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Medical research on zestril
Transport of Angiotensin-converting Enzyme Inhibitors by H+/Peptide Transporters Revisited.
J Pharmacol Exp Ther. 2008 Aug 19;
Knutter I, Wollesky C, Kottra G, Hahn M, Fischer W, Zebisch K, Neubert R, Daniel H, Brandsch M
Angiotensin-converting enzyme (ACE) inhibitors are often regarded as substrates for the peptide transporters PEPT1 and PEPT2. Even though the conclusions drawn from published data are quite inconsistent, in most review articles PEPT1 is claimed to mediate the intestinal absorption of ACE inhibitors and thus to determine their oral availability. We systematically investigated the interaction of a series of ACE inhibitors with PEPT1 and PEPT2. First, we studied the effect of fourteen ACE inhibitors including new drugs on the uptake of the dipeptide [(14)C]Gly-Sar into human intestinal Caco-2 cells constitutively expressing PEPT1 and rat renal SKPT cells expressing PEPT2. In a second approach, the interaction of ACE inhibitors with heterologously expressed human PEPT1 and PEPT2 was determined. In both assay systems, zofenopril and fosinopril were found to have very high affinity for binding to peptide transporters. Medium to low affinity for transporter interaction was found for benazepril, quinapril, trandolapril, spirapril, cilazapril, ramipril, moexipril, quinaprilat and perindopril. For enalapril, lisinopril and captopril very weak affinity or lack of interaction was found. Transport currents of PEPT1 and PEPT2 expressed in Xenopus laevis oocytes were recorded by the two-electrode voltage clamp technique. Statistically significant, but very low currents were only observed for lisinopril, enalapril, quinapril and benazepril at PEPT1 and for spirapril at PEPT2. For the other ACE inhibitors electrogenic transport activity was extremely low or not measurable at all. The present results suggest that peptide transporters do not control intestinal absorption and renal reabsorption of ACE-inhibitors.
Appl Spectrosc. 2008 Aug; 62(8): 889-94
Widjaja E, Tan WJ
The solid-state intramolecular cyclization of lisinopril to diketopiperazine was investigated by in situ Fourier transform infrared (FT-IR) microscopy. Using a controllable heating cell, the isothermal transformation was monitored in situ at 147.5, 150, 152.5, 155, and 157.5 degrees C. The collected time-dependent FT-IR spectra at each isothermal temperature were preprocessed and analyzed using a multivariate chemometric approach. The pure component spectra of the observable component (lisinopril and diketopiperazine) were resolved and their time-dependent relative contributions were also determined. Model-free and various model fitting methods were implemented in the kinetic analysis to estimate the activation energy of the intramolecular cyclization reaction. Arrhenius plots indicate that the activation energy is circa 327 kJ/mol.
J Hypertens. 2008 Sep; 26(9): 1860-1867
Menne J, Farsang C, Deák L, Klebs S, Meier M, Handrock R, Sieder C, Haller H
OBJECTIVES: Microalbuminuria is known as an independent predictor for stroke, myocardial infarction, and death. The purpose of the VALERIA trial was a comparison of the efficacy and safety of combination therapy of valsartan and lisinopril with valsartan and lisinopril high-dose monotherapy in patients with hypertension and microalbuminuria. METHODS: This was a randomized, double-blind, interventional, parallel-group study. After a washout/placebo- run-in phase of 3 weeks, 133 patients were randomized to treatment (1: 1:1) with either lisinopril 40 mg, valsartan 320 mg, or a combination of valsartan/lisinopril 320/20 mg for 30 weeks. RESULTS: At baseline, the urine albumin creatinine ratio was similar for the three treatment groups (geometric means, lisinopril 9.6 mg/mmol, valsartan 9.1 mg/mmol, and valsartan/lisinopril 9.5 mg/mmol). After 30 weeks of treatment, the geometric mean urine albumin creatinine ratio had decreased in all three groups by 41, 51, and 62% to 5.7 mg/mmol (lisinopril), 4.5 mg/mmol (valsartan), and 3.6 mg/mmol (valsartan/lisinopril). The decrease for valsartan/lisinopril was statistically significantly greater compared with lisinopril [adjusted ratio 60%, confidence interval (38-94%), P = 0.029]. Normalization of microalbuminuria was greatest with valsartan and valsartan/lisinopril (lisinopril 17%, valsartan 31%, and valsartan/lisinopril 38% of patients) and was statistically significant for lisinopril in contrast with valsartan/lisinopril (P = 0.034). Differences in blood pressure reduction between the groups were not statistically significant. All treatments were safe and well tolerated. CONCLUSION: The combination of valsartan and lisinopril provided a significantly better reduction of urine albumin creatinine ratio and more than doubled the rate of patients with normalized urine albumin creatinine ratio compared with lisinopril alone. All treatments were safe and well tolerated.
Bioorg Khim. 2008 Jul-Aug; 34(4): 471-8
Mukhametova LI, Gulin DA, Binevskii PV, Aisina RB, Kost OA, Nikolskaya II
The effects of hypotensive agents (captopril, enalaprilate, and lisinopril) on the activities of components of the fibrinolytic system (FS) and the effects of antifibrinolytic agents (6-aminohexanoic acid (6-AHA) and tranexamic acid (t-AMCHA)) on the activities of angiotensin converting enzyme (ACE) were studied in vitro. Enalaprilate did not affect the FS activity. Captopril considerably inhibited the amidase activities of urokinase (u-PA), plasminogen tissue activator (t-PA), and plasmin ([I](50) (2.0-2.6) +/- 0.1 mM), and the activation of Glu-plasminogen affected by t-PA and u-PA ([I](50) (1.50-1.80) +/- 0.06 mM), which may be due to the presence of a mercapto group in the inhibitor molecule. Lisinopril did not affect the amidase activities of FS enzymes, but stimulated Glu-plasminogen and u-PA activation and inhibited activation of t-PA-fibrin-bound Glu-plasminogen ([I](50) (12.0 +/- 0.5) mM). Presumably, these effects can be explained by the presence in lisinopril of a Lys side residue, whose binding to lysine-binding Glu-plasminogen centers resulted, on the one hand, in the transformation of its closed conformation to a semi-open one and, on the other hand, in its desorption from fibrin. Unspecific inhibition of the activity of ACE, a key enzyme of the renin-angiotensin system, in the presence of 6-AHA and t-AMCHA ([I](50) 10.0 +/- 0.5 and 7.5 +/- 0.4 mM, respectively) was found. A decrease in the ACE activity along with the growth of the fibrin monomer concentration was revealed. The data demonstrate that, along with endogenous mediated interactions, relations based on the direct interactions of exogenous inhibitors of one system affecting the activities of components of another system can take place.
J Pharm Biomed Anal. 2008 Jun 11;
Kumar V, Malik S, Singh S
A polypill for cardiovascular diseases (CVD) is under development. It is proposed to contain a combination of antithrombotic agent (aspirin), low-dose blood pressure lowering agents, i.e., angiotensin-converting enzyme inhibitor (lisinopril), one among a beta-blocker (atenolol) or diuretic (hydrochlorothiazide), and a statin (simvastatin/atorvastatin/pravatsatin, etc.). Due to the presence of multiple drugs in the same formulation, there is a strong likelihood of interaction among the drugs and/or their products. In a previous study, we observed formation of a number of interaction/degradation products from atenolol and lisinopril in the presence of aspirin. Accordingly, the purpose of this study was to characterize the resolved products using high resolution mass spectrometric and fragmentation analyses using a LC-MS/TOF system. Initially, studies were carried out on the drugs (atenolol, lisinopril and aspirin) to establish their complete fragmentation pattern. These studies were then extended to degraded samples to postulate the structures of interaction/degradation products. The characterized structures were justified through mechanistic explanations.
Reduction of proteinuria with angiotensin receptor blockers.
Nat Clin Pract Cardiovasc Med. 2008 Jul; 5 Suppl 1: S36-43
Galle J
Renal pathophysiology is elicited by activation of angiotensin II type 1 (AT(1)) receptors at all stages of renovascular disease. Angiotensin receptor blockers (ARBs) that specifically block the AT(1) receptor offer the potential to prevent or delay progression to end-stage renal disease independently of reductions in blood pressure. Proteinuria--an early and sensitive marker for progressive renal dysfunction--is reduced by ARB use in patients with type 2 diabetic nephropathy and microalbuminuria or macroalbuminuria. Retrospective analysis of data available from early trials has confirmed this finding and has shown that albuminuria reduction is associated with lessening of cardiovascular risk. The ARB telmisartan is equivalent to enalapril in preventing glomerular filtration rate decline, and equivalent to valsartan in reducing proteinuria. Telmisartan is more effective than conventional therapy in lowering the risk of transition to overt nephropathy in hypertensive and normotensive patients. An additive effect has been seen in smaller studies when telmisartan has been added to lisinopril therapy, and high-dose telmisartan reduces albuminuria better than low-dose telmisartan. Similar data were obtained with other ARBs such as candesartan, losartan, valsartan, or irbesartan. These data support the proposition that blockade of the renin-angiotensin system beyond that required for maximum blood pressure reduction provides optimum renal protection.
A case of renal transplantation.
Mymensingh Med J. 2008 Jul; 17(2): 214-6
Muinuddin G, Paul SK, Rahman MH, Jahan S, Begum A, Salam MA, Hossain MM
A 12-year-old boy was admitted in paediatric nephrology unit of Bangabandhu Sheikh Mujib Medical University (BSMMU) with massive proteinuria, hypertension, respiratory distress and anaemia and diagnosed as nephrotic syndrome. Percutaneous needle biopsy was consistent with diffuse endocapillary proliferative glomerulonephritis and initially managed conservatively with injection methyl prednisolone, cyclophosphamide, lisinopril etc. without any improvement. Living-related renal transplantation was done successfully from paternal uncle. Two episodes of acute rejection occurred, one immediately after transplantation and another after one month. These were managed with IV methyl prednisolone for 3 days. At present, he is on oral prednisolone, cyclosporine, azathioprine and antihypertensives with normal haemoglobin and stable serum creatinine level (pre-transplant level 12.5mg/dl to post-transplant level 1.5mg/dl). He has been maintaining his normal life including schooling for last few months. It is concluded that a patient with uncommon presentation of nephrotic syndrome should be confirmed by renal biopsy and renal transplantation may be considered if conservative measures fail.
Effect of antihypertensive treatment on retinal microvascular changes in hypertension.
J Hypertens. 2008 Aug; 26(8): 1703-7
Hughes AD, Stanton AV, Jabbar AS, Chapman N, Martinez-Perez ME, McG Thom SA
OBJECTIVE: Hypertension causes arteriolar narrowing and rarefaction in the retinal circulation, but the extent to which these changes are reversible by antihypertensive treatment is not well studied. We compared the effect of antihypertensive treatment with a calcium-channel-blocker-based regimen and an angiotensin-converting-enzyme-inhibitor-based regimen on the retinal microvasculature. METHODS: Twenty-five patients (17 men, age range 24-71 years) with untreated hypertension were randomized to treatment with an amlodipine-based (n = 12) or lisinopril-based (n = 13) regimen in a double-blind, prospective parallel limb trial for 52 weeks. Measurements of blood pressure and the retinal microvasculature were made at baseline and at the end of the study. RESULTS: Both the amlodipine-based and lisinopril-based treatments reduced blood pressure to similar extents. Blood pressure reduction was associated with a reduction in arteriolar narrowing, a widening of arteriolar branch angle and an increase in arteriolar density. There were no significant differences between the two treatment regimens. CONCLUSION: Antihypertensive treatment is associated with improvement in arteriolar narrowing and rarefaction. Improved microvascular structure may contribute to the beneficial effects of antihypertensive treatment in hypertension.
Biol Pharm Bull. 2008 Jul; 31(7): 1356-61
Yayama K, Miyagi R, Sugiyama K, Sugaya T, Fukamizu A, Okamoto H
Angiotensin II (Ang II) is an important mediator stimulating liver fibrosis after liver injury. However, it is not known whether Ang II plays a role in liver regeneration. Here, we investigate the effects of Ang II type 1 (AT(1)) receptor blocker (ARB), angiotensin-converting enzyme inhibitor (ACEI), systemic infusion of Ang II, and genetic deficiency of the AT(1a) receptor (AT1a-KO) on the hepatic regenerative response to partial hepatectomy (PH) in mice. Administration of ARB (candesartan cilexetil and losartan) or ACEI (enarapril and lisinopril) enhanced 5-bromo-2'-deoxyuridine (BrdU) incorporation into hepatocyte nuclei in remnant liver as well as the restoration of liver weight after PH. Systemic infusion of Ang II (100 ng/kg/min) suppressed the PH-induced BrdU incorporation and the restoration of liver weight. In contrast to Ang II infusion, these hepatic responses to PH were significantly greater in AT1a-KO mice than in wild-type mice. The PH-induced increases in hepatic levels of hepatocyte growth factor (HGF) mRNA and plasma HGF concentrations were greater in candesartan- and enarapril-treated mice or in AT1a-KO mice than in vehicle-treated mice or wild-type mice, respectively, whereas they were less in Ang II-infused mice than in vehicle-infused mice. In contrast to HGF, blockades of the renin-angiotensin system or Ang II infusion produced opposite effects on the PH-induce increases in hepatic transforming growth factor (TGF)-beta 1 mRNA and plasma TGF-beta 1 levels. These studies suggest that Ang II plays a role in the liver regeneration as a suppressor of hepatocyte proliferation via the AT(1) receptor-mediated control of growth factor production.
Hypertension. 2008 Jul; 52(1): 65-71
Jennings JR, Muldoon MF, Price J, Christie IC, Meltzer CC
Hypertension is associated with mild decrements in cognition. In addition, regional cerebral blood flow responses during memory processing are blunted in parietal and thalamic areas among untreated hypertensive adults, who, compared with normotensive subjects, manifest greater correlation in blood flow response across task-related brain regions. Here, we test whether pharmacological treatment of hypertension normalizes regional cerebral blood flow responses and whether it does so differentially according to drug class. Treatment with lisinopril, an angiotensin-converting enzyme blocker, known to enhance vasodilative responsivity, was compared with treatment with atenolol, a beta-blocker. Untreated hypertensive volunteers (n=28) were randomly assigned and treated for 1 year. Whole brain and regional cerebral flow responses to memory processing and acutely administered acetazolamide, a vasodilator, were assessed pretreatment and posttreatment. Peripheral brachial artery dilation during reactive hyperemia was also measured. Quantitative blood flow measures showed no difference in the magnitude of regional cerebral blood flow responses pretreatment and posttreatment to either memory tasks or acetazolamide injection. Brachial artery flow-mediated dilation increased with treatment. No differences between medications were observed. In brain regions active in memory processing, however, regional cerebral blood flow responses were more highly correlated after treatment. Specificity of cerebral blood flow to different regions appears to decline with treatment of hypertension. This greater correlation among active brain regions, which is present as well in untreated hypertensive relative to normotensive volunteers, may represent compensation in the face of less region-specific responsivity in individuals with hypertension.