Enalapril Maleate Research Articles

Synthesis of diketopiperazine: A kinetic study by means of thermoanalytical methods

The enalapril maleate (EM) decomposition to diketopiperazine was monitored in helium flow by thermogravimetry at different heating rates between 0.2 and 5 °C min −1. The activation energy value was obtained (198 kJ mol −1) from the Kissinger–Akahira–Sunose isoconversional method. Isothermal experiments were simulated (125, 130, 135 and 155 °C) using the model-free method, employing only the activation energy value. The reaction model of the process was studied by means of the master-plot method. The reaction mechanism depends on the temperature; for experiments below 235 °C, the probable mechanism is nucleation. Instead, when the temperature overcomes the EM melting point, the reaction occurs in liquid state and its kinetics is better described by first order reaction. To avoid the complexity of model changes, experimental results are fitted using the model-free method.

Efficacy and safety of a fixed-dose combination of lercanidipine and enalapril in daily practice. A comparison of office, self-measured and ambulatory blood pressure

Background: A fixed-dose combination (FDC) of enalapril and lercanidipine has been shown to be effective and safe in reducing blood pressure in randomized clinical trials. This study aims to determine effectiveness and safety in daily practice.Methods: This was a prospective, open-label, uncontrolled multicenter study, with a 3-month follow-up at general practitioners and internists. Patients were treated with an FDC of 20 mg enalapril maleate and 10 mg lercanidipine hydrochloride, and blood pressure was determined in the office (OBPM) and by discretionary self- (SBPM) and ambulatory- (ABPM) measurements.Results: Out of 622 patients (mean age 61.3 ± 13.3 years, 54.2% male): blood pressure was reduced by -29.2/-14.2 mmHg (OBPM) from baseline (164.4/95.2 mmHg). Pulse pressure was reduced by -15.0 ± 16.4 mmHg. Prevalence of microalbuminuria was reduced from 14.6% at baseline to 6.5% (p < 0.001). SBPM data were available for 71% of patients and ABPM for 12%. In the latter patients, blood pressure variability index was significantly reduced compared with baseline over 24 h (14.2 ± 4.2 vs 16.3 ± 4.0; p < 0.001) and with nighttime ABPM (13.7 ± 4.9 vs 15.2 ± 4.4; p = 0.022). Treatment was associated with a low incidence of adverse events (3.4%).Conclusions: The FDC of 20 mg enalapril-maleate and 10 mg lercanidipine-hydrochloride seems to be effective and well tolerated in clinical practice. It improved vascular surrogate end points, including pulse pressure, blood pressure variability and microalbuminuria.

Clinical evaluation of enalapril maleate and furosemide usage in dogs with degenerative myxomatous mitral valve, CHF functional class Ib

Degenerative myxomatous mitral valve (DMMV) is a heart disease of high incidence in small animal clinical medicine, affecting mainly older dogs and small breeds. Thus, a scientific investigation was performed in order to evaluate the clinical use of the medicines furosemide and enalapril maleate in dogs with this disease in CHF functional class Ib before and after the treatment was established. For this purpose 16 dogs with the given valve disease were used, separated into two groups: the first received furosemide (n=8) and the second received enalapril maleate (n=8) throughout 56 days. The dogs were evaluated in four stages (T0, T14, T28 and T56 day) in relation to clinical signs, hematological, biochemical and serum assessment, which included serum angiotensin converting enzyme (ACE) and aldosterone, as well as radiography, electrocardiography, Doppler-echocardiography and blood pressure. The results regarding the clinical, hematological and serum chemistry evaluations revealed no significant changes in both groups, but significant reductions in the values of ACE and aldosterone in the group receiving enalapril maleate were verified. The radiographic examination revealed reductions of VHS values and variable Pms wave of the electrocardiogram in both groups, but no changes in blood pressure values were identified. The echocardiogram showed a significant decrease of the variables LVDd/s in the studied groups and the FS% in animals that received only enalapril. Therefore, analysis of results showed that monotherapy based on enalapril maleate showed better efficiency of symptoms control in patients with CHF functional class Ib.

Adsorption Studies of Enalapril Maleat in Solution on Selected Iraqi Clays

The possibilities of using locally available two Iraqi clays kaolin and attapulgite are have been investigated for adsorption of model drug solution of enalapril maleate. U.V. spectrophotometric technique has been utilized to produce quantitative adsorption data at different temperatures. The effect of acidity on the quantity adsorbed of this drug was investigated at Ph = 1.2 in an attempt to simulate the acidity of gastric fluid and at neutral pH. The possible effect of ionic strength on the amount of drug being adsorbed was studied using normal saline at different concentrations. The equilibrium adsorption contact times were determined for both two adsorbents used adsorption isotherms have been analyzed by the Freundlich and Langmuir models. The results of these studies demonstrated that enalapril maleate is adsorbed by both kaolin and attapuligate surfaces, and these two surfaces can be used as a physical antidotes against poisoning by the above drug overdose in vitro.

A comparative study of complexation of enalapril with α-, β- and γ-cyclodextrins in aqueous medium: structure elucidation of inclusion complexes using NMR spectroscopic and molecular mechanics methods

Structural studies of complexes of enalapril maleate with α-, β- and γ-cyclodextrins were carried by NMR spectroscopy and computational methods. The formation of complexes of enalapril with all the three cyclodextrins was established by chemical shift changes observed in the cavity protons of cyclodextrins in the presence of enalapril maleate. The stoichiometry of the complexes was determined to be 1:1 by 1H NMR titrations studies using Scott’s method. Intermolecular cross peaks observed in the 2D ROESY spectra of mixtures of enalapril maleate with three cyclodextrins helped in establishing the probable structures of these inclusion complexes which were supported by molecular mechanics (MM2) studies. Enalapril forms 1:1 inclusion complex with all the studied cyclodextrins through aromatic ring. The mode of approach of aromatic ring to the α-cyclodextrin cavity was found to be different from those of β- and γ-cyclodextrins, which were identical.

Relevance of air-to-liquid mass ratio effect on final granule properties of an Enalapril maleate formulation

Background: In the production of enalapril maleate tablets, the granulation process is the most crucial step. Numerous variables are known to influence the fluid bed granulation process and thus the final granule quality. In this study a novel descriptor for the nozzle parameter “air-to-liquid mass ratio” is presented. Granules manufacturing processes were designed by application of statistical experimental design.Aim: The influence of the critical process parameter (CPP)—air-to-liquid mass ratio—on pharmaceutic properties of granules was studied. Air-to-liquid mass ratio can be considered as important variable influencing the droplet size of atomized liquid binder solution.Results/Conclusion: A significant influence of air-to-liquid mass ratio on granule final particle size distribution was found. Increasing air-to-liquid mass ratio resulted in increased granules particle size distribution. Decreasing air-to-liquid mass ratio led to granules with reduced tapped density. Thus, it can be concluded that the parameter “air-to-liquid mass ratio” is a critical process parameter in the production of enalapril maleate granules.

Enalapril:β-CD complex: Stability enhancement in solid state

Complexation of enalapril maleate with β-cyclodextrin was used to overcome the known enalapril maleate–excipient interaction in solid state. The complex formation was characterized by 13C solid state nuclear magnetic resonance, X-ray powder diffraction and scanning electron microscopy. Additionally, thermogravimetric analysis (TGA) was used to evaluate the compatibility between magnesium stearate with enalapril maleate alone or in the complex form. Degradation of the drug at 40°C/75% relative humidity in the presence of magnesium stearate was monitored by high performance liquid chromatography (HPLC). Enalapril maleate in the complex form was more stable than the drug alone, with the drug recovery after 6 month being: 95±1% and 82.1±0.5%, respectively. This satisfactory high stability of the enalapril:β-CD complex will be potentially useful for its application as solid pharmaceutical dosage products.

Fast gradient high performance liquid chromatography method with UV detection for simultaneous determination of seven angiotensin converting enzyme inhibitors together with hydrochlorothiazide in pharmaceutical dosage forms and spiked human plasma and urine

The development of a reversed phase liquid chromatographic method for the simultaneous determination of seven angiotensin converting enzyme (ACE) inhibitors; five drugs namely benazepril HCl (BZL), enalapril maleate (ENL), fosinopril sodium (FSP), lisinopril (LSP) and ramipril (RMP) and two metabolites captopril disulfide (CPD) and enalaprilat (ENT) together with hydrochlorothiazide (HCT) is described. The method can serve as a substitute for many published papers for the analysis of the targeted compounds with or without hydrochloothiazide in pharmaceutical formulations as well as in spiked human plasma and urine samples. The method utilizes a simple gradient procedure for the separation in a 11min run time using acetonitrile aqueous ammonia buffer (pH 9) solution and an Extend RP-C18 (25μm particle size, 4.6mm×250mm, Agilent) HPLC column. The effluent was monitored on a UV detector at 215nm. The effect of pH, solvent strength and analysis time on the peak shape and quantification were carefully studied in order to optimize the method. Adopting the proposed procedure, the analytes produce well-shaped peaks with good linear relationship over the investigated concentration ranges. The limits of detection (LOD) and limits of quantification (LOQ) from standard drug solutions lie in the range of 17–64 and 56–212ngmL−1, respectively. Correlation coefficient values (r) higher than 0.997 were obtained for all the studied drugs in spiked human plasma and urine samples. The intra-day and inter-day precision of the method was evaluated with relative standard deviation values being satisfactory for their purposed analysis. The method was validated with respect to specificity, recovery, accuracy, precision and linearity.

Rapid and sensitive liquid chromatography/tandem mass spectrometry method for simultaneous determination of enalapril and its major metabolite enalaprilat, in human plasma: Application to a bioequivalence study

A rapid and most sensitive method for simultaneous determination of enalapril (ENP) and its metabolite, enalaprilat (ENPT), in human plasma using ESI-LC-MS/MS (electrospray ionization liquid chromatography tandem mass spectrometry) positive ion multiple reactions monitoring (MRM) mode, was developed and validated. The procedure involves a simple solid-phase extraction (SPE) followed by evaporation of the sample. Chromatographic separation was carried out on a Hypurity C(18) column (50 mm × 4.6 mm, 5 µm) with an isocratic mobile phase and a total run time of 2.0 min only. The MRM of ENP and ENPT is 377.10 → 234.20 and 349.20 → 206.10 respectively. The standard calibration curves showed excellent linearity within the range of 0.064 to 431.806 ng/mL for ENA and 0.064 to 431.720 ng/mL for ENPT (r ≥ 0.990). This is the only method which can quantitate upto 0.064 ng/mL for both ENP and ENPT in a single run with the shortest analysis time. In matrix effect experiment, this method shows a % CV (% coefficients of variation) of less than 5, which means that the proposed method is free from any kind of irregular ionization process. This method was successfully applied to a pharmacokinetic study after oral administration of enalapril maleate 20 mg tablet in Indian healthy male volunteers.

ALTERAÇÕES ELETROCARDIOGRÁFICAS DE UM CÃO COM ESTENOSE DE VALVA PULMONAR, ANTES E APÓS TERAPIA A BASE DE MALEATO DE ENALAPRIL E ATENOLOL

The pulmonary valve stenosis is a congenital heart malformation characterized by impairment in the outflow of the right ventricle leading to clinical signs of congestive heart failure (CHF). Therefore, the objective was to report the electrocardiogram (ECG) changes of a female 8 months old dog, poodle, with asymptomatic stenosis of the pulmonary valve before and after therapy the basis of enalapril and atenolol. Physical examination was observed tachycardia and pulmonary systolic murmur grade V / VI and tricuspid grade III / VI, with the diagnosis confirmed through radiographic, ECG and echocardiographic examinations, and therapy based on enalapril maleate (0.50 mg / kg) once daily and atenolol (0.25 mg / kg) every 12 hours, both orally. Initially, the ECG showed sinus tachycardia (250 bpm) and an increase in amplitude of the waves PmV, SmV and TmV, suggesting atrial and right ventricular myocardial hypoxia, cardiac axis deviation to the right. At 15, 90, 120 and 210 days of therapy subsequent ECGs showed sinus rhythm with a gradual reduction in heart rate and amplitude values of P waves, S and TmV. The changes described suggest improvement of the electrocardiographic tracing due to the reduction in pre-and post-cardiac load, obtained through therapy. Therefore, we concluded that the ECG performed during the seven months subsequently showed electrocardiographic changes that demonstrate the benefits of therapy based on enalapril maleate associated with atenolol in the dog with pulmonary valve stenosis.

Optimisation and validation of liquid chromatographic and partial least-squares-1 methods for simultaneous determination of enalapril maleate and nitrendipine in pharmaceutical preparations

AbstractSimultaneous determination of enalapril maleate (ENA) and nitrendipine (NIT) in pharmaceutical preparations was performed using liquid chromatography (LC) and the partial least-squares-1 (PLS-1) method. In LC, the separation was achieved on a C8 column and the optimum mobile phase for good separation in a gradient elution programme was found to be acetonitrile-water (φ r = 81: 19) and optimum flow-rate, temperature, injection volume, and detection wavelength were set at 1.0 mL min−1, 25°C, 10 μL, and 210 nm, respectively. Dienogest was selected as an internal standard. In the spectrophotometry, a PLS-1 chemometric method was used. The absorbance data matrix related to the concentration data matrix was established by measurement of absorbances in their zero order spectra with an increment of Δλ = 1 nm in the 220–290 nm range for ENA and with Δλ = 1 nm in the 230–290 nm range for NIT in the PLS-1 method. Following this step, calibration was established by using this data matrix to predict the unknown concentrations of ENA and NIT in their binary mixture. These optimised methods were validated and successfully applied to a pharmaceutical preparation in tablet form and the results were subjected to comparison.

SPECTROPHOTOMETRY MICRODETERMINATION OF SOME ANTIHYPERTENSIVE DRUGS IN PURE FORM AND IN PHARMACEUTICAL FORMULATIONS

Simple, rapid, accurate, precise and sensitive spectrophotometric method for the microdetermination of enalapril maleate (ENM) and lisinopril dihydrate (LIS) has been developed. The method is based on oxidation of the drug by potassium permanganate in acidic medium and determine the unreacted oxidant by measuring the decrease in absorbance for three different acidic dyes; acid red 73 (AR), amaranth dye [acid red 27] (AM) and acid orange 7 (AO) at a suitable λ max (510, 521 and 484 nm for ENM and 509, 521 and 485 nm for LIS), respectively. Regression analysis of Beer’s law plots showed good correlation in the concentration ranges 0.7–12, 0.5–7.6 and 0.6–9.5 µg mL–1 and 0.5–9.0, 0.4–6.1 and 0.4–7.2 µg mL–1 for ENM and LIS using AR, AM and AO, respectively. The apparent molar absorptivity, Sandell sensitivity, detection and quantitation limits are calculated. Statistical treatment of the results reflects that the proposed procedures are precise, accurate and easily applicable for the determination of ENM and LIS in pure and in pharmaceutical preparations.

Chemical stability of enalapril maleate drug substance and tablets by a stability-indicating liquid chromatographic method

The chemical stability of enalapril drug substance and tablets was studied by a stability-indicating liquid chromatographic method. Stress testing was performed on drug substance under various conditions. Accelerated stability testing was carried out for different formulations of enalapril tablets. Chromatographic separation was achieved on a RP-18 column, using a mobile phase of methanol phosphate buffer at 1.0 mL min1 and UV detection. Degradation of the drug substance was greater under hydrolytic conditions. After 180 days of accelerated stability testing most enalapril tablets showed more than 10% of degradation. Enalapril drug substance and tablets showed instability under stress and accelerated testing respectively, with possible implications on the therapeutic activity.

SIMULTANEOUS IN VITRO HPLC DETERMINATION OF ENALAPRIL MALEATE AND LERCANIDIPINE HCL

A reversed-phase liquid chromatographic (RP-HPLC) method was developed for the simultaneous determination of a binary mixture of enalapril maleate and Lercanidipine HCl in pure form, synthetic mixture, and synthetic tablets. The analysis was carried out using Hibar® C18, pre-packed column. Mobile phase, containing acetonitrile:methanol:water:orthophosphoric acid (35:35:30:0.2) adjusted to pH 3.0 with triethylamine, was pumped at a flow rate of 1.0 mL min−1 with UV-detection at 210 nm. The method showed good linearity in the range of 5.0–100.0 μg mL−1 for both drugs. The detection limit of the proposed method was 0.80 and 0.93 μg mL−1, and the quantitation limit was 2.42 and 2.80 μg mL−1 for ENM and LER, respectively.

Possible pharmacological interactions in hypertensive and/or diabetic elderly in family health units at Blumenau (SC)

The aim of this study was to examine the possible adverse drug-drug interactions in the elderly population (&gt;60 years) diagnosed either with diabetes, arterial hypertension or both, at a Family Health Unit (FHU) clinic in Blumenau, state of Santa Catarina, Brazil. For this purpose 318 subjects were interviewed using a pretested form with social and demographic aspects regarding their disease and its complications. All drugs used by this population were grouped, and the drug-drug interactions were detected by using the "Drug Interaction Checker" software, and classified for frequency and severity. The average age of patients was 70.6 years, with a higher number of female patients (216; 67.9%). Most subjects were being treated for both diseases (149; 46.86%). Out of a total of 1,541 medications prescribed, the most prevalent were: hydrochlorothiazide (131; 8.4%) and enalapril maleate (130; 8.4%). A total of 295 possible drug-drug interactions were detected in 152 patients (1.9 interactions per subject), 275 (93.2%) moderate and 20 (6.8%) severe or highly severe. The possible interaction prevalence was 0.93 (0.55 to 1.40 depending on health unit). The most frequent possible interaction was that between acetylsalicylic acid and enalapril maleate (37; 12.5%). Patients had an average consumption of 6.6 drugs and 9.8% of subjects reported physical discomfort when using medicines. Elderly patients use many medications that could cause adverse reactions and possible drug-drug interactions, where this issue warrants closer attention of prescribers and health providers.

Linking a pharmaceutical claims database with a birth defects registry to investigate birth defect rates of suspected teratogens

Data linkage of population administrative data is being investigated as a tool for pharmacovigilance in pregnancy in Australia. Records of prescriptions of known or suspected teratogens dispensed to pregnant women have been linked to a birth defects registry to determine if defects associated with medicine exposure can be detected. The Pharmaceutical Benefits Scheme is a national claims database that has been linked with population-based data to extract linkages for women with a pregnancy event in Western Australia from 2002 to 2005 (n = 106 074). Records of births to the women who were dispensed medicines in categories D or X of the Australian ADEC pregnancy risk category were linked to the Birth Defects Registry of Western Australia. Population rates of registered birth defects per 1000 births were calculated for each medicine. There were 47 medicines dispensed at least once during pregnancy with 23 associated with a registered birth defect to a woman dispensed the medicine. When the birth defect rate for each medicine was compared with the rate for all other women not dispensed that medicine, most medicines showed an increased risk. Medicines with the higher risks were medroxyprogesterone acetate (OR: 1.8; 95%CI: 1.4-2.3), follitropin alfa (OR: 2.5; 95%CI: 1.2-5.0), carbamazepine (OR: 3.1; 95%CI: 1.7-5.6) and enalapril maleate (OR: 8.1; 95%CI: 1.6-41.7). Many known associations between medicines and birth defects were identified, suggesting that linked administrative data could be an important means of pharmacovigilance in pregnancy in Australia.

Role of continuous moisture profile monitoring by inline NIR spectroscopy during fluid bed granulation of an Enalapril formulation

Background: Granulation and tableting are closely related process steps in the supply chain of pharmaceutical products. Even today, these steps are still optimized independently by trial and error. On the framework of a process analytical technology approach, these processes were evaluated in an integrated approach. Enalapril maleate is a low-dose drug substance with poor granulating and tableting behavior. In order to verify how granulation influences tableting properties, different granulation experiments were performed. Methods: Granulation experiments with fast spraying rate and fast drying as well as fast spraying rate and slow drying, and also combinations of both were run. The obtained granules were then promptly compressed into tablets in a rotary press and subjected to hardness testing. The progress of spraying and drying was controlled by a continuous near-infrared spectroscopic measuring setup. This study confirms that the tablet characteristics. Result/Conclusion: after compression of the granules in comparison to placebo granules are dependent not only on the residual moisture content of the granules but also on the moisture profiles during the entire fluid bed granulation process.

Blood pressure levels and adherence to treatment of hypertensive patients, users of a school pharmacy

Adherence to pharmacological treatment for hypertension is considered a key factor in guaranteeing successful therapy outcomes. Knowledge of the disease, its complications, as well as the need for changes in lifestyle, call for patient motivation and continuous interactive education. The evidence regarding the beneficial effects of changes in life style by hypertensive individuals in reducing the complications of the disease, as well as in its prevention are indisputable. However, the challenges posed by patient adherence to treatment prescribed by doctors remain. The aim of this study was to assess blood pressure levels together with degree of adherence to pharmacological treatment with Enalapril Maleate by means of the Morisky-Green Test, in hypertensive patients who were users of a School Pharmacy. Of the 102 patients interviewed, 65.7% had controlled blood pressure, but only 36.3% indicated total compliance with the pharmacological treatment. The Morisky-Green test proved ineffective in associating controlled blood pressure levels and positive attitudes toward taking antihypertensive medicines.

Metanálise de estudos de bioequivalência: a intercambiabilidade de genéricos e similares que contêm Hidroclorotiazida é possível, mas não àqueles com Maleato de Enalapril

The generic drugs program provided a better population's access to medicines. To ensure interchangeability between a brand-name and generic or similar drugs is necessary that they are bioequivalent. With the growing number of generic drugs, it is common for patients to replace a generic to another or one similar. However, this exchange can not guarantee the maintenance of bioequivalence. To evaluate the safety interchangeability between different generic and similar drugs with Hydrochlorothiazide and Enalapril Maleate, a meta-analysis was carried out with several bioequivalence studies with these drugs. Data from bioequivalence of generic and similar drugs approved by the National Health Surveillance Agency (Anvisa) (drug regulatory agency in Brazil) were used. The compatibility of data from each study was analyzed and the determination of a confidence interval for the differences between the means of pharmacokinetic parameters, area under the curve (ASC0-t) and maximum plasma concentration (Cmax), was made for each study by meta-analysis. The interchangeability between the combinations of the three products with Hydrochlorothiazide was confirmed based on the obtained confidence intervals. For the drugs studied with Enalapril Maleate interchangeability has not been confirmed for 50% of the product comparisons. The exchange was established between the three products with hydrochlorothiazide. However, for the Enalapril Maleate half of the products studied are not interchangeable, considering they do not match the established intervals for bioequivalence tests, so the pharmacokinetics behavior and thus the effectiveness of the product may be changed.

Enalaprilat and enalapril maleate eyedrops lower intraocular pressure in rabbits

This study aimed to develop low-viscosity aqueous eyedrops containing enalaprilat and its prodrug enalapril maleate in solution, and to evaluate the eyedrops in rabbits. Aqueous eyedrops with hydroxypropyl-beta-cyclodextrin containing 0.01-2.9% (w/v) enalaprilat, 1.0% (w/v) enalapril maleate with cyclodextrin or 0.5% (w/v) timolol were prepared. The eyedrops were administered to rabbits and intraocular pressure (IOP) was measured at various time intervals after the administration and the results (mean of 10 experiments +/- standard error of the mean) are expressed as the change from baseline (24.7 +/- 3.3 mmHg). Enalaprilat possessed sufficient stability to be formulated as an aqueous eyedrop solution with a shelf-life of several years at room temperature. The maximum decline in IOP after topical administration of one drop of 2.9% enalaprilat solution was 6.2 +/- 0.7 mmHg at 4 hours after administration. Duration of activity exceeded 10 hours. A 1% enalaprilat solution lowered IOP by 4.4 +/- 0.8 mmHg at 4 hours after administration and had similar duration, and was more potent than 0.5% timolol. The enalapril maleate eyedrops resulted in delayed action, showing maximum potency at 10-22 hours after administration and duration of up to 32 hours. Enalaprilat eyedrops lower IOP in rabbits. The decline in IOP is proportional to the concentration of dissolved enalaprilat in low-viscosity aqueous eyedrop formulations.