, we quantified the total number of claims and the total dispensed 'defined daily doses' (DDD) for preparations containing (1) hydrochlorothiazide, (2) angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II-receptor blockers (ARB), (3) calcium-channel blockers (CCB) and (4) thiazide-like diuretics per 10 000 persons. Using segmented linear regression, we quantified the pre-DHPC trend, the immediate change and the post-DHPC change in trend for total claims and DDD for the four drug classes weighted for the demographic distribution of the Swiss population. ACE inhibitors and ARB were the most frequently claimed antihypertensive drugs with 300-400 claims per 10 000 persons, which increased by 5.4% during the study period. The average number of hydrochlorothiazide claims (157/10 000 persons in 2015) declined by 35% between 2015 and 2021. The decrease started prior to the DHPC, but the DHPC was associated with an immediate 6.1% decline and an accelerated decline in claims over time after the DHPC (similar results for DDD). This coincided with a 23% increase in claims of CCB (dihydropyridine type) over 7 years, whereas use of other antihypertensives increased less. Our results suggest that the DHPC by Swissmedic in 2018 accelerated a pre-existing decline in the use of hydrochlorothiazide in Switzerland.

The synthesis of novel unnatural amino acid by intramolecular aza-Michael addition reaction as multitarget enzyme inhibitors.

Synthesis of novel unnatural amino acids (UAAs) from 4-oxo-4-phenylbut-2-enoic acid derivatives with intramolecular aza-Michael addition reaction in the presence of chlorosulfonyl isocyanate (CSI) was reported in soft conditions without any metal catalyst. Acids and base as a catalyst, and solvents effects were investigated for the synthesis of novel UAAs. This novel method provides inexpensive, practicable, and efficient approach to generate UAAs. The use of UAAs has attracted great interest in the development of therapeutic agents and drug discovery to improve their properties. In this context, in addition to the synthesis of new UAAs, their inhibition effects on important metabolic enzymes of acetylcholinesterase (AChE) and carbonic anhydrases I and II (hCA I and II) enzymes were investigated. The compound 2g showed the best inhibition for CA I and AChE enzymes, while compound 2i exhibited the best inhibition profile against CA II isoenzyme. The inhibition values of these compounds were found as 1.85 ± 0.64 for AChE, 0.53 ± 0.07 for hCA I, 0.44 ± 0.15 µM for hCA II, respectively, and they showed a stronger inhibitory property than acetazolamide (standard inhibitor for hCA I and II) and tacrine (standard inhibitor for AChE) molecules. The activity of the studied molecule against different proteins that are hCA I (PDB ID: 2CAB), hCA II (PDB ID: 5AML), and AChE (PDB ID: 1OCE) was examined. Finally, the drug properties of the studied molecule were examined by performing absorption, distribution, metabolism, excretion, and toxicity analysis.

P103 EFFICACY AND SAFETY OF TRIPLE VERSUS DUAL COMBINATIONS OF ANTIHYPERTENSIVE DRUGS: A SYSTEMATIC REVIEW AND META-ANALYSIS OF DOUBLE-BLIND RANDOMIZED CLINICAL TRIALS

Background: Some patients taking two blood pressure (BP) lowering drugs do not achieve and maintain BP <140/90mmHg on two drugs and substantially more do not reach <130/80 mmHg targets that are increasingly recommended by guidelines. Objective: To evaluate, among adults with hypertension, triple combination of antihypertensive drugs (AHTDs) compared to dual combinations of AHTDs for BP-lowering efficacy and safety. Methods: We searched multiple databases and the USFDA website until December 2023 for randomized, double-blind trials involving adults with hypertension, that compared triple versus dual combinations of AHTDs from five major classes (angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, calcium channel blockers, beta-blockers, and diuretics) over a minimum of 4 weeks. Drugs and doses were categorized by standard daily doses based on WHO daily defined dose. Primary outcomes were reduction in BP and treatment withdrawals due to adverse events (WDAE). Meta-analyses were conducted using random-effects model. Results: Twenty-four trials (15,533 participants) were included. Overall, triple compared with dual combination reduced BP by 5.1/3.7 mmHg (95% CI 4.3-5.9/3.0-4.4, p<0.001 for both), improved BP control by 69% versus 54% (relative risk [RR] 1.35 [95% CI: 1.25%-1.45%], p=<0.001). Incidence of WDAE was 4.2% versus 2.9% (RR 1.9 [95% CI: 1.3-2.4], P=0.004). Addition of a third drug to dual combinations at 0.5, 1, 1.5 and 2 standard doses resulted in additional SBP reduction of 3.4 (95% CI: 2.2-4.6), 6.1 (95% CI: 4.8-7.0), 4.5 (95% CI: 1.7-7.6) and 7.5 (95% CI: 6.2-8.8) mmHg, respectively with no significant difference in incidence of WDAEs [RR 1.63 (95% CI: 0.84-3.18) vs 1.58 (95% CI: 1.14-2.19) vs 0.94 (95% CI: 0.44-1.98)]. Conclusion: Triple combinations of AHTDs reduce BP significantly, compared to dual combinations. Adding a third AHTD to dual combination, at 0.5 or 1 standard dose appear to produce most BP reduction and can avoid dose-related adverse effects.

Diagnosis and Treatment of Membranous Nephropathy in Integrative Medicine

Membranous nephropathy (MN) is a common glomerular disease. The related pathological changes are primarily characterized by the deposition of immune complexes beneath the epithelial cells of the glomerular basement membrane, accompanied by diffuse thickening of the basement membrane. Its etiology and pathogenesis are not fully understood yet; however, they are associated with genetics, infections, tumors, drugs, heavy metals poisoning, environmental pollution, and the loss of immune tolerance. Over 10 target antigens, including the phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain containing 7A (THSD7A), associated with MN have been identified, each having different clinical implications. Clinical manifestations of MN patients mainly include proteinuria and nephrotic syndrome, with a propensity to form thrombi. Its diagnostic accuracy can be enhanced by combining clinical manifestations, serum antibody testing, and renal biopsy. Proteinuria, estimated glomerular filtration rate (eGFR), and PLA2R antibody levels are vital for the prognostic risk stratification of MN. Low-risk patients primarily undergo non-immunosuppressive treatment (angiotensin-converting enzyme inhibitor [ACEI]/angiotensin II receptor blocker [ARB], sodium-glucose cotransporter 2 inhibitor [SGLT2i], anticoagulants, and traditional Chinese medicine [TCM] treatments), while high-risk patients need to consider using steroids and immunosuppressants, such as cyclophosphamide (CTX), calcineurin inhibitors (CNIs), and anti-cluster of differentiation 20 (anti-CD20) monoclonal antibodies. TCM holds that MN is the imbalance of Fei (lung), Pi (spleen), and Shen (kidney) function, leading to the generation of Neixie such as Shi, Re, Du, and Yu. This disease is difficult to heal because of Shire and Yu. The treatment is based on the use of Jianpi Bushen, simultaneously emphasizing the use of drugs for Qingre Qushi Huoxue. Dialectical use of TCM can obviously improve the clinical response rate and alleviate symptoms such as edema and fatigue by increasing the serum albumin level more rapidly while introducing fewer adverse reactions. Combined with Western medicine, TCM can also reduce toxicity and increase efficiency. This article systematically reviews the etiology, podocyte antigens, clinical manifestations, diagnostic approaches, risk assessment, and integrative medicine therapeutic strategies for MN, aiming to deepen the understanding of MN and guide clinical practice.

O90 EFFICACY AND SAFETY OF DUAL COMBINATIONS OF ANTIHYPERTENSIVE DRUGS AS FIRST-LINE THERAPY: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

Background: Hypertension remains the primary cause of mortality worldwide, resulting in about 11 million deaths annually. Despite recent hypertension guidelines advocating for dual combination of antihypertensive drugs as the first-line therapy for most patients, many patients do not receive this therapy. Objective: To assess, among adults with hypertension, dual combinations of AHTDs compared to monotherapy as first-line treatment for blood pressure (BP)-lowering efficacy and safety. Methods: We systematically searched multiple electronic databases until December 2022 to identify relevant randomized, double-blind trials. We included trials involving adults with hypertension who were either treatment naive or untreated for at least 2 weeks, compared dual combinations of drugs with monotherapy from 5 major classes of AHTDs (angiotensin converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, beta blockers, and diuretics), for a duration of at least 4 weeks and reported data on BP reduction. AHTDs and their combinations were categorized based on standard daily doses. Outcomes were reduction in BP, treatment related adverse events (TRAE) and withdrawals from the treatment due to adverse events (WDAE). Meta-analyses were conducted using random-effects model. Results: We included 98 trials (636 comparisons and 25892 participants). Overall, baseline mean BP was 159/102 mmHg. Overall BP reduction with dual combination compared to monotherapy was 4.4 (CI: 3.8-5.1)/3.5 (CI:3.2-3.9) mmHg. Compared with standard-dose monotherapy, dual combinations of <1 + <1, 1 + <1 and 1 + 1 (i.e. low-to-standard dose), showed a dose-response relationship in reducing BP by 1.4 (CI: 0.01-2.7)/2.3 (CI: 1.4-3.1), 4.4 (CI: 3.6-5.2)/ 3.3 (CI: 2.9-3.8) and 7.8 (CI: 6.2-8.9)/5.2 (CI: 4.4-5.9) mmHg, respectively. TRAEs [4.8% vs 4.9%; RR 0.92 (0.80 to 1.06)] and WDAEs [0.8% vs 0.9%; RR 1.8 (1.5 to 2.1)] were uncommon with low-to-standard dose dual combinations, with no significant difference compared with standard-dose monotherapy. Conclusion: First-line treatment with low-to-standard dose dual combination therapy is more efficacious and equally safe compared to monotherapy to reduce BP.

Unraveling the role of the renin-angiotensin system in severe mental illnesses: An insight into psychopathology and cognitive deficits

Severe mental illnesses (SMI), especially schizophrenia and bipolar disorder (BD), are associated with significant distress to patients, reduced life expectancy and a higher cost of care. There is growing evidence that SMI may increase the risk of dementia in later life, posing an additional challenge in the management of these patients. SMI present a complex and highly heterogeneous pathophysiology, which has hampered the understanding of its underlying pathological mechanisms and limited the success of the available therapies. Despite the advances in therapeutic approaches in psychiatry over the past decades, treatment resistance is still a common problem in clinical practice, highlighting the urgent need for novel therapeutic targets for SMI. The discovery that renin-angiotensin system (RAS) components are expressed in the central nervous system opened new possibilities for investigating a potential role for this system in the neurobiology of SMI. The safety and efficacy of AT1 receptor blockers and angiotensin-converting enzyme inhibitors in cardiovascular and metabolic diseases, common medical comorbidities among SMI patients and well-known risk factors for dementia, suggest the potential scalability of these strategies for the management of SMI outcomes including the risk of subsequent dementia. This review aimed to discuss the available evidence from animal models and human studies of the potential involvement of RAS in the pathophysiology of SMI. We also provided a reflection on drawbacks and perspectives that can foster the development of new related therapeutic strategies.

O44 LOW ADHERENCE TO HYPERTENSION MANAGEMENT IN THE COLOMBIAN COMMUNITY IMPLEMENTATION RE-HOPE STUDY

Background and objective: Uncontrolled hypertension is a leading cause of death worldwide, and it's associated with a high socioeconomic burden. Demographic, social, behavioral, and health system-related factors contribute to low adherence to hypertension management. Recognizing adherence rates is a mainstay for improving hypertension control. This study examined the level of adherence to hypertension management and control in the participants belonging to the implementation, integration, and institutionalization of a community-based care strategy to reduce the risk of cardiovascular disease in Santander (ReHOPE) study. Methods This cross-sectional analysis was conducted in 12 municipalities of Santander, Colombia, from May to December 2023. Participants over 18 with hypertension, not in a cardiovascular risk program, were included. Data were collected door-to-door by trained community health providers using standardized questionnaires for socio-demographic information, medication use, lifestyle details, and hypertension knowledge. Physical exams provided anthropometric and blood pressure values. Medication adherence was assessed with the Morisky 4-item scale. Continuous variables are presented as central tendency measures, and categorical variables as frequencies and proportions. Analysis was performed using R software. Results: A total of 2,617 participants were included. The mean age was 65.09 (SD 12.09), and 64.3% were women. The mean systolic blood pressure was 133.94 mmHg (SD 16.53). The median waist-to-hip ratio (WHR) was 0.96 (IQR 0.92-1.00) in men and 0.91 (IQR 0.87-0.96) in women. Among participants, 33.9% had uncontrolled hypertension, 28.5% were not aware of their condition, and 69.2% reported no physical activity. High WHR was found in 84.8% of the participants. Antihypertensive monotherapy use was reported in half of the participants (53.8%). The most frequently used pharmacological group was angiotensin-converting enzyme inhibitors (81.8%). Hypertension control was observed in 66.1%, and 12.6% had high adherence. Conclusions: Low medication adherence was observed, only 12.6% of participants reported high adherence and nearly 40% had uncontrolled hypertension. Additionally, nearly 30% were undetected by the healthcare system. Thus, improving medication adherence and healthcare strategies is essential to enhance health outcomes.

Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers are Associated with Improved Amputation Free Survival in Chronic Limb-Threatening Ischemia

BackgroundIn the Heart Outcomes Prevention Evaluation (HOPE) study, investigators found that ramipril was associated with improved survival as well as decreased MI and stroke rates in patients with peripheral arterial disease. Nonetheless, their effect on chronic limb-threatening ischemia (CLTI)-specific outcomes is unclear. We aim to assess the effect of ACEIs/ARBs on amputation-free survival in CLTI patients undergoing peripheral vascular intervention (PVI) in a Medicare-linked database. MethodsPatients undergoing PVI in the VQI-VISION database were included. Primary outcome included amputation-free survival. Kaplan Meier survival and multivariable Cox regression analyses were used to assess one-year outcomes. ResultsA total of 34,284 patients were included, and 46.3% of whom were discharged on ACEIs/ARBs. Patients discharged on ACEIs/ARBs were more likely to be smokers, diabetics, and hypertensive. They were also more likely to present with rest pain. The overall one-year survival for patients on ACEIs/ARBs vs those who are not was (79.1% vs 69.4%, P<0.001). Freedom from amputation was 87.8% for patients on ACEIs/ARBs vs 84.2% for those who were not (P<0.001). Amputation-free survival was 70.5% vs 59.5% for ACEIs/ARBs vs no ACEIs/ARBs (P<0.001). After adjusting for potential confounders, ACEIs/ARBs use was associated with lower one-year mortality (HR: 0.77, 95%CI (0.7-0.8), P<0.001), amputation (HR: 0.89, 95%CI (0.8-0.9), P<0.001), and amputation or death (HR: 0.79, 95%CI (0.76-0.8), P<0.001). ConclusionsACEIs/ARBs were independently associated with lower amputation, improved survival, and amputation-free survival at one year in CLTI patients undergoing PVI. The fact that more than half the patients were not discharged on these medications presents an area for potential quality improvement.

In Silico Screening of Sulfonamide Derivatives against Glycolytic Enzymes Reveals Mutation‐Independent Interactions of Sulfisoxazole and Sulfamethazine

AbstractGlycolysis is a highly conserved biochemical process that involves the sequential conversion of glucose to pyruvate and the generation of adenosine triphosphate (ATP), generating energy for cellular functions. This is carried out by several enzymes that play an important role in glucose metabolism. The sulfonamide group of drugs is commonly used as an antibiotic that inhibits the bacterial folic acid production pathway, although its effects on glycolytic enzymes are unclear. Since altered glycolytic enzyme expression is linked to a variety of metabolic disorders as well as cancer, the quest for new ligands against glycolytic enzymes is never over. We revealed that different sulfonamide derivatives interact with glycolytic enzymes with varying binding affinities. Among the selected sulfonamides, sulfisoxazole and sulfamethazine had greater binding scores to certain glycolytic enzymes than others. In silico point mutation analysis predicts that sulfisoxazole and sulfamethazine interact with certain glycolytic enzymes in a residue‐independent manner. This research generates a repository of the 2D interactions of sulfonamide derivatives with glycolytic enzymes, binding energies, impacts of induced point mutations on the local environment, and changes in protein structural flexibility. In the future, sulfisoxazole and sulfamethazine may be repurposed as specific glycolytic enzyme inhibitors to combat a variety of glycolysis‐related metabolic disorders.

Prevalence of Potential Drug Interactions With Direct-Acting Antivirals for COVID-19 Among Hospitalized Patients

PurposeClinicians consider polypharmacy, comorbidities, and other factors including the potential for drug-drug interactions (DDIs) when evaluating therapeutic options for specific clinical diagnoses. Contemporary treatment for coronavirus disease 2019 (COVID-19) includes direct-acting antivirals (DAAs). We sought to characterize patients’ characteristics, comorbidities, and medications received during their hospitalization for COVID-19 and quantify potential DDIs that clinicians consider in selecting appropriate DAAs. MethodsPatients hospitalized with a primary diagnosis of COVID-19 between May 2020 and December 2022 from the PINC AI Healthcare Database were identified. Medications administered during the hospitalization with the potential to cause DDIs with nirmatrelvir/ritonavir, remdesivir, or molnupiravir (per the Emergency Use Authorization factsheet or package insert) were assessed. For DDIs with nirmatrelvir/ritonavir, medications are categorized as “Contraindicated,” “Avoid Concomitant Use,” or “Other DDIs” (includes recommendation for dose modification or clinical and laboratory monitoring). For remdesivir, coadministration with chloroquine phosphate and hydroxychloroquine sulfate was not recommended. For molnupiravir, no drugs are listed as having potential DDIs. In a subset of patients, a multivariable logistic regression model was used to examine the association between documented patient/hospital characteristics and the likelihood of being “Contraindicated” to receive nirmatrelvir/ritonavir. FindingsOf the 788,238 patients hospitalized for COVID-19 in 920 hospitals, 53% were ≥ 65 years old, and 31% had Charlson Comorbidity Index (CCI) ≥ 3. During the study period, about half of the patients received medications categorized as “Contraindicated” (11%) and/or “Avoid Concomitant Use” (41%) with nirmatrelvir/ritonavir. The frequency of administered drugs was higher in those aged ≥ 65 years (68%), CCI ≥ 3 (78%), with high-risk underlying conditions (55%). About 1% of patients received medications that were not recommended to be coadmistered with remdesivir. Among a subset of patients hospitalized for COVID-19 in 2022, those who were older, had higher CCI, high-risk underlying conditions, severe hepatic impairment, Medicare insurance, and hospitalized in larger hospitals were significantly more likely to be categorized as “Contraindicated” when considering nirmatrelvir/ritonavir as a therapeutic option to manage COVID-19. ImplicationsA significant proportion of patients hospitalized for COVID-19 receive medications for other conditions that have the potential to result in DDIs with DAAs; most predominantly with nirmatrelvir/ritonavir, a strong CYP3A enzyme inhibitor, fewer with remdesivir, and none with molnupiravir. Higher age and comorbidity burden were significantly associated with a higher likelihood of receiving medications that are “Contraindicated” with nirmatrelvir/ritonavir. In the evolving COVID-19 era, these findings provide insights into patients hospitalized for COVID-19, and the polypharmacy evaluations that clinicians may encounter when selecting among DAAs to manage COVID-19.