Lisinopril increases lung ACE2 levels and SARS-CoV-2 viral load and decreases inflammation but not disease severity in experimental COVID-19.

COVID-19 causes more severe and frequently fatal disease in patients with pre-existing comorbidities such as hypertension and heart disease. SARS-CoV-2 virus enters host cells through the angiotensin-converting enzyme 2 (ACE2), which is fundamental in maintaining arterial pressure through the renin-angiotensin system (RAS). Hypertensive patients commonly use medications such as angiotensin-converting enzyme inhibitors (ACEi), which can modulate the expression of ACE2 and, therefore, potentially impact the susceptibility and severity of SARS-CoV-2 infection. Here we assessed whether treatment of ACE2-humanized (K18-hACE2) mice with the ACEi Lisinopril affects lung ACE2 levels and the outcome of experimental COVID-19. K18-hACE2 mice were treated for 21 days with Lisinopril 10 mg/kg and were then infected with 105 PFU of SARS-CoV-2 (Wuhan strain). Body weight, clinical score, respiratory function, survival, lung ACE2 levels, viral load, lung histology, and cytokine (IL-6, IL-33, and TNF-α) levels were assessed. Mice treated with Lisinopril for 21 days showed increased levels of ACE2 in the lungs. Infection with SARS-CoV-2 led to massive decrease in lung ACE2 levels at 3 days post-infection (dpi) in treated and untreated animals, but Lisinopril-treated mice showed a fast recovery (5dpi) of ACE2 levels. Higher ACE2 levels in Lisinopril-treated mice led to remarkably higher lung viral loads at 3 and 6/7dpi. Lisinopril-treated mice showed decreased levels of the pro-inflammatory cytokines IL-6 and TNF-α in the serum and lungs at 6/7dpi. Marginal improvements in body weight, clinical score and survival were observed in Lisinopril-treated mice. No differences between treated and untreated infected mice were observed in respiratory function and lung histology. Lisinopril treatment showed both deleterious (higher viral loads) and beneficial (anti-inflammatory and probably anti-constrictory and anti-coagulant) effects in experimental COVID-19. These effects seem to compensate each other, resulting in marginal beneficial effects in terms of outcome for Lisinopril-treated animals.

Angiotensin converting enzyme inhibitor and coenzyme Q10 as adjunctive treatment for patients with ventricular septal rupture following late onset myocardial infarction: a case report.

Ventricular Septal Rupture (VSR) is a rare complication of acute myocardial infarction and has a high mortality rate. Surgery is the definitive treatment. However, in hospitals with limited facilities, treating acute myocardial infarction patients with ventricular septal rupture, is challenging. A 74-year-old woman came to the emergency room of Dr. Koesma General Hospital, Tuban, East Java in December, 2019 with late-onset Acute Myocardial Infarction. On the following day, a new holosystolic murmur was heard in the left lower sternal border with palpable thrill. Transthoracic echocardiography showed VSR with severe pulmonary hypertension. This was followed by a drop in the blood pressure to 80/50 mmHg. The blood pressure was dependent on vasopressors until lisinopril and coenzyme Q10 were introduced. After 3 months, the haemodynamics of the patient were stable. This proved that the use of angiotensin-converting enzyme and coenzyme Q10 promotes more energy production, enables tissue healing and leads to balanced remodelling to increase the survival rate in cases of non-surgical treatment.

A Comparative Study of the Safety and Efficacy Between Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers on the Management of Hypertension: A Systematic Review.

Renin-angiotensin-aldosterone system (RAAS) inhibitors, including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), are commonly used in the management of hypertension. High blood pressure is a vital risk factor for cardiovascular disease. This study aims to establish any significant difference in using ACEIs and ARBs in managing hypertension. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to conduct this systematic review. We searched PubMed, MEDLINE, and ScienceDirect for articles published in the last 20 years (2003 to 2023). Our search was last done on the 27th of June, 2023. Following the initial search, 8,313 articles were found on PubMed. After screening the articles selected from the databases, 10 articles examining 1,621,445 patients were selected for the final study. Three articles were identified that compared ACEI and ARB in their capacity to lower blood pressure. Six articles compared both medications' capacity to reduce cardiovascular events and mortality. Five articles were identified that compared both classes of drugs for adverse effects. This study was made to determine whether or not there is a difference between the use of ACEIs and ARBs in the treatment of hypertension. The study showed that both ACEIs and ARBs are similar in their efficacy in lowering blood pressure. However, ACEI was revealed to be superior to ARB in reducing cardiovascular events and all-cause mortality. ARB was shown to be better tolerated by patients than ACEI.

In silico elucidation for the identification of potential phytochemical against ACE-II inhibitors.

CONTEXT: The present study aims to investigate the therapeutic potential of phytocompounds derived from Annona reticulata leaves for the treatment of hypertension, utilizing computational methodologies. Gaining a comprehensive understanding of the molecular interactions between neophytadiene and γ-sitosterol holds significant importance in the advancement of innovative therapeutic approaches. This study aims to examine the inhibitory effects of neophytadiene and γ-sitosterol using molecular docking and dynamics simulations. Additionally, we will evaluate their stability and predict their drug-like properties as well as their ADME/toxicity profiles. Neophytadiene and γ-sitosterol have a substantial binding affinity with 1O8A, as shown by the docking study. The stability of the complexes was confirmed through molecular dynamics simulations, while distinct clusters were identified using PCA. These findings suggest the presence of potential stabilizers. The drug-likeness and ADME/toxicity predictions revealed positive characteristics, such as efficient absorption rates, limited distribution volume and non-hazardous profiles. The neophytadiene and γ-sitosterol exhibit potential as hypertension medication options. Computational investigations reveal that these compounds exhibit high affinity for binding, stability and favourable pharmacokinetic properties. The results of this study lay the groundwork for additional experimental verification and highlight the promising prospects of utilizing natural compounds in the field of pharmaceutical research. METHODS: Target proteins (1O8A) were used to perform molecular docking with representative molecules. Stability, conformational changes and binding energies were assessed through molecular dynamics simulations lasting 100 ns. Principal component analysis (PCA) was utilized to analyze molecular dynamics (MD) simulation data, to identify potential compounds that could stabilize the main protease. The safety and pharmacokinetic profiles of the compounds were evaluated through drug-likeness and ADME/toxicity predictions.

Pharmacokinetic and Bioequivalence Study of Lisinopril/Hydrochlorothiazide Tablet Under Fasting and Postprandial Conditions in Healthy Chinese Subjects.

The objective of this research was to evaluate and compare the pharmacokinetic profiles and safety of lisinopril/hydrochlorothiazide (10 mg/12.5 mg) tablets in the test and reference formulations administered to participants in both fasting and postprandial states and to evaluate the bioequivalence of the 2 products in healthy Chinese volunteers. This study employed a single-center, randomized, open-label, single-dose dosing trial involving a cumulative 96 healthy adult participants (60 in the fasting group and 36 in the postprandial group). Each group comprised 2 sequence sets, and a 2-week washout period was implemented. There were no statistically significant differences in time to maximum concentration and terminal elimination half-life between the test and control groups under fasting and postprandial conditions (P > .05), and the 90% CIs for area under the plasma concentration-time curve and maximum plasma concentration were within the bioequivalence range of 80%-125%. Pharmacokinetic results indicate a large food effect for lisinopril, meaning that there is a loss of approximately 20%-25% of systemic exposure from fasting to postprandial administration for both preparations. The study demonstrated that a single oral dose of generic lisinopril/hydrochlorothiazide is bioequivalent to the reference product and well tolerated, with no significant adverse events observed, and that both products are similarly safe in a cohort of healthy Chinese male and female participants, following administration under fasting and postprandial conditions.

Population pharmacokinetics of lisinopril in hypertensive children and adolescents with normal to mildly reduced kidney function.

AIMS: Lisinopril, an angiotensin-converting enzyme inhibitor, is a frequently prescribed antihypertensive drug in the paediatric population, while being used off-label under the age of 6 years in the USA and for all paediatric patients globally. The SAFEPEDRUG project (IWT-130033) investigated lisinopril pharmacokinetics in hypertensive paediatric patients corresponding with the day-to-day clinical population. METHODS: The dose-escalation pilot study included 13 children with primary and secondary hypertension who received oral lisinopril once daily in the morning; doses ranged from 0.05 to 0.2 mg kg-1 . Patients were aged between 1.9 and 17.9 years (median 13.5 years) and weight ranged between 9.62 and 97.2 kg (median 53.2 kg). All data were analysed using Monolix version 2020R1 (Lixoft, France) and R version 3.6.2. RESULTS: A 1-compartment model with first-order absorption and first-order elimination optimally describes the data. Parameter estimates of absorption rate constant (0.075 h-1 [0.062, 0.088], typical value [95% confidence interval]), volume of distribution (31.38 L 70 kg-1 [10.5, 52.3]) and elimination clearance (24.2 L h-1 70 kg-1 [19.5, 28.9]) show good predictive ability. Significant covariate effects include total body weight on elimination clearance, and distribution volume and estimated glomerular filtration rate (eGFR) on elimination clearance. The effects of eGFR on the elimination clearance are optimally described by a linear effect centred around 105 mL min-1  1.73 m-2 . The effects of body weight were implemented using fixed allometric exponents centred around an adult weight of 70 kg. CONCLUSION: Lisinopril dose and regimen adjustments for paediatric patients should include eGFR on top of weight adjustments. An expanded model characterizing the pharmacodynamic effect is required to identify the optimal dose and dosing regimen.

Captopril to Lisinopril Conversion in Pediatric Cardiothoracic Surgery Patients Less Than 7 Years of Age (RISE-7).

Hypertension after cardiothoracic surgery is common, often requiring pharmacologic management. The recommended first-line antihypertensives in pediatrics are angiotensin converting enzyme inhibitors. Captopril and enalapril are approved for infants and children; however, lisinopril is only approved for > 7 years of age. This study evaluated safety and efficacy of converting from captopril to lisinopril in patients utilizing a pre-defined conversion of 3 mg captopril to 1 mg lisinopril. This was a single center, retrospective study including patients less than 7 years of age admitted for cardiothoracic surgery who received both captopril and lisinopril from 01/01/2017 to 06/01/2022.The primary outcome was mean change in systolic blood pressure (SBP) from baseline for 72 h after conversion of captopril to lisinopril. A total of 99 patients were enrolled. There was a significant decrease in mean SBP (99.12 mmHg vs 94.86 mmHg; p = 0.007) with no difference in DBP (59.23 mmHg vs 61.95 mmHg; p = 0.07) after conversion to lisinopril. Of the 99 patients who were transitioned to lisinopril, 79 (80%) had controlled SBP, 20 (20%) remained hypertensive, 13 (13%) received an increase in their lisinopril dose, and 2 (2%) required an additional antihypertensive agent. There was a low overall rate of AKI (3%) and hyperkalemia (4%) respectively. This study demonstrates that utilizing lisinopril with a conversion rate of 3 mg of captopril to 1 mg of lisinopril was safe and effective for controlling hypertension in pediatric patients following cardiothoracic surgery.

Nephroprotective effects of diminazene on doxorubicin-induced acute kidney injury in rats.

This study aimed to investigate the potential protective effects of diminazene, an activator of angiotensin II converting enzyme (ACE2), on kidney function and structure in rats with acute kidney injury (AKI) induced by the anticancer drug doxorubicin (DOX). The impact of diminazene was compared to that of two other drugs: the ACE inhibitor lisinopril and the angiotensin II type 1 (AT1) receptor blocker valsartan. Rats were subjected to a single intraperitoneal injection of DOX (13.5 mg/kg) on the 5th day, either alone or in combination with diminazene (15 mg/kg/day), lisinopril (10 mg/kg/day), or valsartan (30 mg/kg/day) for 8 consecutive days. Various markers related to kidney function, oxidative stress, and inflammation were measured in plasma and urine. Additionally, kidney tissues were assessed histopathologically. DOX-induced nephrotoxicity was confirmed by elevated levels of plasma urea, creatinine, and neutrophil gelatinase-associated lipocalin (NGAL). DOX also led to increased urinary N-acetyl-ß-D-glucosaminidase (NAG) activity and decreased creatinine clearance, albumin levels, and osmolality. Moreover, DOX caused a reduction in renal oxidative stress markers, including superoxide dismutase (SOD), glutathione reductase (GR), and catalase activities, while increasing malondialdehyde (MDA) levels. It also raised plasma inflammatory markers, tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1ß). Concurrently administering diminazene significantly mitigated these DOX-induced changes, including histopathological alterations like renal tubule necrosis, tubular casts, shrunken glomeruli, and increased renal fibrosis. Similar protective effects were observed with lisinopril and valsartan. These protective effects, at least in part, appear to result from the anti-inflammatory and antioxidant properties of these drugs. In summary, this study suggests that the administration of diminazene, lisinopril, or valsartan had comparable effects in ameliorating the biochemical and histopathological aspects of DOX-induced acute kidney injury in rats.

Enalapril Is Superior to Lisinopril in Improving Endothelial Function without a Difference in Blood-Pressure-Lowering Effects in Newly Diagnosed Hypertensives.

Angiotensin-converting enzyme (ACE) inhibitors are the primarily chosen drugs to treat various cardiovascular diseases, such as hypertension. Although the most recent guidelines do not differentiate among the various ACE inhibitory drugs, there are substantial pharmacological differences. GOAL: Here, we tested if lipophilicity affects the efficacy of ACE inhibitory drugs when used as the first therapy in newly identified hypertensives in a prospective study. METHODS: We tested the differences in the cardiovascular efficacy of the hydrophilic lisinopril (8.3 ± 3.0 mg/day) and the lipophilic enalapril (5.5 ± 2.3 mg/day) (n = 59 patients). The cardiovascular parameters were determined using sonography (flow-mediated dilation (FMD) in the brachial artery, intima-media thickness of the carotid artery), 24 h ambulatory blood pressure monitoring (peripheral arterial blood pressure), and arteriography (aortic blood pressure, augmentation index, and pulse wave velocity) before and after the initiation of ACE inhibitor therapy. RESULTS: Both enalapril and lisinopril decreased blood pressure. However, lisinopril failed to improve arterial endothelial function (lack of effects on FMD) when compared to enalapril. Enalapril-mediated improved arterial endothelial function (FMD) positively correlated with its blood-pressure-lowering effect. In contrast, there was no correlation between the decrease in systolic blood pressure and FMD in the case of lisinopril treatment. CONCLUSION: The blood-pressure-lowering effects of ACE inhibitor drugs are independent of their lipophilicity. In contrast, the effects of ACE inhibition on arterial endothelial function are associated with lipophilicity: the hydrophilic lisinopril was unable to improve, while the lipophilic enalapril significantly improved endothelial function. Moreover, the effects on blood pressure and endothelial function did not correlate in lisinopril-treated patients, suggesting divergent mechanisms in the regulation of blood pressure and endothelial function upon ACE inhibitory treatment.

Angioedema From Triple Therapy: A Case Report.

Angioedema is a rare but potentially life-threatening complication associated with angiotensin-converting enzyme (ACE) inhibitors. Although the pathophysiology is well understood, cases involving the concurrent use of other medications are less explored. We present a unique case of ACE inhibitor-induced angioedema in a 57-year-old male, which developed soon after receiving intravenous contrast. The patient's medication list included a dipeptidyl peptidase-IV inhibitor and a calcium channel blocker. Studies have shown an increased risk of angioedema with the combined use of these medications, likely due to alterations in bradykinin metabolism. This case highlights the importance of medication review and consideration of potential drug interactions when prescribing ACE inhibitors. It emphasizes the significance of diagnostic accuracy to avoid the mislabeling of allergies and consideration of other etiologies in angioedema. Healthcare providers ought to be mindful of the increased risk of angioedema when prescribing dipeptidyl peptidase-IV inhibitors and calcium-channel blockers with ACE inhibitors, as these are frequently used medications.

Effect of eucalyptol on matrix metalloproteinase-9 and its tissue inhibitor in hypertensive rats.

Effects of eucalyptol, a key component of eucalyptus globules, on matrix metalloproteinase-9 (MMP-9) and its tissue inhibitor (TIMP-1), compared with lisinopril, were investigated in a model of hypertension induced by chronic intraperitoneal (IP) injection of low dose nicotine in rats. The hypertensive rats were randomly allocated to 4 groups (n=8): Positive control (PC, untreated), eucalyptol-treated group (1.0 mg/kg, IP), lisinopril-treated group (10 mg/kg, IP), and eucalyptol+lisinopril-treated group. Systolic blood pressure and plasma levels of MMP-9 and TIMP-1 were measured. All treatments decreased the elevated blood pressure and plasma levels of MMP-9 and TIMP-1 most significantly with the combination group which showed non-significant differences from the normal control group. Lisinopril reduced plasma levels of MMP-9 and TIMP-1 more significantly than eucalyptol. In conclusion, eucalyptol significantly decreased the increased plasma levels of MMP-9 and TIMP-1 in nicotine-induced hypertension in rats. Moreover, its combination with lisinopril exerted more significant effects compared to each drug alone. This makes this combination particularly useful in hypertension and related cardiovascular disorders where suppression of MMP-9 and TIMP-1 activities decreases the related complications and improves the overall morbidity and mortality. To our knowledge, the current data are novel, and may open the way for development of a co-delivery system of both drugs which could be beneficial in treatment of hypertension in chronic smokers.

Unresolved Chronic Diarrhea: A Case of Angiotensin-Converting Enzyme Inhibitor-Induced Mesenteric Angioedema.

Angiotensin-converting enzyme inhibitors (ACEI) are frequently prescribed for cardiovascular and renal diseases. However, ACEI-induced visceral angioedema is a rare occurrence that often goes unnoticed and poses a diagnostic challenge due to its non-specific and diverse symptoms. Key diagnostic indicators on a CT scan include the 'target' sign, elongation of bowel loops, enlarged mesenteric vessels, mesenteric edema with or without ascites, thickened omentum, and the absence of vascular compromise or adenopathy. Discontinuation of ACEI usually results in symptom resolution within 48 hours. While this phenomenon is more commonly observed in females and African Americans, we present a case of a Caucasian male who underwent an extensive diagnostic evaluation, including exploratory surgery, before ACEI-induced angioedema was considered. LEARNING POINTS: The occurrence of angiotensin-converting enzyme inhibitors (ACEI)-induced visceral angioedema is infrequent, frequently overlooked, and presents a diagnostic challenge due to its wide range of non-specific symptoms.While ACEI-induced visceral angioedema is more frequently observed in females and African Americans, it is crucial not to overlook the possibility of this phenomenon in other demographic groups as well.Its rarity emphasizes the importance of including it in the list of potential conditions to be considered, thus preventing unnecessary tests and procedures.

Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema: A Case Report With a Review of Management Options.

Angiotensin-converting enzyme inhibitors (ACEIs) are widely used for heart failure, renal failure, diabetic nephropathy, stroke, arterial hypertension, and a number of other cardiovascular or related conditions. ACEI-induced angioedema is a rare entity but can result in life-threatening emergencies. It mainly occurs in patients starting on ACEI as an antihypertensive. We present a case of lisinopril-induced angioedema in an African American patient managed in the emergency department. After appropriate evaluation, the patient was declared safe to be observed in the emergency department. Intubation was not performed. Early identification of angioedema is paramount, and emergency physicians should maintain airways or intubate such patients if indicated. There should be a high level of suspicion of angioedema in patients taking ACEIs if they present with symptoms of respiratory compromise.

Optimization and evaluation of Lisinopril mucoadhesive sustained release matrix pellets: In-vitro and ex-vivo studies.

Lisinopril (LIS) is antihypertensive drug, classified as a class III drug with high water solubility and low permeability. To overcome the low permeability, 32 factorial designs aimed to formulate LIS as a sustained-release (LIS-SR) matrix pellet by extrusion/spheronization. Matrix pellets were composed of wet mass containing Avicel® and polymeric matrix polymers (sodium alginate (SA) and chitosan (CS)). Evaluation of the effect of two independent variables, matrix-forming units (SA and CS) on mean line torque, on pellet size, dissolution rate after 6 h, and mucoadhesion strength of the pellets were assessed using Statgraphics software. The tested formulations (F1-F9) showed that mean line torque ranged from 1.583 to 0.461 Nm, with LIS content in the LIS-SR pellets ranged from 87.9 to 103%, sizes varied from 1906 to 1404 µm and high percentages of drug released from pellets formulations (68.48 to 74.18 %), while the mean zeta potential value of mucoadhesive range from -17.5 to -22.9 mV. The selection of optimized formulation must have the following desirability: maximum peak torque, maximum pellets' particle size, and minimum % LIS release after 6hr. LIS optimized sustained release pellet formula composed of 2,159 % SA and 0.357 % CS was chosen as optimized formula. It's showed a 1.055 Nm mean line torque was responsible for the increased pellet size to 1830.8 µm with decreased release rate 56.2 % after 6 hr, and -20.33 mV average mucin zeta potential. Ex-vivo mucoadhesion studies revealed that that the optimize formulation, exhibited excellent mucoadhesive properties, after 1 h, about 73% of the pellets were still attached to the mucus membrane. Additionally, ex-vivo permeation determination of LIS from the optimized LIS-SR formulation was found to be significantly higher (1.7-folds) as compared to free LIS. In conclusion: LIS-SR matrix pellets, prepared with an extrusion/spheronization have desirable excellent characteristics in-vitro and ex-vivo sustained-release pellet formulation of LIS-SR was able to sustain the release of LIS for up to 8 h.

A Fatal Case of Lisinopril-Induced Acute Necrotizing Pancreatitis.

Angiotensin-converting enzyme inhibitors (ACE-I), such as lisinopril, are used as first-line therapy in the treatment of hypertension, heart failure with reduced ejection fraction, and proteinuric chronic kidney disease due to their beneficial effects on reducing morbidity and mortality. Commonly cited adverse effects of lisinopril include hyperkalemia, acute kidney injury, and angioedema, and while uncommon, there have been reports of lisinopril-induced necrotizing pancreatitis in the literature. The true incidence of drug-induced pancreatitis is unknown since establishing a causal relationship between medication's adverse effects and disease occurrence is difficult; however, there are validated tools such as the Adverse Drug Reaction Probability Scale that can aid in determining causality. Here, we present a case of a 63-year-old man with a history of hypertension who was being treated with lisinopril for eight months and developed a fatal case of lisinopril-induced severe necrotizing pancreatitis.

Use of Naloxone in Angiotensin-Converting Enzyme Inhibitor Overdose: A Case Report.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitor overdose is an uncommonly presenting toxicologic emergency. Management is primarily supportive care, but a small body of evidence exists to support naloxone for management of hypotension. CASE REPORT: We present a case of accidental ACE inhibitor overdose. The patient took approximately 300 mg lisinopril over 48 h and presented for evaluation of syncope. He was hypotensive and unresponsive to fluids. We administered naloxone with immediate and sustained resolution in hypotension. The mechanism of action is briefly discussed. WHY SHOULD AN EMERGENCY MEDICINE PHYSICIAN BE AWARE OF THIS?: Naloxone is a rapid, low-risk, low-cost, and effective intervention for hypotension due to ACE inhibitor toxicity. It is supported by basic science research and clinical experience.

Progressive development of melanoma-induced cachexia differentially impacts organ systems in mice.

Cachexia is a systemic wasting syndrome that increases cancer-associated mortality. How cachexia progressively and differentially impacts distinct tissues is largely unknown. Here, we find that the heart and skeletal muscle undergo wasting at early stages and are the tissues transcriptionally most impacted by cachexia. We also identify general and organ-specific transcriptional changes that indicate functional derangement by cachexia even in tissues that do not undergo wasting, such as the brain. Secreted factors constitute a top category of cancer-regulated genes in host tissues, and these changes include upregulation of the angiotensin-converting enzyme (ACE). ACE inhibition with the drug lisinopril improves muscle force and partially impedes cachexia-induced transcriptional changes, although wasting is not prevented, suggesting that cancer-induced host-secreted factors can regulate tissue function during cachexia. Altogether, by defining prevalent and temporal and tissue-specific responses to cachexia, this resource highlights biomarkers and possible targets for general and tissue-tailored anti-cachexia therapies.