Simultaneous determination of indapamide, perindopril and its active metabolite perindoprilat in human plasma using UPLC-MS/MS method.

Lots of studies showed the combination therapy of perindopril, indapamide and amlodipine could increase BP lowering efficacy and the benefits of high-risk patients. To evaluate potential pharmacokinetic interaction, a simultaneous UPLC-MS/MS quantification method of perindopril, perindoprilat and indapamide in human plasma was developed and validated. The plasma samples were prepared by solid phase extraction, and then separated on an X-terra MS C18 (2.1 mm × 150 mm, 3.5 µm) with isocratic elution. The ion transitions at m/z 369.165 â†’ 172.000 (perindopril), m/z 341.146 â†’ 170.112 (perindoprilat), m/z 366.010 â†’ 132.100 (indapamide), m/z 389.120 â†’ 206.200 (S10211-1, IS1) and m/z 394.080 â†’ 160.200 (S1641, IS2) were monitored under the positive ion mode of electrospray ionization with multiple reaction monitoring. This method exhibited great sensitivity, linearity, accuracy, and precision for the determination of perindopril, perindoprilat and indapamide over the range of 0.250-50.0 ng/mL. The average extraction recovery of perindopril, perindoprilat and indapamide samples at low, medium, and high concentration levels were between 85.9% and 93.6%, respectively. The stability of analytes over different storage and processing conditions in the whole study was also validated. The method is fast, accurate, sensitive and reproducible, which is suitable for the detection of the concentration of perindopril, perindoprilat and indapamide in human plasma.

Bioequivalence study of two perindopril tert-butylamine tablet formulations in healthy Chinese subjects under fasting and fed conditions: A randomized, open-label, single-dose, crossover trial.

BACKGROUND: To evaluate the bioequivalence between test and reference formulations of perindopril tert-butylamine under fasting and fed conditions and to assess their pharmacokinetic (PK) and safety profiles. METHOD: A randomized, open-label, single-dose, crossover trial was conducted in healthy Chinese subjects. Test or reference perindopril tert-butylamine tablets (4 mg) were randomly given to subjects under fasting (2-period crossover, with an administration sequence of test tablet (T), reference tablet (R) or RT) and fed (4-period crossover, with an administration sequence of TRTR or RTRT) conditions, while each single administration was followed by a 14-day washout period. The plasma concentrations and corresponding non-compartmental PK parameters of perindopril and perindoprilat were determined. The two formulations were considered to be bioequivalent if the 90 % confidence intervals (CIs) of the geometric mean (GM) ratio (test/reference) for Cmax, AUC0-t, and AUC0-∞ (perindopril) was both within the range of 80-125 %. Safety assessments including vital signs, physical examination, laboratory examination, 12-lead ECG and reports of treatment emergent adverse events (TEAEs) were carefully documented. RESULTS: A total of 64 subjects (32 in each trial) were randomized and all completed the trials. Regardless of fasting or fed trials, the PK characteristics of perindopril and perindoprilat for the test formulation were similar to those of the reference formulation (all P > 0.05). The 90 % CIs of the geometric mean (GM) ratio for Cmax, AUC0-t, and AUC0-∞, respectively, were 92.86-106.81 %, 98.44-102.88 % and 98.48-103.02 % under the fasting condition and 90.64-110.04 %, 96.95-101.90 % and 96.83-101.78 % under the fed condition, which were both within the pre-specified range of 80-125 %. A total of 10 (31.3 %) fasted subjects and 11 (34.4 %) fed subjects experienced 11 and 24 TEAEs, respectively, all of which were within the severity of grade 1. The incidence of TEAEs and drug-related TEAEs were similar between test and reference formulations (all P > 0.05) and no serious TEAEs or deaths occurred during the trials. CONCLUSIONS: The test and reference formulations of perindopril tert-butylamine tablets (4 mg) were bioequivalent and well tolerated in healthy Chinese subjects under fasting and fed conditions.

Determination of amlodipine, indapamide and perindopril in human plasma by a novel LC-MS/MS method: Application to a bioequivalence study.

A robust and rapid UPLC-MS/MS method has been developed, optimized and validated for determination of amlodipine (AML), indapamide (IND) and perindopril (PRN) in human plasma. A positive electrospray ionization mode was used in a Xevo TQD LC-MS/MS instrument. A single sample preparation step using extraction technique was applied to extract the three analytes from plasma samples. There was no need to extract indapamide from blood samples in a further step. Extraction of the three drugs and internal standards was done using a solvent mixture composed of methyl tertiary butyl ether, dichloromethane and ethyl acetate. The prepared samples were analyzed using an Acquity UPLC HSS C18 (100 × 2.1 mm, 1.7 µm) column. Ammonium acetate and methanol, pumped at a flow rate of 0.3 ml/min, were used as a mobile phase. Method validation was done as per the US Food and Drug Administration guidelines. Linearity was achieved in the range of 0.2-15 ng/ml for AML, 0.5-50 ng/ml for IND and 0.5-120 ng/ml for PRN. Accuracy and precision were estimated and found to be within the acceptable ranges. The rapid chromatography permits analysis of many samples per batch, making the method suitable for clinical and pharmacokinetic investigations. The developed and validated method was applied to estimate AML, IND, and PRN in a fasting bioequivalence study in healthy human volunteers.

Myocardial blood flow in patients with hypertrophic cardiomyopathy receiving perindopril (CARAPaCE): a pilot study.

AIMS: Coronary microvascular dysfunction (CMD) represents a powerful independent predictor of adverse outcome in hypertrophic cardiomyopathy (HCM). No treatment for CMD exists. The angiotensin-converting enzyme (ACE)-inhibitor perindopril improves myocardial blood flow (MBF) in animal models of cardiac hypertrophy and in hypertensive patients. Whether HCM patients with CMD may benefit is unknown. METHODS: Fourteen HCM patients aged 18-60 years with CMD [MBF post 0.56 mg/kg dipyridamole (Dip) infusion <2.1 ml/min∗g] were included. Presence of left ventricular outflow obstruction, hypertension and coronary artery disease were exclusion criteria. Perindopril was administered after the initial Dip 13N-NH3 PET study at 10 mg for 6 months. After wash-out, a second PET was performed. MBF before and after treatment was compared. RESULTS: No relevant associations were found between baseline MBF values and sex, genetics, history of angina, type of HCM (apical/classic), maximum left ventricular thickness and left ventricular mass. No significant improvement in Dip-MBF was observed with treatment (1.79 ±â€Š0.30 vs.1.76 ±â€Š0.26 ml/min∗g at baseline; P = 0.59). A limited but significant improvement in Dip-MBF was seen only in the subset without evidence of fibrosis at cardiac MRI (n = 4; 28%; 2.03 ±â€Š0.13 vs.1.77 ±â€Š0.26 ml/min∗g at baseline; P = 0.014). The drug was generally well tolerated: only one patient temporarily stopped the drug, because of cough. CONCLUSION: A 6-month perindopril treatment course in HCM patients with CMD was not associated with significant improvement in Dip-MBF. A limited but significant improvement was observed only in the subset of patients without myocardial fibrosis, suggesting potential utility in early disease stages.

A UPLC-MS/MS method for quantification of perindopril and perindoprilat and applied in a bioequivalence study for their pharmacokinetic parameter measurement
.

OBJECTIVES: To investigate the pharmacokinetic parameters of perindopril and perindoprilat in healthy volunteers, a simple and sensitive UPLC-MS/MS method with isotope-labeled internal standards of perindopril-d4 and perindoprilat-d4 was established and further applied in a bioequivalence study. MATERIALS AND METHODS: A simple and sensitive UPLC-MS/MS method with isotope-labeled internal standards of perindopril-d4 and perindoprilat-d4 was validated and applied in a single-center, randomized, cross-over, and two-period bioequivalence study. 20 healthy Chinese subjects (16 males and 4 females) were enrolled and had their plasma concentrations of perindopril and perindoprilat quantified and calculated for the pharmacokinetic parameters. After acetonitrile precipitation, the analytes and internal standards were gradient eluted with methanol-acetonitrile-ammonium acetate on an Acquity UPLC BEH C18 (2.1 × 50 mm, 1.7 µm) column. Detection was carried out in a multireaction monitoring mode using positive ionization electrospray mass spectrometry. RESULTS: The total chromatographic run time was 4 minutes with retention time for perindopril and perindopril-d4 of ~ 1.86 minutes, whereas perindoprilat and perindoprilat-d4 was ~ 1.79 minutes. The calibration curves of perindopril and perindoprilat were linear over 0.4 - 80 ng/mL and 0.2 - 40 ng/mL, respectively. The method was fully validated to meet the requirement for bioassay in accuracy (89.6 - 112.4%), precision (coefficient of variation (CV) ≤ 13.8%), recovery (79.65 - 97.83%), matrix effect (CV ≤ 5.9%), and stability (CV ≤ 10.0%). The 90% confidence intervals (CIs) for the geometric mean ratios of Cmax, AUC0-tlast, and AUC0-∞ of perindopril and perindoprilat all fell within the bioequivalence acceptance criteria (80 - 125%). There were no significant differences between the two formulations in terms of tmax and T1/2 of perindopril and perindoprilat. There was no adverse event in this clinical study. Interestingly, it was found that the pharmacokinetics of perindoprilat in 1 subject were significantly different from that of the others which may be associated with genetic diversity. CONCLUSION: This method was successfully applied to the bioequivalence test of two perindopril tert-butylamine tablets. The two one-sided t-tests showed that these two products were bioequivalent.

Thiolation of arabinoxylan and its application in the fabrication of pH-sensitive thiolated arabinoxylan grafted acrylic acid copolymer.

Current research work was conducted to synthesize Thiol modified arabinoxylan and its application in fabrication of hydrogel. Thioglycolic acid was esterified with arabinoxylan to prepare Thiolatedarabinoxylan. Appearance of peak at 2533.34 cm-1 in FTIR and thiol content showed successful thiolation. The pH-dependent Thiolatedarabinoxylan/acrylic acid (TAX/AA) hydrogels of perindopril erbumine were prepared via free-radical co-polymerization. Perindopril erbumine (PE) was employed as model drug. Different batches with different feed ratio of TAX, AA, and MBA were prepared and their influence on swelling, solvent penetration, and consequent drug release was investigated. Swelling coefficients increased with increase in pH. TAX/AA hydrogels were characterized by Fourier-transform infrared spectroscopy (FT-IR), Thermal Analysis (TA), X-Ray diffraction (XRD), and scanning electron microscope (SEM). Dissolution studies were performed at pH 1.2 and 7.4 in which drug release showed direct correlation with TAX and AA ratio. In vivo studies showed that Cmax of TAX-co-AA based hydrogel was 81.57 ± 0.35 ng/ml which was maintained for a longer time after its administration. All the results of in vivo studies were significant and TAX-co-AA based hydrogel enhances the bioavailability of perindopril erbumine.

Combination Antihypertensive Therapy with Perindopril and Indapamide in Patients with Essential Hypertension: Effect on Endothelial and Cognitive Markers of Vascular Improvement.

INTRODUCTION: The objective of this study was to assess the impact of a single-pill combination (SPC) of perindopril/indapamide (PER/IND) at full doses (10/2.5 mg) on endothelial and cognitive function as a clinical intermediate marker of vascular improvement. METHODS: This open-label, uncontrolled, observational study enrolled 30 patients (20 females and 10 males) with grade II-III uncontrolled arterial hypertension (SBP/DBP ≥ 160/100 mmHg) and no evidence of cerebrovascular disease. All patients underwent assessment of macro- and microvascular endothelial function parameters at baseline and after 12 months of treatment with SPC PER/IND using photoplethysmography and video capillaroscopy. Cognitive function was assessed using the Montreal Cognitive Assessment scale (MoCA). RESULTS: All patients (mean age 60.06 ± 10.19 years) were at high risk for cardiovascular events: mean body mass index (BMI) 31.2 ± 3.9 kg/m2, 33% diagnosed with coronary artery disease angina class I, 30% with impaired glucose tolerance, and 7% with type 2 diabetes. Impaired endothelial function was observed at the both micro- and macrovascular levels. Endothelial function parameters improved after 12-month treatment with SPC PER/IND with an increase in occlusion index from 1.4 to 1.8 (P < 0.00005) and phase shift from 5.0 to 10.8 (P < 0.00001); all values achieved levels in the normal range. Resting capillary network density (CND) increased from 44.8 to 52 cap/mm2 (P < 0.00007), and CND after a venous occlusion test increased from 55 to 61 cap/mm2 (P < 0.006). Signs of cognitive impairment were present at baseline with a mean MoCA score of 23 (normal cognitive function score ≥ 26), but improved after 12-month treatment with a mean MoCA score of 27 (P< 0.0001). Treatment was well tolerated. CONCLUSION: SPC PER/IND at full doses for 12 months improves endothelial function, structural and functional parameters of the microcirculation, as well as cognitive function in patients with arterial hypertension at high cardiovascular risk. FUNDING: Les Laboratoires Servier.

The Influence of Microneedles on the Percutaneous Penetration of Selected Antihypertensive Agents: Diltiazem Hydrochloride and Perindopril Erbumine.

BACKGROUND: It is well documented in the scientific literature that high blood pressure can lead to cardiovascular disease. Untreated hypertension has clinical consequences such as coronary artery disease, stroke or kidney failure. Diltiazem hydrochloride (DH), a calcium-channel blocker, and perindopril erbumine (PE), an inhibitor of the angiotensin converting enzyme are used for the management of hypertension. OBJECTIVE: This project will examine the effect of microneedle rollers on the transport of DH and PE across pig ear skin. The use of the transcutaneous route of administration reduces and in sometimes eliminates the trauma and pain associated with injections. Furthermore, there is increased patient compliance. The purpose of this project was to study the effect of stainless steel microneedles on the transdermal delivery of DH and PE. METHOD: We utilized vertical Franz diffusion cells to study in vitro transport of DH and PE across microneedle- treated pig ear skin. Confocal laser scanning microscopy (CLSM) was used to characterize microchannel depth. Transdermal flux values were determined from the slope of the linear portion of the cumulative amount versus time curve. RESULTS: There was a 113.59-fold increase in the transdermal permeation of DH following the application of microneedle roller compared to passive diffusion. CONCLUSION: In the case of PE, there was an 11.99-fold increase in the drug transport across pig skin following the application of microneedle rollers in comparison with passive diffusion. Student's t-test and Mann-Whitney's rank sum test were used to determine statistically significant differences between experimental and control groups.

Investigation of a potential pharmacokinetic interaction between perindopril arginine and amlodipine when administered as a single perindopril/amlodipine fixed-dose combination tablet in healthy Chinese male volunteers.

OBJECTIVES: To determine whether a potential pharmacokinetic interaction exists between perindopril arginine 5 mg and amlodipine 5 mg, after administration as a fixed-combination of perindopril 5 mg/amlodipine 5 mg (S05985). METHODS: A total of 30 subjects was enrolled into this single center, open-label, randomized, 3-period cross-over study and was randomized to receive 1 tablet of S05985, 1 tablet of perindopril tert-butylamine 4 mg, or 1 tablet of amlodipine 5 mg. The doses of both perindopril salts correspond to 3.34 mg of perindopril expressed as free acid. Serial blood samples were collected in each treatment period for determination of plasma amlodipine, perindopril, and perindoprilat concentrations and for calculation of the respective pharmacokinetic parameters (AUC(0-∞), AUC(0-t), C(max), and t(max)). Statistical analyses of the pharmacokinetic parameters included ANOVA and calculations of 90% confidence intervals for the ratio of the geometric means for Cmax, AUC(0-t), and AUC(0-∞). Safety was also assessed. RESULTS: A total of 29 subjects completed the study per protocol. There was no serious adverse event. All 90% confidence intervals for C(max), AUC(0-t), and AUC(0-∞) for perindopril, perindoprilat, and amlodipine were within the limits (80.00 - 125%), indicating that both treatments were bioequivalent. CONCLUSION: These results indicate that no drug-drug interaction exists after single-dose oral administration of S05985 (perindopril 5 mg and amlodipine 5 mg) when compared to single-dose administration of each component alone, i.e., perindopril tert-butylamine 4 mg and amlodipine 5 mg, given separately.

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.

Investigation into the interchangeability of generic formulations using immunosuppressants and a broad selection of medicines.

PURPOSE: To date, the interchangeability of generic drugs has only been investigated for a limited number of medicines. The objective of this study was to investigate generic-generic drug interchangeability in a large subset of generic formulations in order to cover a broad spectrum of drugs. METHODS: Orally administered drugs for investigation in this study were selected using strict, predefined criteria, with the purpose to avoid bias. This selection procedure yielded atorvastatin, bicalutamide, naratriptan, olanzapine, perindopril, and venlafaxine. Further, ciclosporin, tacrolimus, and mycophenolate mofetil were investigated as test immunosuppressants. Adjusted indirect comparisons were conducted between generic drugs containing the same active substance, and the 90% confidence interval (CI) for AUC and Cmax was calculated. RESULTS: In total, 120 bioequivalence studies were identified in the Dutch medicine regulatory agency's database, allowing 292 indirect comparisons between generic drugs. The indirect comparison results indicated that in the vast majority of cases, i.e., 80.5%, the 90% CIs for both AUCt and Cmax fell within the bioequivalence criteria (in 90.1 and 87.0% for AUCt and Cmax, respectively). In 1% of the 292 indirect comparison for AUCt and 3% for Cmax, a wider range of 75-133% (or 80-125%) was exceeded. CONCLUSIONS: Overall, our study suggests that exposure-related risks associated with the exchange of different generic drugs in clinical practice are not increased to a relevant extent compared to the situation in which a generic is exchanged with the innovator.

Development and in vitro/in vivo evaluation of immediate release perindopril tablets.

Perindopril erbumine (PE) is a BCS (Biopharmaceutics Classification System) class 3 drug with high solubility and low permeability. It is an inhibitor of the enzyme that converts angiotensin I (Angiotensin Converting Enzyme, ACE) into angiotensin II as well as causing the degradation of the vasodilator bradykinin into an inactive heptapeptide. The aim of this study was to develop an alternative drug product by using a different salt of perindopril and to evaluate the bioequivalence between PE, not still licensed, and perindopril arginine (PA), licensed in many countries, and to prepare PE tablets by using direct compression method. Many different formulations were prepared, among which F3-coded formulation was only selected due to releasing of 98.03% active substance at 45th minute. Bioequivalence study was planned as a cross-designed, randomized, open-labeled, single-dose, single-center study and conducted in 24 male healthy volunteers via peroral route. The results of bioequivalence study were evaluated for Perindopril and Perindoprilat according to Cmax, tmax and AUC criteria. The geometric mean ratios (90% CI) of perindopril and perindoprilat followed test and reference drug were calculated for AUC0-t and Cmax, 105.946% (100.218-112.002%) and 110.437% (102.534-118.948%); 109.542% (98.364-121.992%) and 115.729% (101.031-132.565%), respectively. The 90% confidence intervals of them were found within the standard bioequivalence range (80-125%).

[Direct comparison of endothelial and metabolic effects of perindopril combination with indapamide retard or hydrochlorothiazide].

OBJECTIVE: Our aim was to compare changes of vascular and metabolic parameters in patients with essential hypertension on treatment with combination of perindopril with either indapamide retard or hydrochlorothiazide. METHODS: The study involved 40 patients who were randomly assigned to perindopril 5-10 mg/day in combination with indapamide retard (P+I) 1.5 mg/day (n = 20) or with hydrochlorothiazide (P+HT) 25 mg/day (n=20). Waist circumference, body mass index, blood lipids and glucose, endothelial function (EF) determined as the change of resistance index after inhalation of salbutamol, arterial stiffness measured as mean pulse wave velocity after sublingual trinitroglycerin (PWVtng) were evaluated at baseline and 6 months thereafter. Vascular responses were calculated from digital pulse waves registered using photoplethysmography. RESULTS: Dynamics of BP after 6 months did not differ significantly between groups. Treatment with combination of P+HT resulted in significant decrease of EF (-24,3%, p<0,05) accompanied by negative changes of triglycerides (+13,4%, p<0,05) and glucose levels (+9,8%, p<0,05), whereas combination of P+I did not affect endothelial function and was metabolically neutral. PWVtng significantly decreases on both regiments of treatment with the trend in favor of P+I combination (-13,4%, p<0,001 versus -9,8%, p<0,01 for P+I and P+HT combinations, respectively). CONCLUSION: Thus, despite the similar BP reduction the combination of ACE-inhibitor--perindopril with indapamide retard possesses more favorable vascular and metabolic effects compared to combination with hydrochlorothiazide that potentially may account for different prognosis of patients with arterial hypertension on long-term treatment.

[Perindopril in the treatment of hypertension and cardiovascular diseases: evolution continues with the orodispersible dosage form]. / Perindopril v lécbe hypertenze a kardiovaskulárních chorob: evoluce pokracuje orodisperzní formou.

Perindopril is a long acting ACE inhibitor with a 24- hour lasting effect. Its positive effect on a reduction in cardiovascular events has been confirmed in a range of large randomized clinical trials and in a wide spectrum of patients: hypertonic patients, diabetics, patients with stable ischaemic heart disease, elderly patients, or patients who have undergone a cerebrovascular accident. The extending range of various fixed combinations as well as new pharmaceutical dosage forms, including the newly introduced orodispersible tablets of perindopril, enables optimization of treatment for every patient, an increase in the patients treatment adherence, and also improvement in longterm blood pressure control with a consequent effect on reduction of morbidity and mortality.

Leave-one-out procedure in the validation of elimination rate constant analysis.

Many registration agencies and other organizations define how to calculate the elimination rate constant (kel) value. No validation procedures have been introduced to verify the correct selection of the concentration-time (C-T) points used for the kel calculation. The purpose of this paper is to discover whether kel analysis can be subjected to the condensed validation procedure and what acceptance criteria should be adopted for such a procedure. For the analysis, data collected during bioequivalence studies of 4 drugs were selected, including 2 highly lipophilic drugs (itraconazole, atorvastatin) and 2 weakly lipophilic drugs (trimetazidine, perindopril). Pharmacokinetic calculations were performed with the use of WinNonlin Professional v 5.3. Internal validation of the kel analysis using leave-one-out cross-validation was performed. The present analysis proves that the C-T selection process for the kel calculations cannot be automated. In each of the analysed data series there were such C-T sequences that did not meet even one of the validation criteria. This paper proposes 3 validation criteria which need to be met in order to confirm the optimal selection of C-T data to calculate kel: Q 2≥0.6, R2≥ 0.85, Q 2-R2<0.3, were Q 2 - squared cross-validated correlation coefficient, R2 - coefficient of determination). Application of the validation procedure for the kel analysis under discussion proves the accuracy of the calculations, even if repeated kel analysis is based on a different sequence of points in the elimination phase.

[Vascular effects of perindopril arginine and indapamide fixed combination in patients with arterial hypertension].

The aim of the study was to investigate the dynamics of arterial stiffness and endothelial function parameters under the influence of perindopril arginine and indapamide fixed combination in arterial hypertension (AH) patients. 30 persons with 1-3 degree AH were included into the study. The treatment duration was 24 weeks. Central aortic blood pressure (BP), augmentation pressure and index (AIx), carotid-femoral and carotid-radial pulse wave velocity (PWV), brachial artery endothelium-dependent vasodilatation (EDVD), office and ambulatory BP as well as orthostatic BP falls were evaluated under the influence of selected therapy. 27 patients completed the study protocol. Results showed that aortic systolic BP was significantly reduced by 10.7 mmHg, augmentation pressure - by 3.6 mmHg and AIx - by 6.5%. Carotid-radial PWV decreased by 0.8 m/s. Carotid-femoral PWV did not change. We also revealed the EDVD increase by week 12. The EDVD growth was correlated with degree of aortic systolic BP reduction (r=-0.48, p=0.02). Office and ambulatory BP declined by 15.8/10.0 and 10.0/7.5 mmHg respectively. The target BP <140/90 mmHg was achieved in 20 (74.1%) persons. At the same time the orthostatic hypotension did not rise. Conclusion. We concluded that perindopril arginine/indapamide fixed combination improved vascular function in hypertensive patients by wave reflection reduction, peripheral arterial stiffness lowering and endothelial function improvement.

Comparative study of Mg/Al- and Zn/Al-layered double hydroxide-perindopril erbumine nanocomposites for inhibition of angiotensin-converting enzyme.

The intercalation of a drug active, perindopril, into Mg/Al-layered double hydroxide for the formation of a new nanocomposite, PMAE, was accomplished using a simple ion exchange technique. A relatively high loading percentage of perindopril of about 36.5% (w/w) indicates that intercalation of the active took place in the Mg/Al inorganic interlayer. Intercalation was further supported by Fourier transform infrared spectroscopy, and thermal analysis shows markedly enhanced thermal stability of the active. The release of perindopril from the nanocomposite occurred in a controlled manner governed by pseudo-second order kinetics. MTT assay showed no cytotoxicity effects from either Mg/Al-layered double hydroxide or its nanocomposite, PMAE. Mg/Al-layered double hydroxide showed angiotensin-converting enzyme inhibitory activity, with 5.6% inhibition after 90 minutes of incubation. On incubation of angiotensin-converting enzyme with 0.5 µg/mL of the PMAE nanocomposite, inhibition of the enzyme increased from 56.6% to 70.6% at 30 and 90 minutes, respectively. These results are comparable with data reported in the literature for Zn/Al-perindopril.

[Remodeling of vascular bed in patients with arterial hypertension: possibilities of diagnostics and correction].

Arterial hypertension determines the remodeling of the vascular bed at all levels, resulting in a high risk of developing cardiovascular complications. Recent studies performed on the basis of evidence-based medicine, demonstrated the high efficiency of the combination drug therapy with perindopril and amlodipine in preventing such complications. This may be due to the positive influence of a fixed combination of these drugs on the parameters of the state of the microcirculatory level of the vascular bed.

Controlled release and angiotensin-converting enzyme inhibition properties of an antihypertensive drug based on a perindopril erbumine-layered double hydroxide nanocomposite.

BACKGROUND: The intercalation of perindopril erbumine into Zn/Al-NO(3)-layered double hydroxide resulted in the formation of a host-guest type of material. By virtue of the ion-exchange properties of layered double hydroxide, perindopril erbumine was released in a sustained manner. Therefore, this intercalated material can be used as a controlled-release formulation. RESULTS: Perindopril was intercalated into the interlayers and formed a well ordered, layered organic-inorganic nanocomposite. The basal spacing of the products was expanded to 21.7 Å and 19.9 Å by the ion-exchange and coprecipitation methods, respectively, in a bilayer and a monolayer arrangement, respectively. The release of perindopril from the nanocomposite synthesized by the coprecipitation method was slower than that of its counterpart synthesized by the ion-exchange method. The rate of release was governed by pseudo-second order kinetics. An in vitro antihypertensive assay showed that the intercalation process results in effectiveness similar to that of the antihypertensive properties of perindopril. CONCLUSION: Intercalated perindopril showed better thermal stability than its free counterpart. The resulting material showed sustained-release properties and can therefore be used as a controlled-release formulation.

[Efficiency perindopril at patients with arterial hypertension and obesity].

We gave perindopril (10 mg/day) for 24 weeks to 30 patients with arterial hypertension and obesity and proved its ability to effectively lower arterial pressure, exert cardio-, angio-, and nephro-protection, improve parameters of lipid, carbohydrate and purine metabolisms in these patients. Moreover perindopril in these patients diminished manifestations of insulin resistance, hyperleptinemia, and inflammation; it also exerted pronounced positive effect on anthropometric parameters and percent of fat deposits. Basing on the aggregate of clinical and pharmacodynamics effects perindopril can be considered the drug of choice for treatment of arterial hypertension at the background of obesity.