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.

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.

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.

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.

The ACE Inhibitor Lisinopril Stimulates Melanoma Cell Invasiveness by Inducing MMP2 Secretion.

BACKGROUND/AIMS: Hypertension is treated primarily with angiotensin II (ATII) receptor blockers (ARBs) and angiotensin converting enzyme (ACE) inhibitors (ACEIs). Both ATII and ACEIs can trigger signal transduction via ACE, and a possible correlation between ARB/ACEI therapy and an increased risk of cancer is highly controversial. The question of whether or not ACE as a potential signal transducer affects human melanoma (MV3) cell behavior prompted the present study. METHODS: Expression of ACE, ATII receptor types 1, 2 (AT1R, AT2R), COX2 and MMP2 in MV3 cells was examined by qPCR. AT1R, AT2R and ACE were inhibited with losartan, EMA401 and lisinopril, respectively. Adhesion, migration and invasiveness of MV3 cells seeded on a hepatocyte (Huh7) monolayer or a reconstituted collagen type I matrix were analyzed using video microscopy and Boyden chambers. Integrity of the Huh7 cell layer was confirmed by measuring transepithelial electrical resistance (TEER). ERK1/2 phosphorylation and MMP2 secretion were evaluated by Western blotting. MMP2 activity was inhibited with ARP-100. RESULTS: Losartan, EMA401 and lisinopril stimulated MV3 melanoma cell migration and invasion in a coculture model with Huh7 cells while leaving proliferation and adhesion largely unaffected. The drugs did not interfere with TEER of the hepatocyte monolayer nor with MV3 cell proliferation, but tended to increase the phosphorylation of ERK1/2 and the expression of both COX2 and MMP2. Lisinopril caused a significant increase in MV3 cells' MMP2 secretion and an accelerated MV3 cell-mediated TEER breakdown. The MMP2 inhibitor ARP-100 could antagonize the lisinopril-stimulated invasion of the hepatocyte layer. CONCLUSION: Lisinopril stimulates MV3 cell invasion by increasing the expression and secretion of MMP2.

Underreported Risk of Lisinopril-Induced Angioedema in a Veteran Population.

BACKGROUND: Lisinopril-induced angioedema (LIA) is a rare but serious adverse drug event (ADE) with a published incidence of 0.1% to 0.7%. It is well known that ADEs are widely underreported; however, LIA is one of the most reported ADEs within the Veterans Health Administration (VHA). OBJECTIVE: To estimate the effect of underreporting on the risk of LIA within VHA. METHODS: The reported risk of LIA was calculated from reports submitted to the Veterans Affairs (VA) Adverse Drug Event Reporting System (VA ADERS) and the number of veterans prescribed lisinopril. To estimate underreporting, local chart review identified cases of LIA that were compared to reports submitted. The underreporting rate was then applied to the national reported risk. RESULTS: Locally, 68 reports of LIA were submitted of the 21 262 patients prescribed lisinopril, for a reported risk of 0.32%. Nationwide, 14 289 reports of LIA were submitted of the 3 109 661 patients prescribed lisinopril, for a crude reported risk of 0.46%. Of the 324 patients identified for chart review, 240 patients were diagnosed with LIA, suggesting that at least 71.7% of cases were unreported. When this underreporting rate is extrapolated to the national reported risk, a better estimate of the risk of LIA within VHA could increase to 1.6%. CONCLUSION AND RELEVANCE: When estimating the effect of underreporting, the risk of LIA increases to approximately 1.6% or 1 in 63 patients. Because this ADE may affect more patients than previously understood, providers may wish to take LIA into consideration when prescribing lisinopril.

Intestinal absorption pathways of lisinopril: Mechanistic investigations.

Lisinopril is an antihypertensive drug with poor intestinal permeability. Enhancement of intestinal absorption depends on a clear understanding of the permeation pathways and absorption mechanisms. Unfortunately, these are not fully elucidated for lisinopril. Accordingly, the aim was to determine lisinopril permeation pathways and obstacles limiting membrane transport with subsequent nomination of appropriate permeation enhancers. This employed an in situ rabbit intestinal perfusion technique, which revealed site-dependent absorptive clearance (PeA/L) from a lisinopril simple solution (5 µg/ml), with paracellular absorption playing a role. Regional drug permeability ranked as colon> duodenum> jejunum> ileum opposing intestinal expression rank of P-glycoprotein (P-gp) efflux transporters. Duodenal and jejunal perfusion of a higher lisinopril concentration (50 µg/ml) reflected saturable absorption, suggesting carrier-mediated transport. The effect of piperine and verapamil as P-gp inhibitors on intestinal absorption of lisinopril was investigated. Coperfusion with either piperine or verapamil significantly enhanced lisinopril absorption, with enhancement being dominant in the ileum segment. This supported the contribution of P-gp transporters to poor lisinopril permeability. On the other hand, coperfusion of lisinopril with zinc acetate dihydrate significantly multiplied lisinopril PeA/L by 2.3- and 6.6-fold in duodenum and ileum segments, respectively, through magnifying intestinal water flux. The study explored the barriers limiting lisinopril intestinal absorption. Moreover, the study exposed clinically relevant lisinopril interactions with common coadministered cargos that should be considered for an appropriate lisinopril regimen. However, this requires further in vivo verification.

Targeting inflammation and redox perturbations by lisinopril mitigates Freund's adjuvant-induced arthritis in rats: role of JAK-2/STAT-3/RANKL axis, MMPs, and VEGF.

BACKGROUND: Cardiovascular disorders are major complications of rheumatoid arthritis (RA). Hence, finding effective agents that can target RA progression and its cardiovascular consequences is demanding. The present work aimed to explore the potential of lisinopril, an angiotensin-converting enzyme inhibitor, to mitigate adjuvant's-induced arthritis with emphasis on the pro-inflammatory signals, articular degradation cues, and angiogenesis alongside JAK-2/STAT-3 and Nrf2/HO-1 pathways. METHODS: Lisinopril (10 mg/kg/day) was administered by oral gavage for 3 weeks and the target signals were examined by biochemical assays, ELISA, histopathology, immunoblotting, and immunohistochemistry. RESULTS: Lisinopril attenuated the progression of arthritis as proven by lowering paw edema, arthritic index, and gait scores alongside diminishing the immune-cell infiltration/aberrant histopathology in the dorsal pouch lining. These favorable actions were associated with curtailing the production of inflammatory cytokines (TNF-α, IL-6, IL-1ß, and IL-17) and the pro-inflammatory angiotensin II alongside upregulating the anti-inflammatory angiotensin-(1-7) in the hind paw of arthritic rats. At the molecular level, lisinopril inhibited the upstream JAK-2/STAT-3 pathway by downregulating the protein expression of p-JAK-2/total JAK-2 and p-STAT-3/total STAT-3 ratio and the nuclear levels of NF-κBp65. Meanwhile, lisinopril curbed the downstream cartilage degradation signals matrix metalloproteinases (MMP-3 and MMP-9) and the bone erosion cue RANKL. Equally important, the protein expression of the angiogenesis signal VEGF was downregulated in the hind paw/dorsal lining. With respect to oxidative stress, lisinopril suppressed the paw lipid peroxides and boosted GSH and Nrf-2/HO-1 pathway. CONCLUSION: Lisinopril attenuated adjuvant-induced arthritis via inhibition of inflammation, articular degradation cues, and angiogenesis.

EFFECTIVENESS OF LISINOPRIL AND AMLODIPINE COMBINATION AT HYPERTENSION WITH COMORBIDITY OF ARTERIOSCLEROSIS OBLITERANS IN GENERAL PRACTICE.

OBJECTIVE: The aim: To analyze the dynamics of daily monitoring of blood pressure, intracardiac (according to echocardiography), peripheral hemodynamics (according to ultrasound of the vessels of the lower extremity), the thickness of the intima-media complex (according to carotid sonography) in patients with hypertension the effect of treatment with a combination of lisinopril and amlodipine. PATIENTS AND METHODS: Materials and methods: The study included 40 patients with hypertension with 2 (29 patients) and 3 (11 patients) degrees of hypertension in combination with AOLE with I-III stages of chronic insufficiency of the lower extremity, which revealed hyperkinetic, eukinetic, and hypokinetic types of hypertension with a predominance of the sympathetic nervous system. The groups are comparable in age, sex, duration of hypertension, and medications received in the previous stages. For antihypertensive therapy, the most common drugs for use were selected - lisinopril + amplodipine in fixed doses of 10 and 5 mg, respectively. If after 2 weeks we did not reduce the mean level of SBP and DBP by 10% or more from baseline, we doubled the dose of lisinopril without changing the dose of amlodipine. RESULTS: Results: After 6 months of treatment, in particular, an increase in the pulse index - by 24.8%, a decrease in the resistance index - by 21.1%, an increase in linear and volumetric blood velocity - by 25.6% and 27.4%, respectively, while achieving the target blood pressure. CONCLUSION: Conclusions: It is proved that in the absence of individual contraindications the combination of lisinopril and amlodipine is optimal and universal for effective treatment of patients with hypertension in combination with AOLE in all types of central hemodynamics.

A rapid dynamic in vivo near-infrared fluorescence imaging assay to track lung vascular permeability after acute radiation injury.

To develop a dynamic in vivo near-infrared (NIR) fluorescence imaging assay to quantify sequential changes in lung vascular permeability-surface area product (PS) in rodents. Dynamic NIR imaging methods for determining lung vascular permeability-surface area product were developed and tested on non-irradiated and 13 Gy irradiated rats with/without treatment with lisinopril, a radiation mitigator. A physiologically-based pharmacokinetic (PBPK) model of indocyanine green (ICG) pulmonary disposition was applied to in vivo imaging data and PS was estimated. In vivo results were validated by five accepted assays: ex vivo perfused lung imaging, endothelial filtration coefficient (Kf) measurement, pulmonary vascular resistance measurement, Evan's blue dye uptake, and histopathology. A PBPK model-derived measure of lung vascular permeability-surface area product increased from 2.60 ± 0.40 [CL: 2.42-2.78] mL/min in the non-irradiated group to 6.94 ± 8.25 [CL: 3.56-10.31] mL/min in 13 Gy group after 42 days. Lisinopril treatment lowered PS in the 13 Gy group to 4.76 ± 6.17 [CL: 2.12-7.40] mL/min. A much higher up to 5× change in PS values was observed in rats exhibiting severe radiation injury. Ex vivo Kf (mL/min/cm H2O/g dry lung weight), a measure of pulmonary vascular permeability, showed similar trends in lungs of irradiated rats (0.164 ± 0.081 [CL: 0.11-0.22]) as compared to non-irradiated controls (0.022 ± 0.003 [CL: 0.019-0.025]), with reduction to 0.070 ± 0.035 [CL: 0.045-0.096] for irradiated rats treated with lisinopril. Similar trends were observed for ex vivo pulmonary vascular resistance, Evan's blue uptake, and histopathology. Our results suggest that whole body dynamic NIR fluorescence imaging can replace current assays, which are all terminal. The imaging accurately tracks changes in PS and changes in lung interstitial transport in vivo in response to radiation injury.

Metabolomic profiling of metoprolol hypertension treatment reveals altered gut microbiota-derived urinary metabolites.

INTRODUCTION: Metoprolol succinate is a long-acting beta-blocker prescribed for the management of hypertension (HTN) and other cardiovascular diseases. Metabolomics, the study of end-stage metabolites of upstream biologic processes, yield insight into mechanisms of drug effectiveness and safety. Our aim was to determine metabolomic profiles associated with metoprolol effectiveness for the treatment of hypertension. METHODS: We performed a prospective pragmatic trial (NCT02293096) that enrolled patients between 30 and 80 years with uncontrolled HTN. Patients were started on metoprolol succinate at a dose based upon systolic blood pressure (SBP). Urine and blood pressure measurements were collected weekly. Individuals with a 10% decline in SBP or heart rate (HR) were considered responsive. Genotype for the CYP2D6 enzyme, the primary metabolic pathway for metoprolol, was evaluated for each subject. Unbiased metabolomic analyses were performed on urine samples using UPLC-QTOF mass spectrometry. RESULTS: Urinary metoprolol metabolite ratios are indicative of patient CYP2D6 genotypes. Patients taking metoprolol had significantly higher urinary levels of many gut microbiota-dependent metabolites including hydroxyhippuric acid, hippuric acid, and methyluric acid. Urinary metoprolol metabolite profiles of normal metabolizer (NM) patients more closely correlate to ultra-rapid metabolizer (UM) patients than NM patients. Metabolites did not predict either 10% SBP or HR decline. CONCLUSION: In summary, urinary metabolites predict CYP2D6 genotype in hypertensive patients taking metoprolol. Metoprolol succinate therapy affects the microbiome-derived metabolites.

Physiologically based pharmacokinetic modelling of lisinopril in children: A case story of angiotensin converting enzyme inhibitors.

AIMS: Lisinopril is an angiotensin converting enzyme inhibitor to treat hypertension. It shows complex pharmacokinetics (PK), and its PK behaviour in paediatric populations is not well characterized. The aim of this study was to develop a physiologically based PK (PBPK) model for lisinopril to describe the drug's PK in children. METHODS: The PBPK model development was performed in a step-wise manner. An adult model was initially developed to characterize lisinopril's disposition and absorption and verified using literature data. Subsequently, the adult PBPK model was extrapolated to the paediatric population (0.5-18 years old) by accounting for age-dependent physiological and anatomical changes. Model performance was evaluated by comparing the PK profiles and drug exposures of observed vs predicted data. RESULTS: The disposition of lisinopril was well described by a minimal PBPK model-an effective strategy to capture the biphasic elimination of the drug. The absorption of lisinopril was described by the intestinal peptide transporter-mediated uptake. The adult model adequately described the literature data with predictions within a twofold range of clinical observations. Good model predictivity was also observed in children older than 6 years of age. The model overpredicted the drug exposure in children under 6 years, probably due to not incorporating the actual, unknown ontogeny of the intestinal peptide transporter. CONCLUSIONS: The PBPK model predicted the PK of lisinopril in adults and children above 6 years of age well. Model refinement in children under 6 years warrants future informative ontogeny data of the intestinal peptide transporter.

Chaotropic salts impact in HPLC approaches for simultaneous analysis of hydrophilic and lipophilic drugs.

Simultaneous determination of drugs with different physicochemical properties necessitates thorough research and careful selection of high-performance liquid chromatography conditions. In the present study, various concepts of high-performance liquid chromatography method development for this aim have been discussed. Moreover, the work was motivated by the advantages of utilizing different chaotropic anions as a new promising approach to overcome the limitations of ion-pairing agents commonly used for this purpose. Based on log P values, atorvastatin (log P = 6.36) and lisinopril (log P = -1.22) were chosen as representative examples for lipophilic and hydrophilic drugs, respectively. Several simple, economic, fast, and reliable high-performance liquid chromatography methods were developed for their simultaneous analysis and are presented in a comparative manner, highlighting their advantages and limitations. Peak elution profile showed satisfying retentions and resolution about 3. Photo-diode array calculations were exploited for identifying the molecules by their ultra-violet spectra and peak purity, calculated and presented as rectangular-shaped ratio grams. The linearity check showed excellent results and satisfactory system suitability parameters of both peaks. This confirms the investigation results and conclusions for the influence of the chaotropic salts on N-containing molecules, by increasing their retentivities, and improving peak shapes, even on different quality columns without end-capping and base-deactivating of separation matrixes.

[Tactics of antihypertensive therapy during COVID-19 pandemic].

Results of foreign and Russian studies indicate a higher mortality rate of patients with concomitant cardiovascular diseases (CVD) due to the new coronavirus infection COVID-19. It has been proven that arterial hypertension, as one of the significant risk factors for the development of concomitant cardiovascular diseases, is associated with a more severe prognosis of COVID-19. This article presents the results of modern studies and large meta-analyzes of necessity and safety of the use of blockers of the renin-angiotensin-aldosterone system in patients with arterial hypertension and COVID-19. The data of studies show that an angiotensin-converting enzyme inhibitor (ACE inhibitor) and a thiazide-like diuretic is a pathogenetically rational combination. It realizes various ways of lowering blood pressure by reducing the activity of the renin-angiotensin-aldosterone system, which is achieved by using an ACE inhibitor, and natriuresis due to diuretics. As an example, a highly effective fixed combination of drugs is considered, characterized by good tolerance, which consists of an ACE inhibitor lisinopril and a thiazide-like diuretic indapamide of prolonged action. The authors expressed the opinion that the appointment of the fixed combination drug Diroton Plus (Gedeon Richter) will contribute to effective control of blood pressure and organoprotection in conditions of increased thrombogenic and prooxidative potential, characteristic of COVID-19 both in the acute stage and within the post-COVID Syndrome.

Effects of lisinopril treatment on the pathophysiology of PCOS and plasminogen activator inhibitor-1 concentrations in rats.

RESEARCH QUESTION: Angiotensin-converting enzyme inhibition results in a significant reduction in plasma concentrations of plasminogen activator inhibitor-1 (PAI-1). What are the effects of lisinopril treatment on PAI-1 concentrations and the morphology and function of the ovaries in the letrozole-induced polycystic ovary syndrome (PCOS) rat model? DESIGN: This prospective randomized controlled animal study involved female Wistar albino rats. Twelve rats were assigned as controls (group I). In the study group (n = 48), letrozole (an aromatase inhibitor) was administered for PCOS modelling for 9 weeks. After confirming disrupted oestrous cycles, the study group was randomized into two groups: group II (n = 24; letrozole only) and group III (n = 24; letrozole + lisinopril 15 mg/kg per day). After 12 weeks, each group was divided randomly into two. Biochemical, histopathological and immunohistochemical analyses was performed in subgroups designated A, and fertilization rates were studied in subgroups designated B. RESULTS: Lisinopril treatment reduced the weight and area of the ovaries, the number and wall thickness of cystic follicles, and serum concentrations of LH and testosterone, relative to group II (P < 0.001). Circulating PAI-1 concentrations were significantly different among three groups (7.7 ± 0.9 ng/ml, 9.8 ± 0.7 ng/ml and 8.6 ± 0.7 ng/ml for groups IA, IIA and IIIA; P < 0.001). Pregnancy rates were 100%, 0% and 16.7% in groups IB, IIB and IIIB. CONCLUSIONS: In the letrozole-induced rodent PCOS model, lisinopril modifies the action of letrozole, possibly by inhibition of systemic and ovarian production of PAI-1. The use of PAI-1 inhibitors deserves further investigation in understanding the pathogenesis of PCOS.

Optimizing the Profile of [99mTc]Tc-NT(7-13) Tracers in Pancreatic Cancer Models by Means of Protease Inhibitors.

BACKGROUND: The overexpression of neurotensin subtype 1 receptors (NTS1Rs) in human tumors may be elegantly exploited for directing neurotensin (NT)-based radionuclide carriers specifically to cancer sites for theranostic purposes. We have recently shown that [99mTc]Tc-DT1 ([99mTc]Tc-[N4-Gly7]NT(7-13)) and [99mTc]Tc-DT5 ([99mTc]Tc-[N4-ßAla7,Dab9]NT(7-13)) show notably improved uptake in human colon adenocarcinoma WiDr xenografts in mice treated with neprilysin (NEP) inhibitors and/or angiotensin-converting enzyme (ACE) inhibitors compared with untreated controls. Aiming toward translation of this promising approach in NTS1R-positive pancreatic ductal adenocarcinoma (PDAC) patients, we now report on the impact of registered NEP/ACE inhibitors on the performance of [99mTc]Tc-DT1 and [99mTc]Tc-DT5 in pancreatic cancer models. METHODS: The cellular uptake of [99mTc]Tc-DT1 and [99mTc]Tc-DT5 was tested in a panel of pancreatic cell lines, and their stability was assessed in mice treated or not treated with Entresto, lisinopril, or their combinations. Biodistribution was conducted in severe combined immunodeficiency (SCID) mice bearing pancreatic AsPC-1 xenografts. RESULTS: The Entresto + lisinopril combination maximized the metabolic stability of the fast-internalizing [99mTc]Tc-DT1 in mice, resulting in notably enhanced tumor uptake (7.05 ± 0.80% injected activity (IA)/g vs. 1.25 ± 0.80% IA/g in non-treated controls at 4 h post-injection; p < 0.0001). CONCLUSIONS: This study has shown the feasibility of optimizing the uptake of [99mTc]Tc-DT1 in pancreatic cancer models with the aid of clinically established NEP/ACE inhibitors, in favor of clinical translation prospects.

[The effect of antihypertensive chronotherapy on indicators of the daily blood pressure profile in elderly patients with arterial hypertension with a history of myocardial infarction.]

Traditional treatment regimens for patients with hypertension are not always effective and need to be improved based on the principles of chronobiology. The purpose of this work is to analyze the effect of preventive chronotherapy with amlodipine, lisinopril, and rosuvastatin on daily blood pressure monitoring. In 62 patients with a history of myocardial infarction and hypertension at the age of 60-74, a fixed combination of amlodipine, lisinopril and rosuvastatin at a dose of 5/10/10 mg 2 hours before reaching maximum systolic blood pressure (preventive chronotherapy), in 63 patients with similar diseases and age, this drug is taken at a dose of 5/10/10mg in the evening, and in 58 people - in the morning (traditional treatment). Daily monitoring of blood pressure before and 6 months after treatment was performed by the «SpacelabsMedical¼ device (USA) with the calculation of generally accepted indicators. The greatest effectiveness of preventive chronotherapy in comparison with other treatment options for achieving the target blood pressure level, reducing the time indices and the variability of systolic blood pressure has been established, which allows us to recommend this fixed combination in geriatric practice.

[Standard headache and neuralgia treatments and SARS-CoV-2: opinion of the Spanish Society of Neurology's Headache Study Group]. / Tratamientos habituales utilizados en cefaleas, neuralgias y SARS-CoV-2. Posicionamiento del grupo de estudio de cefaleas de la Sociedad Española de Neurología.

Introduction: In recent months, doubts have arisen among patients, general practitioners, and neurologists as to whether some drugs commonly used in patients with headaches and neuralgia may favour or complicate the disease caused by SARS-CoV-2. Material and methods: We collected information on the opinions of scientific societies and medicines agencies (American, European, and Spanish) to clarify doubts regarding the use of drugs such as lisinopril, candesartan, ibuprofen, corticosteroids, carbamazepine, and monoclonal antibodies targeting the calcitonin gene-related peptide in the context of the COVID-19 pandemic. Results: We make recommendations about the use of standard headache treatments in the context of the COVID-19 pandemic, based on the current scientific evidence. Conclusions: At present, there is no robust scientific argument to formally contraindicate any of the standard treatments employed for headaches and neuralgias.

Predicting response to lisinopril in treating hypertension: a pilot study.

INTRODUCTION: Only ~ 50% of hypertensive patients will respond to treatment. OBJECTIVE: This pilot study aims to identify clinical and metabolite markers that predict response to lisinopril. METHODS: Hypertensive patients (n = 45) received lisinopril (10 mg) at their baseline visit. Blood pressures were reevaluated one week later. Responders to lisinopril (n = 19) were defined by a 10% decline in systolic blood pressure. Plasma metabolites were evaluated with mass spectrometry. RESULTS: BMI (p = 0.009), GFR (p = 0.015) and 2-oxoglutarate were included in a logistic regression model to predict response to lisinopril. CONCLUSIONS: Further validation cohorts are needed to confirm the predictive values of these clinical and metabolic markers.