Impact of Green Tea Catechin Ingestion on the Pharmacokinetics of Lisinopril in Healthy Volunteers.

Lisinopril, a highly hydrophilic long-acting angiotensin-converting enzyme inhibitor, is frequently prescribed for the treatment of hypertension and congestive heart failure. Green tea consumption may reduce the risk of cardiovascular outcomes and total mortality, whereas green tea or its catechin components has been reported to decrease plasma concentrations of a hydrophilic ß blocker, nadolol, in humans. The aim of this study was to evaluate possible effects of green tea extract (GTE) on the lisinopril pharmacokinetics. In an open-label, randomized, single-center, 2-phase crossover study, 10 healthy subjects ingested 200 mL of an aqueous solution of GTE containing ~ 300 mg of (-)-epigallocatechin gallate, a major catechin component in green tea, or water (control) when receiving 10 mg of lisinopril after overnight fasting. The geometric mean ratio (GTE/control) for maximum plasma concentration and the area under the plasma concentration-time curve of lisinopril were 0.289 (90% confidence interval (CI) 0.226-0.352) and 0.337 (90% CI 0.269-0.405), respectively. In contrast, there were no significant differences in time to reach maximum lisinopril concentration (6 hours in both phases) and renal clearance of lisinopril (57.7 mL/minute in control vs. 56.9 mL/minute in GTE). These results suggest that the extent of intestinal absorption of lisinopril was significantly impaired in the presence of GTE, whereas it had no major effect on the absorption rate and renal excretion of lisinopril. Concomitant use of lisinopril and green tea may decrease oral exposure to lisinopril, and therefore result in reduced therapeutic efficacy.

Prediction of lisinopril pediatric dose from the reference adult dose by employing a physiologically based pharmacokinetic model.

BACKGROUND: This study aimed to assess the pediatric lisinopril doses using an adult physiological based pharmacokinetic (PBPK) model. As the empirical rules of dose calculation cannot calculate gender-specific pediatric doses and ignores the age-related physiological differences. METHODS: A PBPK model of lisinopril for the healthy adult population was developed for oral (fed and fasting) and IV administration using PK-Sim MoBI® and was scaled down to a virtual pediatric population for prediction of lisinopril doses in neonates to infants, infants to toddler, children at pre-school age, children at school age and the adolescents. The pharmacokinetic parameters were predicted for the above groups at decremental doses of 20 mg, 10 mg, 5 mg, 2.5 mg, and 1.5 mg in order to accomplish doses producing the pharmacokinetic parameters, similar (or comparable) to that of the adult population. The above simulated pediatric doses were compared to the doses computed using the conventional four methods, such as Young's rule, Clark's rule, and weight-based and body surface area-based equations and the dose reported in different studies. RESULTS: Though the doses predicted for all subpopulations of children were comparable to those calculated by Young's rule, yet the conventional methods overestimated the pediatric doses when compared to the respective PBPK-predicted doses. The findings of previous real time pharmacokinetic studies in pediatric patients supported the present simulated dose. CONCLUSION: Thus, PBPK seems to have predictability potential for pediatric dose since it takes into consideration the physiological changes related to age and gender.

Assessment of Drug-Drug Interactions between Taspoglutide, a Glucagon-Like Peptide-1 Agonist, and Drugs Commonly Used in Type 2 Diabetes Mellitus: Results of Five Phase I Trials.

BACKGROUND AND OBJECTIVE: Taspoglutide, a glucagon-like peptide-1 agonist, like native glucagon-like peptide-1, delays gastric emptying time and prolongs intestinal transit time, which may alter the pharmacokinetics of concomitantly administered oral drugs. The effect of taspoglutide on the pharmacokinetics of five oral drugs commonly used in patients with type 2 diabetes mellitus was assessed in healthy subjects. METHODS: Five clinical pharmacology studies evaluated the potential drug-drug interaction between multiple subcutaneous taspoglutide doses and a single dose of lisinopril, warfarin, and simvastatin and multiple doses of digoxin and an oral contraceptive containing ethinylestradiol and levonorgestrel. The extent of interaction was quantified using geometric mean ratios and 90% confidence intervals for the maximum plasma concentration and area under the plasma concentration-time curve. In addition to pharmacokinetics, pharmacodynamic effects were assessed for warfarin and the oral contraceptive. RESULTS: Among the tested drugs, the effect of taspoglutide on the pharmacokinetics of simvastatin was most pronounced, on the day of taspoglutide administration, the average exposure to simvastatin was decreased by - 26% and - 58% for the area under the plasma concentration-time curve and maximum plasma concentration, respectively, accompanied by an increase in average exposure to its active metabolite, simvastatin ß-hydroxy acid (+ 74% and + 23% for area under the plasma concentration-time curve and maximum plasma concentration, respectively). Although statistically significant changes in exposure were observed for other test drugs, the 90% confidence intervals for the geometric mean ratio for maximum plasma concentration and area under the plasma concentration-time curve were within the 0.7-1.3 interval. No clinically relevant changes on coagulation (for warfarin) and ovulation-suppressing activity (for the oral contraceptive) were apparent. CONCLUSION: Overall, multiple doses of taspoglutide did not result in changes in the pharmacokinetics of digoxin, an oral contraceptive containing ethinylestradiol and levonorgestrel, lisinopril, warfarin, and simvastatin that would be considered of clinical relevance. Therefore, no dose adjustments are warranted upon co-administration.

Effect of Oral Semaglutide on the Pharmacokinetics of Lisinopril, Warfarin, Digoxin, and Metformin in Healthy Subjects.

BACKGROUND: Oral semaglutide is a tablet co-formulation of the human glucagon-like peptide-1 (GLP-1) analog semaglutide with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). The absorption of coadministered oral drugs may be altered due to enhancement by SNAC, potential gastric emptying delay by semaglutide, or other mechanisms. Two one-sequence crossover trials investigated the effect of oral semaglutide on the pharmacokinetics of lisinopril, warfarin, digoxin, and metformin. METHODS: In trial 1, 52 healthy subjects received lisinopril (20 mg single dose) or warfarin (25 mg single dose) with subsequent coadministration with SNAC alone (300 mg single dose), followed by oral semaglutide 20 mg once daily (steady state). In trial 2, 32 healthy subjects received digoxin (500 µg single dose) or metformin (850 mg twice daily for 4 days), with subsequent coadministration with SNAC alone followed by oral semaglutide, as in trial 1. RESULTS: There were no apparent effects of oral semaglutide on area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) for lisinopril, warfarin, and digoxin. The AUC of metformin was increased by 32% (90% confidence interval 1.23-1.43) by oral semaglutide coadministration versus metformin alone, whereas the Cmax was unaffected. SNAC alone did not affect exposure of lisinopril, warfarin, digoxin, or metformin. Adverse events were in line with those previously observed for GLP-1 receptor agonists. CONCLUSIONS: Oral semaglutide or SNAC alone did not appear to affect the exposure of lisinopril, warfarin, or digoxin, and, based on its wide therapeutic index, the higher metformin exposure with oral semaglutide was not considered clinically relevant.

Effect on the Gastrointestinal Absorption of Drugs from Different Classes in the Biopharmaceutics Classification System, When Treating with Liraglutide.

Like other GLP-1 receptor agonists used for treatment of type 2 diabetes, liraglutide delays gastric emptying. In this clinical absorption study, the primary objective was to investigate the effect of liraglutide (at steady state) on the rate and/or extent of gastrointestinal (GI) absorption of concomitantly orally taken drugs from three classes of the Biopharmaceutics Classification System (BCS). To provide a general prediction on liraglutide drug-drug absorption interaction, single-dose pharmacokinetics of drugs representing BCS classes II (low solubility-high permeability; atorvastatin 40 mg and griseofulvin 500 mg), III (high solubility-low permeability; lisinopril 20 mg), and IV (low solubility-low permeability; digoxin 1 mg) were studied in healthy subjects at steady state of liraglutide 1.8 mg, or placebo, in a two-period crossover design. With liraglutide, the oral drugs atorvastatin, lisinopril, and digoxin showed delayed tmax (by ≤2 h) and did not meet the criterion for bioequivalence for Cmax (reduced Cmax by 27-38%); griseofulvin had similar tmax and 37% increased Cmax. Although the prespecified bioequivalence criterion was not met by all drugs, the overall plasma exposure (AUC) of griseofulvin, atorvastatin, lisinopril, and digoxin only exhibited minor changes and was not considered to be of clinical relevance.

Angiotensin Converting Enzyme Inhibitor Dialyzability and Outcomes in Older Patients Receiving Hemodialysis.

BACKGROUND/AIMS: Some angiotensin converting enzyme (ACE) inhibitors are efficiently removed from circulation by hemodialysis ('high dialyzability'), whereas others are not ('low dialyzability'). In patients receiving hemodialysis, this may influence the effectiveness of ACE inhibitors. METHODS: Using linked healthcare databases we identified older patients receiving chronic hemodialysis who filled new ACE inhibitor prescriptions. The low dialyzability group (n = 3,369) included fosinopril and ramipril. The high dialyzability group (n = 5,974) included enalapril, lisinopril, and perindopril. The primary outcome was all-cause mortality within 180 days of first ACE inhibitor prescription. RESULTS: There were 361 deaths among 5,974 patients (6.0%) prescribed with low dialyzability ACE inhibitors and 179 deaths among 3,369 patients (5.3%) prescribed with high dialyzability ACE inhibitors (relative risk 1.1, 95% CI 0.9-1.3, p = 0.6). CONCLUSION: In this study of older patients receiving hemodialysis, the dialyzability of ACE inhibitors was not associated with mortality or cardiovascular outcomes.

Design of a Dissolving Microneedle Platform for Transdermal Delivery of a Fixed-Dose Combination of Cardiovascular Drugs.

Microneedles (MNs) are a minimally invasive drug delivery platform, designed to enhance transdermal drug delivery by breaching the stratum corneum. For the first time, this study describes the simultaneous delivery of a combination of three drugs using a dissolving polymeric MN system. In the present study, aspirin, lisinopril dihydrate, and atorvastatin calcium trihydrate were used as exemplar cardiovascular drugs and formulated into MN arrays using two biocompatible polymers, poly(vinylpyrrollidone) and poly(methylvinylether/maleic acid). Following fabrication, dissolution, mechanical testing, and determination of drug recovery from the MN arrays, in vitro drug delivery studies were undertaken, followed by HPLC analysis. All three drugs were successfully delivered in vitro across neonatal porcine skin, with similar permeation profiles achieved from both polymer formulations. An average of 126.3 ± 18.1 µg of atorvastatin calcium trihydrate was delivered, notably lower than the 687.9 ± 101.3 µg of lisinopril and 3924 ± 1011 µg of aspirin, because of the hydrophobic nature of the atorvastatin molecule and hence poor dissolution from the array. Polymer deposition into the skin may be an issue with repeat application of such a MN array, hence future work will consider more appropriate MN systems for continuous use, alongside tailoring delivery to less hydrophilic compounds.

Ordering of the Serum Angiotensin-Converting Enzyme Test in Patients Receiving Angiotensin-Converting Enzyme Inhibitor Therapy: An Avoidable but Common Error.

BACKGROUND: Serum angiotensin-converting enzyme (ACE) levels may be decreased by use of ACE inhibitor (ACEI) medication. In this study, we determined how often ACE levels were measured in patients receiving ACEI therapy. METHODS: ACE levels analyzed over a 54-month preintervention time period at an academic medical center were reviewed retrospectively for tests performed during ACEI therapy. These data were compared with a large, deidentified dataset of ACE levels measured at a national reference laboratory; in vitro studies of ACEI inhibition; and liquid chromatography time-of-flight mass spectrometry detection of lisinopril in a subset of clinical specimens. RESULTS: Over a 54-month period, 1,292 patients had ACE levels measured, with 108 patients (8.4%) receiving ACEI therapy at the time of testing. ACE levels measured for patients receiving ACEI therapy were substantially lower. In general, clinical teams did not recognize a medication effect on ACE levels. Introduction of a warning prompt in the electronic health record reduced the ordering of ACE levels in patients receiving ACEIs by > 60% in a 17-month postintervention time period. The deidentified dataset of ACE levels at a reference laboratory showed a bimodal distribution, with a peak of very low ACE levels. Using liquid chromatography time-of-flight mass spectrometry, the presence of lisinopril was confirmed in a subset of specimens with low ACE activity. In vitro studies of two different ACE assays showed significant inhibition of activity at clinically relevant concentrations. CONCLUSIONS: Assessment of ACE activity is often measured for patients receiving ACEIs, potentially leading to low ACE concentrations and inaccurate interpretations.

Pharmacokinetics, Pharmacodynamics, and Safety of Lisinopril in Pediatric Kidney Transplant Patients: Implications for Starting Dose Selection.

Hypertension in pediatric kidney transplant recipients contributes to long-term graft loss, yet treatment options--including angiotensin-converting enzyme inhibitors--are poorly characterized in this vulnerable population. We conducted a multicenter, open-label pharmacokinetic (PK) study of daily oral lisinopril in 22 children (ages 7-17 years) with stable kidney transplant function. Standard noncompartmental PK analyses were performed at steady state. Effects on blood pressure were examined in lisinopril-naïve patients (n = 13). Oral clearance declined in proportion to underlying kidney function; however, in patients with low estimated glomerular filtration rate (30-59 ml/min per 1.73m(2)), exposure (standardized to 0.1 mg/kg/day dose) was within the range reported previously in children without a kidney transplant. In lisinopril-naïve patients, 85% and 77% had a ≥ 6 mmHg reduction in systolic and diastolic blood pressure, respectively. Lisinopril was well tolerated. Our study provides initial insight on lisinopril use in children with a kidney transplant, including starting dose considerations.

[A fixed-dose lisinopril and amlodipine combination in conjunction with rosuvastatin in patients with hypertensive disease and coronary heart disease].

AIM: To evaluate the efficacy and safety of a fixed-dose combination of the angiotensin-converting enzyme inhibitor lisinopril 10 mg and the calcium antagonist amlodipine 5 mg (ekvator) in conjunction with rosuvastatin (mertenil). SUBJECTS AND METHODS: The investigation enrolled 50 patients (mean age 57.9 years) with essential hypertension. All the patients received the fixed-dose antihypertensive combination. Stable Functional Class I or II exertional angina was in 46% of the patients. The remaining 54% were found to have brachiocephalic atherosclerosis. All the patients had dyslipidemia and were given rosuvastatin. RESULTS: The mean systolic blood pressure (SBP) initially reached 164.26 mm Hg. During the whole follow-up, the reduction in mean SBP generally accounted for 22.6% (p = 0.000). At the study inclusion, the mean diastolic blood pressure (DBP) reached 99.38 mm Hg. The total decline in mean DBP was 19.3% (p = 0.000). The mean level of total cholesterol (TC) decreased significantly by 32.1% (p = 0.000); that of triglycerides (TG) also fell significantly by 31.8% (p = 0.04); that of high-density lipoproteins increased insignificantly by 11.1% (p = 0.599); that of low-density lipoproteins (LDL) dropped significantly by 47.5% (p = 0.000). CONCLUSION: Being safe, the fixed-dose lisinopril and amlodipine combination is effective in lowering blood pressure in patients with hypertensive disease (HD) concurrent with coronary heart disease (CHD) or atherosclerotic changes in the carotid artery. The use of rosuvastatin in patients with HD concurrent with CHD during 2 months causes positive changes in the blood lipid composition as a significant reduction in the-levels of (TC), LDL, and TG.

Pharmacokinetic evaluation of lisinopril-tryptophan, a novel C-domain ACE inhibitor.

Angiotensin-converting enzyme (ACE, EC 3.4.15.1) is a metallopeptidase comprised of two homologous catalytic domains (N- and C-domains). The C-domain cleaves the vasoactive angiotensin II precursor, angiotensin I, more efficiently than the N-domain. Thus, C-domain-selective ACE inhibitors have been designed to investigate the pharmacological effects of blocking the C-terminal catalytic site of the enzyme and improve the side effect profile of current ACE inhibitors. Lisinopril-tryptophan (LisW-S), an analogue of the ACE inhibitor lisinopril, is highly selective for the C-domain. In this study, we have analysed the ex vivo domain selectivity and pharmacokinetic profile of LisW-S. The IC50 value of LisW-S was 38.5 nM in rat plasma using the fluorogenic substrate Abz-FRKP(Dnp)P-OH. For the pharmacokinetics analysis of LisW-S, a sensitive and selective LC-MS/MS method was developed and validated to determine the concentration of LisW-S in rat plasma. LisW-S was administered to Wistar rats at a dose of 1 mg/kg bodyweight intravenously, 5 mg/kg bodyweight orally. The Cmax obtained following oral administration of the drug was 0.082 µM and LisW-S had an apparent terminal elimination half-life of around 3.1 h. The pharmacokinetic data indicate that the oral bioavailability of LisW-S was approximately 5.4%. These data provide a basis for better understanding the absorption mechanism of LisW-S and evaluating its clinical application.

[Effect of combination antihypertensive therapy on circadian blood pressure and metabolic parameters in patients with type 2 diabetes mellitus].

AIM: To assess effect of combined antihypertensive therapy with lisinopril and amlodipine on circadian blood pressure (BP), insulin resistance (IR), carbohydrate and lipid metabolism in patients with arterial hypertension (AH) and type 2 diabetes mellitus (DM). MATERIAL AND METHODS: Combination of amlodipine (6.0±0.4 mg/day) and lisinopril (12.0±0.9 mg/day) was given to 30 patients (age 40-65 years) with stage I-II AH and DM type 2) for 24 weeks. All patients underwent ambulatory BP monitoring. Parameter studied comprised glucose levels, glycosylated hemoglobin (HbAlc), basal insulin, lipid profile in the venous blood and insulin resistance (IR). All patients received glucose-lowering drugs and followed diet recommendations. RESULTS: All patients achieved target BP values and concentrations of HbAlc. After 24 weeks of treatment the following parameters were significantly different from baseline values: mean systolic BP (SBP) (-15.6%), mean diastolic BP (DBP), (-16.2%), time index (pressure load--PL) SBP day (-50.1%), PL DBP day (-51.3), PL DBP night (-59.2%), SBP variability (-15.8%), values of morning SBP and DBP increase (both -41.8%), rates of morning rise of SBP (-74.1%) and DBP (-65.8%), percentage of patients with increased variability of SBP (-36.7%), of DBP (- 23.3%), of SBP day (-36.7%), of DBP day (-30.0%). Significant decreases of fasting blood glucose level (-22.1%), concentrations of total cholesterol (-8.8%), low density lipoprotein cholesterol (-15%), triglycerides (-4.4%), and metabolic index (-32.7%) were also observed. CONCLUSION: In patients with hypertension and type 2 DM 24 week antihypertensive therapy with lisinopril and amlodipine significantly improved circadian blood pressure profile, reduced severity of IR without negative effect on carbohydrate and lipid metabolism.

[Potentialities of medicinal correction of cerebrovascular disturbances in patients with arterial hypertension].

The use of up-to-date diagnostic methods for the examination of 72 patients presenting with grade II-III arterial hypertension and high risk of cardiovascular complications made it possible to estimate the state of brachiocephalic arteries before and after combined antihypertensive therapy that continued during 14 days. The following variables were measured: blood flow rate, peripheral vascular resistance indices at the extra- and intracranial levels, metabolic indices of cerebrovascular responsiveness, and coefficient of variability as an indicator of the cerebrovascular reserve capacity under conditions of antihypertensive treatment. Three antihypertensive therapeutic regimens were employed, viz. lisinopril plus indapamide, bisoprolol plus indapamide, and amlodipine plus indapamide. It was shown that all the three regimen resulted in positive changes in the parameters of blood flow and peripheral vascular resistance. At the same time, the use of amlodipine plus indapamide ensured a more gradual reduction of peripheral vascular resistance and the most pronounced increase of cerebrovascular reserve capacity compared with the two remaining regimens. It is concluded that the parameters of peripheral vascular resistance and metabolic indices of cerebrovascular responsiveness are the most sensitive and informative end points for the pharmacotherapeutic treatment of cerebral hemodynamics in the patients presenting with grade II-III arterial hypertension and high risk of development of cardiovascular complications.

Lisinopril pharmacokinetics and erythropoietin requirement in haemodialysis patients.

BACKGROUND: There is ongoing controversy whether angiotensin-converting enzyme inhibitors (ACE-I) contribute to anaemia by causing hyporesponsiveness to erythropoiesis-stimulating agents (ESA). However, it is unknown whether or not plasma levels or area under the curve (AUC) of ACE-I are associated with responsiveness to ESA therapy. MATERIALS AND METHODS: We examined the association between lisinopril AUC, lisinopril plasma levels and ESA requirements that was assessed using an ESA index [(ESA IU/week/body weight kg)/(haemoglobin g/dL)]. After screening 184 haemodialysis patients, 14 fulfilled the inclusion criteria, mainly long-term use of oral lisinopril in the upper end of dosage range for this population with stable haemoglobin levels and intravenous ESA therapy. Lisinopril plasma levels were measured at eight different time points (predialysis, immediate post-dialysis and hourly for 6h thereafter; AUC1), and the seven post-dialysis lisinopril plasma levels were used for calculation of AUC2. RESULTS: The mean ESA index of all patients was 27·90±25·84 (IU/week/kg)/(g/dL). Average lisinopril AUC1 was 1212·48±1209·75 [mg*h/L], whereas AUC2 averaged 947·67±977·07 [mg*h/L]. Two patients (14%) had no detectable lisinopril plasma levels, indicating their noncompliance. There was no association between ESA index and AUC or plasma levels of lisinopril at any time point for all 14 or for the 12 compliant patients. CONCLUSIONS: Our study shows that long-term, high-dose lisinopril therapy has no effect on ESA responsiveness. Thus, avoidance or a dose reduction of ACE-I in dialysis patients will not necessarily lead to reduced ESA requirements and costs.

Quantitative determination of lisinopril in human plasma by high performance liquid chromatography-tandem mass spectrometry and its application in a pharmacokinetic study.

A rapid, selective and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed to determine lisinopril in human plasma. Sample pretreatment involved a one-step protein precipitation with methanol of 0.1 mL plasma. Analysis was performed on an Inertsil ODS-3 column (2.1 × 50 mm i.d., 3 µm) with mobile phase consisting of methanol-water (containing 0.2% formic acid; 55:45, v/v). The detection was performed on a triple quadrupole tandem mass spectrometer in multiple reaction monitoring mode via an electrospray ionization source. Each plasma sample was chromatographed within 2.5 min. The linear calibration curves for lisinopril were obtained in the concentration range of 1.03-206 ng/mL (r(2) ≥ 0.99) with a lower limit of quantification of 1.03 ng/mL. The intra- and inter-day precisions (relative standard deviation) were not higher than 11%, and accuracy (relative error) was within ±6.8%, determined from quality control samples for lisinopril, which corresponded to the guidance of the Food and Drug Administration. The method described herein was fully validated and successfully applied to the pharmacokinetic study of lisinopril tablets in healthy male volunteers after oral administration.

Pharmacokinetics of the combined preparation of lisinopril and hydrochlorothiazide on Chinese healthy volunteers.

The aim of the present study, performed on two different groups of volunteers, is to characterize the pharmacokinetics of lisinopril/hydrochlorothiazide combined tablet. After administration of high, medium and low doses of lisinopril/hydrochlorothiazide combined tablets, AUC and C(max) of two compounds both increase significantly with increase of dose. Neither normalized AUC/Dose nor C(max)/Dose has significant difference between every two tested dose groups. The similar results can be observed as for the parameters of t(max). Lisinopril and hydrochlorothiazide are both eliminated with linear characteristics. After repeated administration of lisinopril/hydrochlorothiazide combined tablets, AUC, C(max) and C(min) of lisinopril in the steady state increase. AUC and C(min) increase significantly. As for hydrochlorothiazide, AUC, C(max), C(min), and t(max) also increase in steady state. AUC and C(min) increase significantly. Administered with the test medication, lisinopril has an fluctuation index (FI) value of 2.29 and reaches a relative steady concentration. But hydrochlorothiazide has an FI value of 4.09 with relatively large fluctuating concentrations.

Effects of ACE inhibitors on cardiac angiotensin II and aldosterone in humans: "Relevance of lipophilicity and affinity for ACE".

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors differ in their lipophilic/hydrophilic index that determines their tissue bioavailability and affinity to ACE, which may result in major differences in the degree of blockade of cardiac ACE. We evaluated the hypothesis that in patients with chronic heart failure (CHF) and activated cardiac renin-angiotensin-aldosterone system (RAAS), lipophilic ACE inhibitors with high affinity for ACE (perindopril and quinapril) will cause marked blockade of cardiac angiotensin (Ang) II and aldosterone generation, but not a hydrophilic ACE inhibitor with low affinity for ACE (lisinopril). METHODS: Patients were randomized to receive perindopril (8 mg/day), quinapril (40 mg/day), or lisinopril (20 mg/day) for 3-4 weeks before cardiac catheterization. The coronary sinus-aortic root gradients for Ang I and II, and aldosterone were determined. RESULTS: A total of 19 patients completed the study. Compared to a healthy control group, all three ACE inhibitors decreased circulating Ang II and aldosterone to a similar extent. There were only minor differences between the three ACE inhibitors for the Ang II gradient between the coronary sinus and aortic root. The gradient for aldosterone tended to be positive in the quinapril group and absent/negative in the lisinopril and perindopril groups. Despite the lowest pulmonary capillary wedge pressure (PCWP), gradients between the coronary sinus and aortic root for Ang II and aldosterone were actually the highest in the quinapril group. CONCLUSIONS: These findings do not support the concept that a hydrophilic ACE inhibitor is less effective in blocking the cardiac RAAS as compared to lipophilic ACE inhibitors.

Iontophoretic delivery of lisinopril: Optimization of process variables by Box-Behnken statistical design.

The objective of the investigation was to optimize the iontophoresis process parameters of lisinopril (LSP) by 3 x 3 factorial design, Box-Behnken statistical design. LSP is an ideal candidate for iontophoretic delivery to avoid the incomplete absorption problem associated after its oral administration. Independent variables selected were current (X(1)), salt (sodium chloride) concentration (X(2)) and medium/pH (X(3)). The dependent variables studied were amount of LSP permeated in 4 h (Y(1): Q(4)), 24 h (Y(2): Q(24)) and lag time (Y(3)). Mathematical equations and response surface plots were used to relate the dependent and independent variables. The regression equation generated for the iontophoretic permeation was Y(1) = 1.98 + 1.23X(1) - 0.49X(2) + 0.025X(3) - 0.49X(1)X(2) + 0.040X(1)X(3) - 0.010X(2)X(3) + 0.58X(1)(2) - 0.17X(2)(2) - 0.18X(3)(2); Y(2) = 7.28 + 3.32X(1) - 1.52X(2) + 0.22X(3) - 1.30X(1)X(2) + 0.49X(1)X(3) - 0.090X(2)X(3) + 0.79X(1)(2) - 0.62X(2)(2) - 0.33X(3)(2) and Y(3) = 0.60 + 0.0038X(1) + 0.12X(2) - 0.011X(3) + 0.005X(1)X(2) - 0.018X(1)X(3) - 0.015X(2)X(3) - 0.00075X(1)(2) + 0.017X(2)(2) - 0.11X(3)(2). The statistical validity of the polynomials was established and optimized process parameters were selected by feasibility and grid search. Validation of the optimization study with 8 confirmatory runs indicated high degree of prognostic ability of response surface methodology. The use of Box-Behnken design approach helped in identifying the critical process parameters in the iontophoretic delivery of lisinopril.

Evaluation of some pharmaceutical formulations of lisinopril through dissolution testing.

AIM: Lisinopril is a drug of the angiotensin converting enzyme (ACE) inhibitor class that is primarily used in treatment of hypertension, congestive heart failure, heart attacks and also in preventing renal and retinal complications of diabetes. We compared the dissolution profiles of Lisinopril 20 mg tablets (Antibiotice S.A. lasi) and Zestril 20 mg tablets (Astra Zeneca). MATERIAL AND METHOD: Because lisinopril is a third class active substance, we performed dissolution tests in standard media at three pH values: 1.2, 4.5 and 6.8 using the paddle apparatus at 75 rpm. RESULTS: Both pharmaceutical formulations present a dissolution percentage more than 85% (Q) of the labeled amount. CONCLUSION: Both pharmaceutical formulations present similar dissolution profile. Key words:

The effect of exenatide on lisinopril pharmacodynamics and pharmacokinetics in patients with hypertension.

OBJECTIVES: This study evaluated the potential effect of exenatide on the pharmacokinetics and pharmacodynamics of lisinopril in patients with mild-to-moderate hypertension. METHODS: 22 patients with mild-to-moderate primary hypertension participated in a double-blind, randomized, placebo-controlled, 2-period, 2-sequence crossover study. Patients on stable lisinopril therapy were randomly assigned to receive subcutaneous exenatide (10 microg b.i.d.) and placebo b.i.d. separated by at least 2 days washout period. The primary pharmacodynamic parameters were baseline-adjusted 24-hour mean systolic and diastolic blood pressure. Steady state plasma lisinopril concentration-time profiles were also assessed. RESULTS: Mean blood pressure changes were not significantly different between exenatide and placebo coadministered with lisinopril. The least squares mean differences (95% CI) between treatments were +1.38 mmHg (-1.41, 4.17) for diastolic and +1.38 mmHg (-1.95, 4.71) for systolic blood pressure. Exenatide delayed the time to attain maximum lisinopril concentration (tmax,ss) by 2 hours but did not significantly alter maximum lisinopril concentration (Cmax,ss) or area under the concentration-time profile (AUCtau,ss) over the 24-hour steady-state dosing interval. CONCLUSIONS: This study demonstrated that concurrent administration of exenatide did not produce clinically relevant changes in blood pressure and did not significantly alter lisinopril pharmacokinetics in patients with mild-to-moderate hypertension.