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Medical research on prinivil
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.
Aliskiren: new drug. Arterial hypertension: no evidence of clinical efficacy.
Prescrire Int. 2008 Apr; 17(94): 47-50
(1) Pharmacological management of arterial hypertension is based on antihypertensive drugs with proven efficacy on morbidity and/or mortality endpoints. (2) Aliskiren is the first renin inhibitor to reach the market. (3) There are no published trials of aliskiren with clinical endpoints. Five double-blind short-term (8 weeks) placebo-controlled trials showed a moderate effect on blood pressure. This effect was not superior to that of other antihypertensive drugs with which aliskiren was compared: hydrochlorothiazide, amlodipine, irbesartan, losartan, valsartan, lisinopril and rampiril. (4) When added to another antihypertensive drug, aliskiren had little or no additional effect on blood pressure. In particular, there is no firm evidence that adding aliskiren to amlodipine 5 mg/day is any more effective than doubling the dose of amlodipine. (5) Aliskiren has not been tested in patients with renovascular hypertension or severe hypertension, but pharmacological data suggest that aliskiren might be less effective in these individuals. (6) Overall, the adverse effect profile of aliskiren does not seem to be any better than that of other antihypertensive drugs. Aliskiren contributes to the onset of angioedema, cough, diarrhea and abdominal pain, hyperuricaemia, gout attacks, kidney stones and skin rash. Pharmacovigilance should focus specifically on certain adverse effects that are known to occur with other drugs acting on renin-angiotensin axis, such as angioedema, muscle disorders and anaemia, even though few such cases were observed with aliskiren during clinical trials. (7) Aliskiren is contraindicated during pregnancy, as are other antihypertensive drugs acting on the renin-angiotensin axis. (8) In practice, it is better not to use aliskiren to treat hypertensive patients because better-assessed antihypertensive drugs with longer follow-up are available.
J Zhejiang Univ Sci B. 2008 May; 9(5): 385-90
Zhu PX, Wang DH, Sun CR, Shen ZQ
Two trace impurities in the bulk drug lisinopril were detected by means of high-performance liquid chromatography coupled with mass spectrometry (HPLC/MS) with a simple and sensitive method suitable for HPLC/MS(n) analysis. The fragmentation behavior of lisinopril and the impurities was investigated, and two unknown impurities were elucidated as 2-(6-amino-1-(1-carboxyethylamino)-1-oxohexan-2-ylamino)-4-phenylbutanoic acid and 6-amino-2-(1-carboxy-3-phenylpro-pylamino)-hexanoic acid on the basis of the multi-stage mass spectrometry and exact mass evidence. The proposed structures of the two unknown impurities were further confirmed by nuclear magnetic resonance (NMR) experiments after preparative isolation.
Hyponatremia associated with tolterodine therapy.
Am J Health Syst Pharm. 2008 Jun 1; 65(11): 1054-6
Madewell KA, Kuo P
PURPOSE: The case of a patient who developed hyponatremia after recent initiation of tolterodine is reported. SUMMARY: An 86-year-old woman arrived at the hospital due to an acute change in her mental status. The patient's daughter found her mother slumped over and stated that she was unresponsive for approximately four minutes. The admitting diagnosis was transient ischemic attack or syncope. Baseline laboratory tests revealed an abnormal basic metabolic panel, including a serum sodium concentration of 125 mmol/L and a serum chloride concentration of 88 mmol/L. The results of a complete blood count and thyroid function tests were within normal limits. Unsuccessful attempts at sodium correction included initial fluid restriction and, later, the administration of 0.9% sodium chloride injection over 24 hours. Physiological causes of hyponatremia were ruled out. The attending physician and team pharmacist reviewed the patient's medication profile for potential causes of hyponatremia. Hydrochlorothiazide, a home medication for the patient, was discontinued at hospital admission and ruled out as a cause of her hyponatremia. A documented association between lisinopril, mirtazapine, or omeprazole and hyponatremia exists in various case reports. However, per the patient's primary care physician, tolterodine was the only modification of an otherwise stable medication profile at an outpatient office visit approximately four weeks prior to admission. Once tolterodine was discontinued, the patient's hyponatremia quickly resolved. Tolterodine was discontinued on hospital day 5, and the hyponatremia was corrected by the next day. CONCLUSION: An 86-year-old woman developed hyponatremia after recent initiation of tolterodine therapy.
Fat redistribution and adipocyte transformation in uninephrectomized rats.
Kidney Int. 2008 May 21;
Zhao HL, Sui Y, Guan J, He L, Zhu X, Fan RR, Xu G, Kong AP, Ho CS, Lai FM, Rowlands DK, Chan JC, Tong PC
Dyslipidemia complicates renal function leading to disturbances of major homeostatic organs in the body. Here we examined the effect of chronic renal dysfunction induced by uninephrectomy on fat redistribution and lipid peroxidation in rats treated with an angiotensin-converting enzyme (ACE) inhibitor (lisinopril) for up to 10 months. Uninephrectomized rats developed fat redistribution and hypercholesterolemia typical of chronic renal failure when compared with sham-operated rats or lisinopril-treated uninephrectomized rats. The weight of the peri-renal fat was significantly less in the untreated compared to the lisinopril-treated uninephrectomized rats or those rats with a sham operation. We also found that there was a shift of heat-protecting unilocular adipocytes to heat-producing multilocular fat cells in the untreated uninephrectomized rats. Similarly in these rats we found a shift of subcutaneous and visceral fat to ectopic fat with excessive lipid accumulation and lipofuscin pigmentation. Lisinopril treatment prevented fat redistribution or transformation and lipid peroxidation. This study shows that ACE inhibition may prevent the fat anomalies associated with chronic renal dysfunction.Kidney International advance online publication, 21 May 2008; doi:10.1038/ki.2008.195.
J Cardiovasc Pharmacol. 2008 Jun; 51(6): 565-72
Ahmad M, White R, Tan J, Huang BS, Leenen FH
The brain renin-angiotensin system contributes significantly to progressive left ventricular (LV) dysfunction in rats after myocardial infarction (MI). The present study evaluated the effects of central versus peripheral plus central angiotensin-converting enzyme (ACE) blockade on sympathetic activity, and LV anatomy and function after MI. METHODS:: Wistar rats were treated for 4 weeks after MI with the lipophilic ACE inhibitor trandolapril at 5 mg/kg/day or the hydrophilic blocker lisinopril at 50 mg/kg/day by once daily subcutaneous injection, or with a central infusion of lisinopril at 0.1 mg/kg/day. RESULTS:: At 24 hours after the last dose, subcutaneous trandolapril caused 70% to 80% ACE inhibition in both brain and kidneys; lisinopril caused 10% to 20% less. Central infusion of lisinopril caused 70% inhibition of brain ACE and minimal (6%) inhibition in the kidneys. All three treatments similarly improved sympathetic reactivity and arterial baroreflex function. All three treatments lowered cardiac Ang I and II, and similarly attenuated the increases in LV end diastolic pressure, circumference, and fibrosis. Both subcutaneous treatments further decreased LV peak systolic pressure and dP/dtmax, whereas icv lisinopril caused no change. CONCLUSION:: Despite marked differences in the extent of peripheral blockade, all three treatments similarly affected sympathetic activity and decreased cardiac Ang II, preload and remodeling after MI. One may speculate that central and peripheral ACE-mediated mechanisms are sequential and therefore only minor additional effects of peripheral ACE blockade are noted.
Ter Arkh. 2008; 80(4): 54-9
AIM: To assess efficacy of monotherapy with ACE inhibitor lisinopril (diroton) or calcium antagonist amlodipine (normodipine) and their combination in patients with metabolic syndrome (MS). MATERIAL AND METHODS: The study enrolled 42 patients (30 females, 12 males) with MS. The examination at baseline and after 12 weeks of treatment included office blood pressure (BP) measurement, 24-hour BP monitoring, heart rate variability (HRV) and carbohydrate profiles estimation. RESULTS: In moderate hypertension BP normalized in 40 and 44% on monotherapy with lisinopril or amlodipine, respectively, and in 78% patients given lisinopril+amlodipine. The latter combination and lisinopril monotherapy had a positive effect on HRV parameters. Lisinopril monotherapy improved carbohydrate metabolism as shown by reduction of postprandial hyperglycemia and hyperinsulinemia in MS patients. CONCLUSION: Combined treatment with amlodipin and lisinopril is more effective than monotherapy with each of the above drugs.
J Nucl Med. 2008 Jun; 49(6): 970-7
Femia FJ, Maresca KP, Hillier SM, Zimmerman CN, Joyal JL, Barrett JA, Aras O, Dilsizian V, Eckelman WC, Babich JW
In animal models of cardiac disease and in human congestive heart failure, expression of angiotensin-converting enzyme (ACE) is upregulated in the failing heart and has been associated with disease progression leading to cardiac failure and fibrosis. To develop probes for imaging ACE expression, a series of di(2-pyridylmethyl)amine (D) chelates capable of binding M(CO)3+ (M = technetium, rhenium) was conjugated to lisinopril by acylation of the epsilon-amine of the lysine residue with a series of di(2-pyridylmethylamino)alkanoic acids where the distance of the chelator from the lisinopril core was investigated by varying the number of methylene spacer groups to produce di(2-pyridylmethyl)amine(Cx)lisinopril analogs: D(C4)lisinopril, D(C5)lisinopril, and D(C8)lisinopril. The inhibitory activity of each rhenium complex was evaluated in vitro against purified rabbit lung ACE and was shown to vary directly with the length of the methylene spacer: Re[D(C8)lisinopril], inhibitory concentration of 50% (IC50) = 3 nM; Re[D(C5)lisinopril], IC50 = 144 nM; and Re[D(C4)lisinopril], IC50 = 1,146 nM, as compared with lisinopril, IC50 = 4 nM. The in vivo specificity for ACE was determined by examining the biodistribution of the 99mTc-[D(C8)lisinopril] analog in rats with and without pretreatment with unlabeled lisinopril. Uptake in the lungs, a tissue that constitutively expresses ACE, was 15.2 percentage injected dose per gram at 10 min after injection and was dramatically reduced by pretreatment with lisinopril, supporting ACE-mediated binding in vivo. Planar anterior imaging analysis of 99mTc-[D(C8)lisinopril] corroborated these data. Thus, high-affinity 99mTc-labeled ACE inhibitor has been designed with potency similar to that of lisinopril and has been demonstrated to specifically localize to tissues that express ACE in vivo. This agent may be useful in monitoring ACE as a function of disease progression in relevant diseases such as heart failure.
Arch Insect Biochem Physiol. 2008 Jul; 68(3): 171-80
Chung JS, Webster SG
Angiotensin-converting enzyme-like enzyme activity (ACELA) was found in Carcinus maenas using reverse phase high performance liquid chromatography (RP-HPLC) analysis of degradation kinetics of a synthetic substrate (Hippuryl-histidyl-leucine) and a specific inhibitor (captopril). Gills contained the highest ACELA, then brain, muscle, and testis, respectively, while no activity was detected in the following tissues: hepatopancreas, hindgut, hypodermis, heart, and hemolymph. ACELA present in gill membranes exhibited a K(m) of 0.23 mM and V(max) of 7.6 nmol with synthetic substrate. The enzyme activity was dependent on Cl- concentration and was markedly inhibited by captopril, lisinopril, and EDTA. Addition of Zn2+ to membranes previously treated with EDTA restored 89% activity, suggesting that C. maenas ACELA is a Zn2+ metalloenzyme. Gill membranes prepared from premolt crabs showed similar levels of ACELA to those of the intermolt animals. Administration of captopril in vivo lengthened the half life of circulating CHH, while in vitro incubation of gill membranes with captopril reduced CHH. These results suggest that C. maenas ACELA present in gills is likely to be involved in degradation of this neuropeptide.
J Microencapsul. 2008 Apr 17; 1-9
Varshosaz J, Soheili M
Lisinopril, an angiotensin converting enzyme (ACE) inhibitor drug, was encapsulated in poly(lactide-co-glicolide) (PLGA) nanoparticles (NP) for site-specific delivery by catheters in prevention of restenosis. NP were prepared by emulsification-diffusion method. The PLGA type, stabilizing agent type and its concentration were studied as process variables. The z-average particle size varied between 265-412 nm. The highest zeta potential was seen in NP prepared with Pluronic F-68. None of the studied variables or their interactions had a significant effect on the particle size while all had main effect on the zeta potential. The highest entrapment efficiency was 93% and all studied variables and their interactions except PLGA type and its interaction with the stabilizer type had significant effects on the loading. Baker-Lonsdale model was the most appropriate model for release of lisinopril from NP. Five per cent PLGA 75 : 25 and 5% Pluronic F-68 showed promising results for 21 days release of lisinopril as an anti-restenotic agent.