Design and fabrication of 3D-printed gastric floating tablets of captopril: effect of geometry and thermal crosslinking of polymer on floating behavior and drug release.

The present study aims to investigate the potential of the 3D printing technique to design gastroretentive floating tablets (GFTs) for modifying the drug release profile of an immediate-release tablet. A 3D-printed floating shell enclosing a captopril tablet was designed having varying number of drug-release windows. The impact of geometrical changes in the design of delivery system and thermal cross-linking of polymers were evaluated to observe the influence on floating ability and drug release. Water uptake, water insolubilization, Differential Scanning Calorimetry (DSC), and Attenuated Total Reflection-Fourier Transform Infrared Spectroscopy (ATR-FTIR) were performed to assess the degree of thermal cross-linking of polyvinyl alcohol (PVA) filament. The 3D-printed GFT9 was considered the optimized gastric floating tablet that exhibited >12 h of total floating time with zero floating lag time and successfully accomplished modified-drug release by exhibiting >80% of drug release in 8 h. The zero-order release model, with an r2 value of 0.9923, best fitted the drug release kinetic data of the GFT9, which followed a super case II drug transport mechanism with an n value of 0.95. The optimized gastric floating device (GFT9) also exhibited the highest MDT values (238.55), representing slow drug release from the system due to thermal crosslinking and the presence of a single drug-releasing window in the device.

Hydrogen Sulphide Release via the Angiotensin Converting Enzyme Inhibitor Zofenopril Prevents Intimal Hyperplasia in Human Vein Segments and in a Mouse Model of Carotid Artery Stenosis.

OBJECTIVE: Hypertension is a major risk factor for intimal hyperplasia (IH) and re-stenosis following vascular and endovascular interventions. Preclinical studies suggest that hydrogen sulphide (H2S), an endogenous gasotransmitter, limits re-stenosis. While there is no clinically available pure H2S releasing compound, the sulfhydryl containing angiotensin converting enzyme inhibitor zofenopril is a source of H2S. Here, it was hypothesised that zofenopril, due to H2S release, would be superior to other non-sulfhydryl containing angiotensin converting enzyme inhibitors (ACEi) in reducing intimal hyperplasia. METHODS: Spontaneously hypertensive male Cx40 deleted mice (Cx40-/-) or wild type (WT) littermates were randomly treated with enalapril 20 mg or zofenopril 30 mg. Discarded human vein segments and primary human smooth muscle cells (SMCs) were treated with the active compound enalaprilat or zofenoprilat. IH was evaluated in mice 28 days after focal carotid artery stenosis surgery and in human vein segments cultured for seven days ex vivo. Human primary smooth muscle cell (SMC) proliferation and migration were studied in vitro. RESULTS: Compared with control animals (intima/media thickness 2.3 ± 0.33 µm), enalapril reduced IH in Cx40-/- hypertensive mice by 30% (1.7 ± 0.35 µm; p = .037), while zofenopril abrogated IH (0.4 ± 0.16 µm; p < .002 vs. control and p > .99 vs. sham operated Cx40-/- mice). In WT normotensive mice, enalapril had no effect (0.9665 ± 0.2 µm in control vs. 1.140 ± 0.27 µm; p > .99), while zofenopril also abrogated IH (0.1623 ± 0.07 µm; p < .008 vs. control and p > .99 vs. sham operated WT mice). Zofenoprilat, but not enalaprilat, also prevented IH in human vein segments ex vivo. The effect of zofenopril on carotid and SMCs correlated with reduced SMC proliferation and migration. Zofenoprilat inhibited the mitogen activated protein kinase and mammalian target of rapamycin pathways in SMCs and human vein segments. CONCLUSION: Zofenopril provides extra beneficial effects compared with non-sulfhydryl ACEi in reducing SMC proliferation and re-stenosis, even in normotensive animals. These findings may hold broad clinical implications for patients suffering from vascular occlusive diseases and hypertension.

Experimental data using candesartan and captopril indicate no double-edged sword effect in COVID-19.

The key link between renin-angiotensin system (RAS) and COVID-19 is ACE2 (angiotensin-converting enzyme 2), which acts as a double-edged sword, because ACE2 increases the tissue anti-inflammatory response but it is also the entry receptor for the virus. There is an important controversy on several drugs that regulate RAS activity and possibly ACE2, and are widely used, particularly by patients most vulnerable to severe COVID-19. In the lung of healthy rats, we observed that candesartan (an angiotensin type-1, AT1, receptor blocker; ARB) and captopril (an ACE inhibitor; ACEI) up-regulated expression of tissue ACE2 and RAS anti-inflammatory axis receptors (AT2 and Mas receptors). This effect was particularly pronounced in rats with metabolic syndrome (obesity, increased blood pressure and hyperglycemia) and aged rats. Treatment of cultures of human type-II pneumocytes with candesartan or captopril induced up-regulation of ACE2 expression in cells. Treatment with viral spike protein induced a decrease in full-length (i.e. transmembrane) ACE2, an increase in levels of a short intracellular ACE2 polypeptide and an increase in ADAM17 activity in cells, together with an increase in levels of soluble ACE2 and major proinflammatory cytokines in the culture medium. Spike protein-induced changes and levels of spike protein internalization in cells were inhibited by pretreatment with the above-mentioned drugs. The results suggest that these drugs increase ACE2 levels and promote the anti-inflammatory RAS axis in the lung. Furthermore, possible up-regulation of viral entry by the drug-induced increase in expression of transmembrane ACE2 is counteracted by additional mechanisms, particularly by drug-induced inhibition of ADAM17 activity.

Angiotensin-Converting Enzyme Inhibitor, Captopril, Improves Scar Healing in Hypertensive Rats.

Pathological cutaneous scars, with aberrant extracellular matrix accumulation, have multiple origins. Antihypertensive medications, such as calcium channel blockers, have been used to treat pathological scars. However, a relationship between angiotensin-converting enzyme (ACE) inhibitors, pathological scars, and blood pressure (BP) has never been reported. Here, we aimed to compare the differences in scar development and the effects of the administration of systemic ACE inhibitor on scar tissue in a normotensive rat, the Wistar Kyoto rat (WKY), a hypertensive rat, and the spontaneously hypertensive rat (SHR). Using an 8-mm punch, we created two full-thickness skin defects in a total of 32 rats (16 WKY and 16 SHR) to obtain a total of 64 wounds. We established control WKY (n = 16), captopril-treated WKY (n = 16), control SHR (n = 16), and captopril-treated SHR (n = 16) groups and started captopril (100 mg/g per day) treatment on day 21 in the appropriate groups. The BP of all groups was measured at 0, 3, and 5 weeks. The scar area was measured by histopathological examination, and scarring was expressed in terms of scar area and fibroblast and capillary counts. The expression of heat shock protein (HSP) 47, type I and III collagens, alpha-smooth muscle actin (α-SMA), Ki67, and vascular endothelial growth factor (VEGF) was investigated using immunohistochemistry. The scar area and fibroblast count were significantly higher in control SHR than in control WKY. The scar area, fibroblast count, and capillary count were significantly smaller in captopril-treated SHR than in control SHR. Immunostaining for α-SMA, Ki67, and VEGF also showed a noticeable decrease in scarring in the treated SHR compared with that in control SHR. Thus, BP affects scar development in a rat model, and an ACE inhibitor is more effective at reducing scars in hypertensive rats than in normotensive rats.

l-Serine-modified polyamidoamine dendrimer as a highly potent renal targeting drug carrier.

Effective delivery of drug carriers selectively to the kidney is challenging because of their uptake by the reticuloendothelial system in the liver and spleen, which limits effective treatment of kidney diseases and results in side effects. To address this issue, we synthesized l-serine (Ser)-modified polyamidoamine dendrimer (PAMAM) as a potent renal targeting drug carrier. Approximately 82% of the dose was accumulated in the kidney at 3 h after i.v. injection of 111In-labeled Ser-PAMAM in mice, while i.v. injection of 111In-labeled unmodified PAMAM, l-threonine modified PAMAM, and l-tyrosine modified PAMAM resulted in kidney accumulations of 28%, 35%, and 31%, respectively. Single-photon emission computed tomography/computed tomography (SPECT/CT) images also indicated that 111In-labeled Ser-PAMAM specifically accumulated in the kidneys. An intrakidney distribution study showed that fluorescein isothiocyanate-labeled Ser-PAMAM accumulated predominantly in renal proximal tubules. Results of a cellular uptake study of Ser-PAMAM in LLC-PK1 cells in the presence of inhibitors [genistein, 5-(N-ethyl-N-isopropyl)amiloride, and lysozyme] revealed that caveolae-mediated endocytosis, micropinocytosis, and megalin were associated with the renal accumulation of Ser-PAMAM. The efficient renal distribution and angiotensin-converting enzyme (ACE) inhibition effect of captopril (CAP), an ACE inhibitor, was observed after i.v. injection of the Ser-PAMAM-CAP conjugate. These findings indicate that Ser-PAMAM is a promising renal targeting drug carrier for the treatment of kidney diseases. Thus, the results of this study demonstrate efficient renal targeting of a drug carrier via Ser modification.

Physicochemical Characterization and Drug Release Properties of Methyl-Substituted Silica Xerogels Made Using Sol-Gel Process.

In this work, a multi-analytical approach involving nitrogen porosimetry, small angle neutron and X-ray scattering, Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopies, X-ray diffraction, thermal analysis and electron microscopy was applied to organically modified silica-based xerogels obtained through the sol-gel process. Starting from a tetraethoxysilane (TEOS) precursor, methyltriethoxysilane (MTES) was added to the reaction mixture at two different pH values (2.0 and 4.5) producing hybrid xerogels with different TEOS/MTES molar ratios. Significant differences in the structure were revealed in terms of the chemical composition of the silica network, hydrophilic/hydrophobic profile, particle dimension, pore shape/size and surface characteristics. The combined use of structural characterization methods allowed us to reveal a relation between the cavity dimensions, the synthesis pH value and the grade of methyl substitution. The effect of the structural properties on the controlled Captopril release efficiency has also been tested. This knowledge facilitates tailoring the pore network for specific usage in biological/medical applications. Knowledge on structural aspects, as reported in this work, represents a key starting point for the production of high-performance silica-based hybrid materials showing enhanced efficacy compared to bare silica prepared using only TEOS.

Antihypertensive effect of rapeseed peptides and their potential in improving the effectiveness of captopril.

BACKGROUND: The main objective of this study was to evaluate the safety and antihypertensive activity of rapeseed peptides and to investigate their potential synergy with captopril. RESULTS: The peptides were nontoxic with the maximum tolerated dose exceeding 25 g kg-1 BW d-1 for mice and they had angiotensin converting enzyme (ACE) inhibitory activity with IC50 value of 1.27 mg mL-1 . Rapeseed peptides did not have a synergistic effect with captopril on inhibiting ACE activity in simulated digestion tests in vitro. But in vivo they could synergistically augment the amplitude range of lowering blood pressure with captopril by approximately 9% and prolong the antihypertensive effect duration time by over 20% in antihypertension tests of spontaneously hypertensive rats. In addition, the inhibiting effect of rapeseed peptides on ACE activity was noticeable in some rat organs in vivo. Nevertheless, when compared to captopril group, the potential synergy of rapeseed peptides with captopril did not cause a further decrease in ACE activity in the organs but their synergy further improved levels of NO (12.7%) and endothelial nitric oxide synthase (74.1%) in rat serum. Further studies of some peptides identified from rapeseed peptides showed that some of the rapeseed peptides (Cys-Leu, Val-Ala-Pro) could markedly increase contents of NO and endothelial nitric oxide synthase. CONCLUSIONS: Rapeseed peptides have antihypertensive activity and they showed potential synergy with captopril in antihypertensive performance in vivo. The synergy was not from ACE inhibition but from other pathways, like improvement in endogenous vasodilator contents. © 2020 Society of Chemical Industry.

A combination of captopril challenge test after saline infusion test improves diagnostic accuracy for primary aldosteronism.

CONTEXT: The saline infusion test (SIT) is a common confirmatory test for primary aldosteronism (PA). According to the guideline, a postinfusion plasma aldosterone concentration (PAC) of 5-10 ng/dL is considered indeterminate, and recommendations for diagnostic strategies are currently limited in this situation. OBJECTIVE: To explore whether an addition of the captopril challenge test (CCT) could improve the diagnostic accuracy in patients with indeterminate SIT. METHODS: A total of 280 hypertensive patients with high risk of PA completed this study. Subjects were defined as SIT indeterminate based on their PAC post-SIT. These patients then underwent the CCT where PACs post-CCT >11 ng/dL were considered positive. Using fludrocortisone suppression test (FST) as the reference standard, diagnostic parameters including area under the receiver-operator characteristic curves (AUC), sensitivity and specificity were calculated. RESULTS: There were 65 subjects (23.2%) diagnosed as PA indeterminate after SIT. With the addition of CCT, true-positive numbers increased from 134 to 147, and false-negative numbers decreased from 27 to 14. Compared to SIT alone, a combination of SIT and CCT showed a higher AUC (0.91 [0.87,0.94] vs 0.87 [0.83,0.91], P = .041) and an increased sensitivity for the diagnosis of PA (0.91 [0.86,0.95] vs 0.83 [0.76,0.89], P = .028), while the specificity remained similar. In the subgroup with indeterminate SIT results, using PAC post-CCT resulted in a 36% higher AUC than using PAC post-SIT alone for the diagnosis of PA. CONCLUSION: For patients under investigation for possible PA who have indeterminate SIT results, an addition of CCT improves the diagnostic accuracy.

Self-Emulsifying Drug Delivery Systems: Hydrophobic Drug Polymer Complexes Provide a Sustained Release in Vitro.

The aim of this study was to develop hydrophobic ionic drug polymer complexes in order to provide sustained drug release from self-emulsifying drug delivery systems (SEDDS). Captopril (CTL) was used as an anionic model drug to form ionic complexes with the cationic polymers Eudragit RS, RL, and E. Complexes of polymer to CTL charge ratio 1:1, 2:1, and 4:1 were incorporated in two SEDDS, namely FA which was 40% Kolliphor RH 40, 20% Kolliphor EL, and 40% castor oil and FB, which was 40% Kolliphor RH 40, 30% glycerol, 15% Kolliphor EL, and 15% castor oil. Blank and complex loaded SEDDS were characterized regarding their droplet size, polydispersity index (PDI), and zeta potential. Resazurin assay was performed on Caco-2 cells to evaluate the biocompatibility of SEDDS. Release of CTL from SEDDS was determined in release medium containing 0.2 mg/mL of 5,5'-dithiobis(2-nitrobenzoic acid) (DNTB) allowing quantification of free drug released into solution via a thiol/disulfide exchange reaction between CTL and DNTB forming a yellow dye. The droplet size of SEDDS FA and SEDDS FB were in the range of 100 ± 20 nm and 40 ± 10 nm, respectively, with a PDI < 0.5. The zeta potential of SEDDS FA and SEDDS FB increased after the incorporation of complexes. Cell viability remained above 80% after incubation with SEDDS FA and SEDDS FB in a concentration of 1% and 3% for 4 h. Without any polymer, CTL was entirely released from both SEDDS within seconds. In contrast, the higher the cationic lipophilic polymer to CTL ratio in SEDDS, the more sustained was the release of CTL. Among the polymers which were evaluated, Eudragit RL provided the most sustained release. SEDDS FA containing Eudragit RL and CTL in a ratio of 1:1 released 64.78 ± 8.28% of CTL, whereas SEDDS FB containing the same complex showed a release of 91.85 ± 1.17% within 1 h. Due to the formation of lipophilic ionic polymer complexes a sustained drug release from oily droplets formed by SEDDS can be achieved. Taking into account that drugs are otherwise instantly released from SEDDS, results of this study might open the door for numerous additional applications of SEDDS for which a sustained drug release is essential.

Parameters of captopril challenge test can predict results of other confirmatory tests for primary aldosteronism and propose the next test to be done.

In Japan, primary aldosteronism (PA) is diagnosed if any one of the captopril challenge test (CCT), saline infusion test (SIT), furosemide-upright test (FUP), and oral salt-loading test (OST) is positive. The present study aimed to investigate if parameters of CCT, the safest confirmatory test, could predict decisions of other tests and propose the next test to diagnose PA in CCT-negative patients. In a cross-sectional design, 142 patients, who were referred to our hospital for the scrutiny of PA and underwent at least two confirmatory tests, were enrolled. While 123 patients underwent all of the CCT, SIT, and FUP, the OST was successfully done in only six patients and excluded from further analyses. CCT parameters showing correlations of higher degrees with SIT and FUP parameters were selected, and their powers to predict SIT and FUP decisions were investigated by receiver operating characteristic analyses. Proposals of the next test based on the CCT parameters were validated with SIT and FUP decisions in subsets of CCT-negative patients divided by cut-offs of the CCT parameters. The plasma aldosterone concentration and plasma renin activity 60 min after the load of CCT (CCT60-PAC and CCT60-PRA) were selected, and CCT60-PAC ≤59.0 pg/mL and CCT60-PRA ≥1.05 ng/mL/h could predict negativities of SIT and FUP, respectively, with >95% specificities. Based on the validation, the present study suggested the SIT as the next test to be done if the CCT-negative patient belonged to the subset with CCT60-PAC >59.0 pg/mL and CCT60-PRA ≥1.05 ng/mL/h, otherwise the FUP should be selected.

Comparison of an angiotensin-I-converting enzyme inhibitory peptide from tilapia (Oreochromis niloticus) with captopril: inhibition kinetics, in vivo effect, simulated gastrointestinal digestion and a molecular docking study.

BACKGROUND: In order to utilize tilapia skin gelatin hydrolysate protein, which is normally discarded as industrial waste in the process of fish manufacture, we study the in vivo and in vitro angiotensin-I-converting enzyme (ACE) inhibitory activity of the peptide Leu-Ser-Gly-Tyr-Gly-Pro (LSGYGP). The aim was to provide a pharmacological basis of the development of minimal side effects of ACE inhibitors by comparative analysis with captopril in molecular docking. RESULTS: This peptide from protein-rich wastes showed excellent ACE inhibitory activity (IC50  = 2.577 µmol L-1 ) and exhibited a mixed noncompetitive inhibitory pattern with Lineweaver-Burk plots. Furthermore, LSGYGP and captopril groups both showed significant decreases in blood pressure after 6 h and maintained good digestive stability over 4 h. Molecular bond interactions differentiate competitive captopril upon hydrogen bond interactions and Zn(II) interaction. The C-terminal Pro generates three interactions (hydrogen bonds, hydrophilic interactions and Van der Waals interactions) in the peptide and effectively interacts with the S1 and S2 pockets of ACE. CONCLUSION: LSGYGP, with an IC50 value of 2.577 µmol L-1 , has an antihypertensive effect in spontaneously hypertensive rats. Through comparison with captopril, this study revealed that LSGYGP may be a potential food-derived ACE inhibitory peptide and could act as a functional food ingredient to prevent hypertension. © 2019 Society of Chemical Industry.

Application of Pickering Emulsion with Cyclodextrin as an Emulsifier to a Transdermal Drug Delivery Vehicle.

The emulsion prepared with ß-cyclodextrin as an emulsifier (ßCDE) is considered to be a Pickering emulsion. We examined the characteristics of ßCDEs using captopril (CP) as a model drug, and studied the in vitro skin permeation of CP from ßCDEs through hairless mouse skin. The stability of ßCDE was increased with increasing ßCD concentration and conversely decreased with increasing CP concentration. The yield stress value from the rheological measurement results was suggested to be one of the factors determining the stability of the ßCDE, and ßCDEs with higher yield stress values were more stable. We found that the skin permeability of CP could be improved by using ßCDE with isopropyl myristate as the oil phase and that the flux of CP depended on the free CP concentration in the water phase of ßCDE.

Vaccarin administration ameliorates hypertension and cardiovascular remodeling in renovascular hypertensive rats.

Sympathetic overdrive, activation of renin angiotensin systems (RAS), and oxidative stress are vitally involved in the pathogenesis of hypertension and cardiovascular remodeling. We recently identified that vaccarin protected endothelial cell function from oxidative stress or high glucose. In this study, we aimed to investigate whether vaccarin attenuated hypertension and cardiovascular remodeling. Two-kidney one-clip (2K1C) model rats were used, and low dose of vaccarin (10 mg/kg), high dose of vaccarin (30 mg/kg), captopril (30 mg/kg) were intraperitoneally administrated. Herein, we showed that 2K1C rats exhibited higher systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), left ventricular mass/body weight ratio, myocardial hypertrophy or fibrosis, media thickness, and media thickness to lumen diameter, which were obviously alleviated by vaccarin and captopril. In addition, both vaccarin and captopril abrogated the increased plasma renin, angiotensin II (Ang II), norepinephrine (NE), and the basal sympathetic activity. The AT1R protein expressions, NADPH oxidase subunit NOX-2 protein levels and malondialdehyde (MDA) content were significantly increased, whereas superoxide dismutase (SOD) and catalase (CAT) activities were decreased in myocardium, aorta, and mesenteric artery of 2K1C rats, both vaccarin and captopril treatment counteracted these changes in renovascular hypertensive rats. Collectively, we concluded that vaccarin may be a novel complementary therapeutic medicine for the prevention and treatment of hypertension. The mechanisms for antihypertensive effects of vaccarin may be associated with inhibition of sympathetic activity, RAS, and oxidative stress.

Bioconjugation of Captopril-Light Subunit of Agaricus bisporus Mushroom Tyrosinase: Characterization and Potential Use as a Drug Carrier for Oral Delivery.

We show that a lectin like protein from the mushroom Agaricus bisporus (LSMT) is capable to permeate the epithelial monolayer barrier of the intestine ex vivo. The protein is not toxic or immunogenic upon prolonged administration and elevated dose in mice. Thus, it could be a candidate as a drug carrier for oral administration. However, its permeability should be tested after the protein has been modified, mimicking the condition in which it is used as a drug carrier. The protein was conjugated to captopril, the selected model of a Biopharmaceutical Classification System (BCS) class III drug, with high solubility but poor permeability. The drug was conjugated to LSMT that had been modified with 4-succinimidyloxycarbonyl-alpha-methyl-2-pyridyldithiotoluene (SMPT) as a linker. The success of LSMT modification was confirmed with TLC and MS; the latter also indicated the amount of captopril molecule linked. The modified LSMT could permeate through the intestinal monolayer barrier, and thus could be absorbed in the intestine after modification. The modified protein appears to remain stable after incubation in simulated gastrointestinal fluids. This pioneering work provides an essential basis for further development of the protein as a drug carrier for oral administration.

Formulation, Characterization, and Optimization of Captopril Fast-Dissolving Oral Films.

This work aimed to using optimization study to formulate a patient-friendly captopril fast-dissolving oral film with satisfactory disintegration time. Films were made with pullulan and hydroxypropyl methyl cellulose (HPMC) by using the solvent-casting method. Cellulose nanofiber (CNF) was used as a compatibilizer and glycerine was used as a plasticizer. In order to find an optimum formulation, a response surface methodology and a central composite design were employed. The concentration percentages of pullulan and glycerine were considered to be the design factors. Disintegration time, tensile strength, percent elongation at break, and folding endurance were considered to be the responses. The results showed that CNF improved the compatibility and tensile strength of the pullulan and HPMC blend. Also, the rigid nature of CNF reduced the film elongation but the addition of glycerine improved its flexibility. All formulations showed an acceptable uniformity content and dissolution rate. Complete dissolution for all formulations occurred within 2 min. Films with 26% pullulan, 74% HPMC, 1% CNF, and 5% glycerine were reported to be optimum formulations for captopril fast-dissolving oral films, with 95% confidence levels. The in vivo comparison of optimized formulation with a conventional captopril sublingual tablet exhibited significant increase in AUC (~ 62%) and Cmax (~ 52%) and a major decrease in Tmax (~ 33%). The overall results showed that the captopril FDF is a promising candidate for enhanced in vivo orotransmucosal absorption.

Early Treatment With Zofenopril and Ramipril in Combination With Acetyl Salicylic Acid in Patients With Left Ventricular Systolic Dysfunction After Acute Myocardial Infarction: Results of a 5-Year Follow-up of Patients of the SMILE-4 Study.

The SMILE-4 study showed that in patients with left ventricular dysfunction (LVD) after acute myocardial infarction, early treatment with zofenopril plus acetyl salicylic acid is associated with an improved 1-year survival, free from death or hospitalization for cardiovascular (CV) causes, as compared to ramipril plus acetyl salicylic acid. We now report CV outcomes during a 5-year follow-up of the patients of the SMILE-4 study. Three hundred eighty-six of the 518 patients completing the study (51.2%) could be tracked after the study end and 265 could be included in the analysis. During the 5.5 (±2.1) years of follow-up, the primary endpoint occurred in 27.8% of patients originally randomized and treated with zofenopril and in 43.8% of patients treated with ramipril [odds ratio (OR) and 95% confidence interval, 0.65 (0.43-0.98), P = 0.041]. Such a result was achieved through a significantly larger reduction in CV hospitalization under zofenopril [OR: 0.61 (0.37-0.99), P = 0.047], whereas reduction in mortality rate with zofenopril did not achieve statistical significance versus ramipril [OR: 0.75 (0.36-1.59), P = 0.459]. These results were in line with those achieved during the initial 1-year follow-up. Benefits of early treatment of patients with LVD after acute myocardial infarction with zofenopril are sustained over many years as compared to ramipril.

Treatment of severe hypertension in a 14-year-old child: Successful blood pressure control with additive administration of captopril, an angiotensin-converting enzyme inhibitor, in a patient with bilateral renovascular hypertension.

We report a 14-year-old boy with recurrent episodes of headache caused by uncontrolled hypertension. The diagnosis of renovascular hypertension due to Takaysu arteritis (TA) was made based on an increase in erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) and computed tomography (CT) image of bilateral renal artery stenosis was taken. Renal scintigraphy revealed normal perfusion and function of the right kidney and severe reduction of the perfusion and function of the left kidney. Careful drug adjustments significantly improved but did not fully control the blood pressure (BP); further, angioplasty, which showed almost occlusion of the left renal artery opening and the minor narrowing of the right renal artery, failed to regain sufficient BP control. The addition of captopril, an angiotensin-converting enzyme (ACE) inhibitor, to conventional antihypertensive drugs successfully and safely lowered BP and preserved the renal function. This unique case suggested that ACE inhibitors achieved better control of BP in a patient with bilateral renal stenosis and that the patient may have hemodynamically significant stenosis caused by unilateral renal artery.

Captopril does not Potentiate Post-Exercise Hypotension: A Randomized Crossover Study.

To evaluate whether captopril (3×50 mg/day) potentiates post-resistance exercise hypotension (PREH) in hypertensives (HT), 12 HT men received captopril and placebo for 4 weeks each in a double-blinded, randomized-crossover design. On each therapy, subjects underwent 2 sessions: Control (C - rest) and Resistance Exercise (RE - 7 exercises, 3 sets to moderate fatigue, 50% of 1 RM -repetition maximum). Measurements were taken before and after 30-60 min (Post1) and 7 h (Post2), and ambulatory blood pressure (BP) was monitored for 24 h. There were no differences in PREH characteristics and mechanisms between the placebo and captopril periods. At Post1, systolic/diastolic BP decreased significantly and similarly after RE with both therapies (Placebo=-13±2/-9±1 mmHg vs. Captopril=-12±2/-10±1 mmHg, P<0.05). RE reduced cardiac output in some subjects and systemic vascular resistance in others. Heart rate and cardiac sympathetic modulation increased, while stroke volume and baroreflex sensitivity decreased after RE (Placebo: +13±2 bpm, +21±5 nu, -11±5 ml, -4±2 ms/mmHg; Captopril: +13±2 bpm, +35±4 nu, 17±5 ml, -3±1 ms/mmHg, P<0.05). At Post2, all variables returned to pre-intervention values. Ambulatory BP was similar between the sessions. Thus, captopril did not potentiate the magnitude and duration of PREH in HT men, and it did not influence PREH mechanisms.

Lactacystin-Induced Model of Hypertension in Rats: Effects of Melatonin and Captopril.

Lactacystin is a proteasome inhibitor that interferes with several factors involved in heart remodelling. The aim of this study was to investigate whether the chronic administration of lactacystin induces hypertension and heart remodelling and whether these changes can be modified by captopril or melatonin. In addition, the lactacystin-model was compared with NG-nitro-l-arginine-methyl ester (L-NAME)- and continuous light-induced hypertension. Six groups of three-month-old male Wistar rats (11 per group) were treated for six weeks as follows: control (vehicle), L-NAME (40 mg/kg/day), continuous light (24 h/day), lactacystin (5 mg/kg/day) alone, and lactacystin with captopril (100 mg/kg/day), or melatonin (10 mg/kg/day). Lactacystin treatment increased systolic blood pressure (SBP) and induced fibrosis of the left ventricle (LV), as observed in L-NAME-hypertension and continuous light-hypertension. LV weight and the cross-sectional area of the aorta were increased only in L-NAME-induced hypertension. The level of oxidative load was preserved or reduced in all three models of hypertension. Nitric oxide synthase (NOS) activity in the LV and kidney was unchanged in the lactacystin group. Nuclear factor-kappa B (NF-κB) protein expression in the LV was increased in all treated groups in the cytoplasm, however, in neither group in the nucleus. Although melatonin had no effect on SBP, only this indolamine (but not captopril) reduced the concentration of insoluble and total collagen in the LV and stimulated the NO-pathway in the lactacystin group. We conclude that chronic administration of lactacystin represents a novel model of hypertension with collagenous rebuilding of the LV, convenient for testing antihypertensive drugs or agents exerting a cardiovascular benefit beyond blood pressure reduction.

Comparison of captopril (0.5%) cream with diltiazem (2%) cream for chronic anal fissure: a prospective randomized double-blind two-centre clinical trial.

AIM: This study compared the efficacy of topical captopril with topical diltiazem in the treatment of chronic anal fissure (CAF). METHOD: Fifty patients aged between 15 and 75 years with CAF were included in a prospective randomized, double-blind clinical trial. They were randomly allocated to either captopril (0.5%) cream or diltiazem (2%) cream in a dose of 2 cm of cream on the perianal skin every 12 h for 8 weeks. The intensity of pain upon defaecation was evaluated every 10 days using a visual analogue scale. Bleeding on defaecation, pruritus and the presence of perianal irritation were also recorded before and during the trial. RESULTS: The average pain scores were lower in the diltiazem group on the 20th and 30th days. From day 40 to the end of the trial the average pain scores of the two groups did not differ significantly. There were no significant differences in bleeding or perianal irritation between the groups, but the incidence of pruritus was considerably higher in the captopril group, and at the end of the trial 45.8% of the patients in this group still suffered from pruritus. CONCLUSION: Topical captopril and diltiazem were found to be equally effective in the management of pain, bleeding and perianal irritation due to CAF, but due to the high incidence of pruritus observed with topical captopril this medication is not recommended for the treatment of CAF.