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Radiology Jul 2017Purpose To determine if commonly administered doses of technetium 99m (Tc) mertiatide (MAG) in the range of 300-370 MBq (approximately 8-10 mCi) contribute to image...
Purpose To determine if commonly administered doses of technetium 99m (Tc) mertiatide (MAG) in the range of 300-370 MBq (approximately 8-10 mCi) contribute to image interpretation and justify the resulting radiation exposure. Materials and Methods The respective institutional review boards approved this HIPAA-compliant study and waived informed consent. Baseline and furosemide Tc-MAG imaging examinations in 50 patients suspected of having renal obstruction and 48 patients suspected of having renovascular hypertension (RVH) were randomly selected from archived databases and were independently scored by three experienced readers without access to 2-second flow images. Readers were blinded to their original scores, and then they rescored each examination with access to high-activity 2-second flow images. Relative renal function was determined after a low activity (62.9 MBq ± 40.7) baseline acquisition for RVH and a high activity (303.4 MBq ± 48.1) acquisition after administration of enalaprilat. Data were analyzed by using random effects analysis of variance and mean and standard error of the mean for the difference between sets of scores and the difference between relative function measurements. Results There was no significant difference in the scores without flow images compared with blinded scores with high-activity flow images for patients suspected of having obstruction (P = .80) or RVH (P = .24). Moreover, there was no significant difference in the relative uptake measurements after administration of low and high activities (P > .99). Conclusion Administered doses of Tc-MAG in the range of 300-370 MBq (approximately 8-10 mCi) do not affect the relative function measurements or contribute to interpretation of images in patients suspected of having RVH or obstruction compared with administration of lower doses; unnecessary radiation exposure can be avoided by administering doses in the range of 37-185 MBq as recommended incurrent guidelines. RSNA, 2017.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Radioisotope Renography; Radiopharmaceuticals; Renal Artery Obstruction; Reproducibility of Results; Retrospective Studies; Technetium Tc 99m Mertiatide
PubMed: 28212051
DOI: 10.1148/radiol.2017152311 -
Drug Discovery Today Aug 2020Enalapril is an angiotensin-converting enzyme (ACE) inhibitor that is used for the treatment of (paediatric) hypertension, heart failure and chronic kidney diseases.... (Review)
Review
Enalapril is an angiotensin-converting enzyme (ACE) inhibitor that is used for the treatment of (paediatric) hypertension, heart failure and chronic kidney diseases. Because its disposition, efficacy and safety differs across the paediatric continuum, data from adults cannot be automatically extrapolated to children. This review highlights paediatric enalapril pharmacokinetic data and demonstrates that these are inadequate to support with certainty an age-related effect on enalapril/enalaprilat pharmacokinetics. In addition, our review shows that evidence to support effective and safe prescribing of enalapril in children is limited, especially in young children and heart failure patients; studies in these groups are either absent or show conflicting results. We provide explanations for observed differences between age groups and indications, and describe areas for future research.
PubMed: 32835726
DOI: 10.1016/j.drudis.2020.08.005 -
Pharmaceutics Sep 2020Enalapril is often used in the treatment of cardiovascular diseases. Clinical data suggest that the urinary excretion of enalaprilat, the active metabolite of enalapril,...
BACKGROUND
Enalapril is often used in the treatment of cardiovascular diseases. Clinical data suggest that the urinary excretion of enalaprilat, the active metabolite of enalapril, is mediated by renal transporters. We aimed to identify enalaprilat specificity for renal proximal tubular transporters.
METHODS
Baculovirus-transduced HEK293 cells overexpressing proximal tubular transporters were used to study enalaprilat cellular uptake. Uptake into cells overexpressing the basolateral transporters OCT2, OAT1, OAT2, or OAT3 and apical transporters OAT4, PEPT1, PEPT2, OCTN1, OCTN2, MATE1, MATE2k, and URAT1 was compared with mock-transduced control cells. Transport by renal efflux transporters MRP2, MPR4, P-gp, and BCRP was tested using a vesicular assay. Enalaprilat concentrations were measured using LC-MS/MS.
RESULTS
Uptake of enalaprilat into cells expressing OAT3 as well as OAT4 was significantly higher compared to control cells. The enalaprilat affinity for OAT3 was 640 (95% CI: 520-770) µM. For OAT4, no reliable affinity constant could be determined using concentrations up to 3 mM. No transport was observed for other transporters.
CONCLUSION
The affinity of enalaprilat for OAT3 and OAT4 was notably low compared to other substrates. Taking this affinity and clinically relevant plasma concentrations of enalaprilat and other OAT3 substrates into account, we believe that drug-drug interactions on a transporter level do not have a therapeutic consequence and will not require dose adjustments of enalaprilat itself or other OAT3 substrates.
PubMed: 33007874
DOI: 10.3390/pharmaceutics12100935 -
Journal of Personalized Medicine Apr 2022The angiotensin-converting enzyme inhibitor enalapril is hydrolysed to an active metabolite, enalaprilat, in the liver via carboxylesterase 1 (CES1). Previous studies...
The angiotensin-converting enzyme inhibitor enalapril is hydrolysed to an active metabolite, enalaprilat, in the liver via carboxylesterase 1 (CES1). Previous studies show that variant rs71647871 in the CES1 gene affects the pharmacokinetics of enalapril on liver samples as well as healthy volunteers. This study included 286 Caucasian patients with arterial hypertension who received enalapril. The concentrations of enalapril and enalaprilat were determined before subsequent intake of the drug and 4 h after it with high-performance liquid chromatography (HPLC) and mass spectrometric detection. The study included genetic markers as follows: rs2244613, rs71647871 (c.428G>A, p.G143E) and three SNPs indicating the presence of a subtype CES1A1c (rs12149368, rs111604615 and rs201577108). Mean peak and trough enalaprilat concentrations, adjusted by clinical variables, were significantly lower in CES1 rs2244613 heterozygotes (by 16.6% and 19.6%) and in CC homozygotes (by 32.7% and 41.4%) vs. the AA genotype. In CES1A1c homozygotes, adjusted mean enalaprilat concentrations were 75% lower vs. heterozygotes and wild-type (WT) homozygotes. Pharmacogenetic markers of the CES1 gene may be a promising predictor for individualisation when prescribing enalapril.
PubMed: 35455696
DOI: 10.3390/jpm12040580 -
Frontiers in Pediatrics 2021Enalapril has an established safety and efficacy in adults and is used in hypertension, heart failure, and renal failure. In pediatric patients, enalapril is labeled...
Enalapril has an established safety and efficacy in adults and is used in hypertension, heart failure, and renal failure. In pediatric patients, enalapril is labeled for children with hypertension and used off label in children with heart failure. The systematic literature search aims to assess the current knowledge about enalapril and its active metabolite enalaprilat pharmacokinetics in children as a basis for dose delineation for pediatric patients with heart failure. A systematic literature review was performed in the PubMed database using relevant keywords. Dose normalization of relevant pharmacokinetic parameters of the identified studies was done for comparison between different diseases and pediatric age groups. The literature search has resulted in three pediatric pharmacokinetic studies of enalapril out of which Wells et al. reported about children with hypertension and Nakamura et al., and Llyod et al. presented data for pediatric heart failure patients. The area under the curve values of enalaprilat in hypertensive pediatric patients increased with respect to the age groups and showed maturation of body functions with increasing age. Dose normalized comparison with the heart failure studies revealed that although the pediatric heart failure patients of > 20 days of age showed the area under the curve a similar to that of hypertensive patients, two pediatric patients of very early age (<20 days) were presented with 5-6-fold higher area under the curve values. Data related to the pharmacokinetics of enalapril and enalaprilat in hypertensive patients and few data for young heart failure children are available. Comparison of dose normalized exposition of the active metabolite enalaprilat indicated similarities between heart failure and hypertensive patients and a potentially high exposition of premature patients but substantially more pharmacokinetic studies are required to have reliable and robust enalapril as well as enalaprilat exposures especially in pediatric patients with heart failure as a basis for any dose delineation.
PubMed: 33643971
DOI: 10.3389/fped.2021.611322 -
The American Journal of Emergency... Feb 2015There are nearly 700,000 annual US emergency department (ED) visits for acute heart failure (AHF). Although blood pressure is elevated on most of these visits, acute... (Review)
Review
There are nearly 700,000 annual US emergency department (ED) visits for acute heart failure (AHF). Although blood pressure is elevated on most of these visits, acute therapy remains focused on preload and not afterload reduction. Data from recent prospective studies suggest that patients with AHF with concomitant acute hypertension benefit from intravenous (IV) vasodilators. To better understand the use of vasodilators for such patients, we conducted a systematic review of (1) currently available intravenous vasodilators for ED patients with AHF, or (2) intravenous vasodilators that are not yet available, but have completed phase III clinical trials in AHF, and may be available for ED use in the future. We used multiterm search queries to retrieve research involving nitroglycerin, nitroprusside, enalaprilat, hydralazine, relaxin, and nesiritide. A total of 2001 unique citations were identified from 3 databases: PubMed, EMBASE, and CINAHL. Of these, 1966 were excluded on the basis of established review criteria, leaving 35 published articles for inclusion. Our primary finding was that intravenous nitrovasodilators, when used in the treatment of AHF in ED and ED-like settings, do improve short-term symptoms and appear safe to administer. There are no data suggesting that they impact mortality. Other commonly used vasodilators such as hydralazine and enalaprilat have very little published data about their safety and efficacy. Of note, few studies enrolled patients early in their course of treatment. Thus, to assess the specific impact of vasodilator therapy on both short- and long-term outcomes, future research efforts should focus on patient recruitment in the ED setting.
Topics: Acute Disease; Emergency Service, Hospital; Heart Failure; Humans; Infusions, Intravenous; Treatment Outcome; Vasodilator Agents
PubMed: 25530194
DOI: 10.1016/j.ajem.2014.09.009 -
RSC Advances Oct 2020SARS-CoV-2 virus invades the host through angiotensin-converting enzyme 2 (ACE2) receptors by decreasing the ACE2 expression of the host. This disturbs the dynamic... (Review)
Review
SARS-CoV-2 virus invades the host through angiotensin-converting enzyme 2 (ACE2) receptors by decreasing the ACE2 expression of the host. This disturbs the dynamic equilibrium between the ACE/Ang II/AT1R axis and ACE2/Ang (1-7)/Mas receptor axis. Therefore, the clinically approved drugs belonging to (i) angiotensin converting enzyme (ACE) inhibitors such as captopril, and enalaprilat, (ii) angiotensin-receptor blockers (ARBs) such as losartan, candesartan, olmesartan, azilsartan, irbesartan, and telmisartan and (iii) the combination of ACE inhibitors and ARBs such as losartan with lisinopril and captopril with losartan, and (iv) recombinant ACE2, were studied for their ability to activate ACE2 in different medical conditions including hypertension, inflammation, cardiovascular, renal and lung diseases. These clinically approved drugs were found to activate ACE2 that had been downregulated in different medical conditions including hypertension, inflammation, cardiovascular, renal and lung diseases. Therefore, these drugs may be repurposed to re-activate the downregulated ACE2 of COVID-19 patients. These drugs either alone or in combination may be repurposed as prophylactics and therapeutics against SARS-CoV-2 virus.
PubMed: 35515386
DOI: 10.1039/d0ra08228g -
Pharmaceutics May 2022Angiotensin-converting enzyme inhibitors (ACEI), such as enalapril, are a cornerstone of treatment for pediatric heart failure which is still used off-label. Using a...
Enalapril and Enalaprilat Pharmacokinetics in Children with Heart Failure Due to Dilated Cardiomyopathy and Congestive Heart Failure after Administration of an Orodispersible Enalapril Minitablet (LENA-Studies).
Angiotensin-converting enzyme inhibitors (ACEI), such as enalapril, are a cornerstone of treatment for pediatric heart failure which is still used off-label. Using a novel age-appropriate formulation of enalapril orodispersible minitablets (ODMTs), phase II/III open-label, multicenter pharmacokinetic (PK) bridging studies were performed in pediatric patients with heart failure due to dilated cardiomyopathy (DCM) and congenital heart disease (CHD) in five participating European countries. Children were treated for 8 weeks with ODMTs according to an age-appropriate dosing schedule. The primary objective was to describe PK parameters (area under the curve (AUC), maximal concentration (Cmax), time to reach maximal concentration (t-max)) of enalapril and its active metabolite enalaprilat. Of 102 patients, 89 patients ( = 26, DCM; = 63 CHD) were included in the primary PK endpoint analysis. Rate and extent of enalapril and its active metabolite enalaprilat were described and etiology and age could be identified as potential PK modifying factors. The dosing schedule appeared to be tolerated well and did not result in any significant drug-related serious adverse events. The PK analysis and the lack of severe safety events supports the applied age-appropriate dosing schedule for the enalapril ODMTs.
PubMed: 35745735
DOI: 10.3390/pharmaceutics14061163 -
Journal of Mass Spectrometry and... Jan 2023Adherence to medication is an important determinant of outcomes in chronic diseases like heart failure. Drug assays provide objective adherence biomarkers. Dried blood...
Validation of a quantitative multiplex LC-MS/MS assay of carvedilol, enalaprilat, and perindoprilat in dried blood spots from heart failure patients and its cross validation with a plasma assay.
INTRODUCTION
Adherence to medication is an important determinant of outcomes in chronic diseases like heart failure. Drug assays provide objective adherence biomarkers. Dried blood spots (DBS) are appealing samples for drug assays due to less demanding transportation and storage requirements.
OBJECTIVES
To analytically validate a LC-MS/MS method for the simultaneous quantification of carvedilol, enalaprilat, and perindoprilat in DBS and evaluate the feasibility of using the method as an adherence determining assay. To validate the assay further clinically by establishing correlation and agreement between plasma and DBS samples from a pharmacokinetic pilot study.
METHODS
The method was validated over a concentration range of 1.00-200 ng/mL according to FDA guidelines. Adherence tracking ability of the assay was evaluated using a pharmacokinetic pilot study. Correlation and agreement were evaluated through Deming regression and Bland-Altman analysis, respectively.
RESULTS
Accuracy, precision, selectivity, and sensitivity were proven with complete and reproducible extraction recovery at all concentrations tested. Stability of the analytes in the matrix and throughout sample processing was proven. The full range of concentrations of the pharmacokinetic pilot study could be quantified for enalaprilat, but not for carvedilol and perindoprilat. The difference between the observed and calculated plasma concentrations was less than 20 % of their mean for >67 % of samples for all analytes.
CONCLUSIONS
The assay is suitable as a screening tool for carvedilol and perindoprilat, while suitable as an adherence determining assay for enalaprilat. Equivalence between observed and predicted plasma concentrations proves DBS and plasma concentrations can be used interchangeably.
PubMed: 36568714
DOI: 10.1016/j.jmsacl.2022.12.003