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Pharmacokinetic/pharmacodynamic modeling of the cardiovascular effects of beta blockers in humans.
Arch Pharm Res. 2008 Jun; 31(6): 814-21
Baek IH, Yun MH, Yun HY, Kwon KI
Pharmacokinetic-pharmacodynamic (PK/PD) analysis is useful study in clinical pharmacology, also PK/PD modeling is major tools for PK/PD analysis. In this study, we sought to characterize the relationship between the cardiovascular effects and plasma concentrations of the beta blocker drugs carvedilol and atenolol using PK/PD modeling in healthy humans. One group received oral doses of atenolol (50 mg) and the other group received oral doses of carvedilol (25 mg). Subsequently, blood samples were taken, and the effects of the drugs on blood pressure were determined. Plasma concentrations of drugs were measured by HPLC, and PK/PD modeling performed by applied biophase model, plasma drug concentrations were linked to the observed systolic blood pressure (SBP) and diastolic blood pressure (DBP) via an effect compartment. The model parameters were estimated using the ADAPT II program. In PK/PD analysis, it was observed the time delay between plasma concentration and effect and the time delay between SBP and DBP. The two time delays were properly explained by PD parameter "K ( eo )" in applied biophase model. As conclusion, the biophase PK/PD model described the relationship between the plasma concentrations of the drugs and the cardiovascular effects, including the time delay between systolic blood pressure and diastolic blood pressure.
Adv Ther. 2008 Jun 12;
Tuncer M, Guntekin U, Gunes Y, Gumrukcuoglu HA, Eryonucu B
INTRODUCTION: IMPAIRED LEFT VENTRICULAR (LV) DIASTOLIC RELAXATION, DETECTED BY PULSED DOPPLER ECHOCARDIOGRAPHY, IS PREDICTIVE OF A HIGHER INCIDENCE OF MAJOR CARDIOVASCULAR EVENTS IN HYPERTENSIVE PATIENTS. AN IMPROVEMENT IN LV DIASTOLIC FUNCTION IS AN IMPORTANT GOAL OF TREATMENT. HOWEVER, TREATMENT OF LV DIASTOLIC DYSFUNCTION REMAINS EMPIRICAL. THE OBJECTIVE OF OUR STUDY WAS TO COMPARE THE SHORT-TERM EFFECTS OF NEBIVOLOL AND ATENOLOL ON DOPPLER DIASTOLIC FILLING PARAMETERS IN HYPERTENSIVE PATIENTS: METHODS: A TOTAL OF 32 PATIENTS WITH MILD-TO-MODERATE HYPERTENSION WERE ENROLLED IN THE STUDY. THE PATIENTS WERE RANDOMLY ASSIGNED TO RECEIVE TREATMENT WITH EITHER NEBIVOLOL (5 MG/DAY) OR ATENOLOL (50 MG/DAY) FOR 1 MONTH. DIASTOLIC FILLING PARAMETERS, WITH PULSED-WAVE DOPPLER TRANSMITRAL FLOW VELOCITIES, WERE MEASURED 1 DAY BEFORE AND 1 MONTH AFTER TREATMENT: RESULTS: COMPARED WITH BASELINE, BOTH AGENTS SIGNIFICANTLY DECREASED HEART RATE AND BLOOD PRESSURE. HOWEVER, THERE WAS NO SIGNIFICANT DIFFERENCE IN PRE-AND POST-TREATMENT VALUES BETWEEN THE NEBIVOLOL AND ATENOLOL GROUPS. BOTH DRUGS SIGNIFICANTLY IMPROVED LV TRANSMITRAL FLOW MEASURED BY EARLY DIASTOLIC FLOW/ATRIAL CONTRACTION SIGNAL (E/A) RATIO, DECREASED DECELERATION TIME (DT) AND ISOVOLUMETRIC CONTRACTION TIME (IVRT), BUT POST-TREATMENT IMPROVEMENT IN E/A, DT AND IVRT VALUES WAS MORE SIGNIFICANT WITH NEBIVOLOL COMPARED WITH ATENOLOL (P=0.05, P=0.05 AND P=0.003, RESPECTIVELY): CONCLUSIONS: ALTHOUGH TREATMENT WITH NEBIVOLOL OR ATENOLOL RESULTS IN IMPROVED LV TRANSMITRAL DIASTOLIC FUNCTION FILLING PARAMETERS (E/A RATIO, IVRT AND DT), NEBIVOLOL HAS A GREATER EFFECT COMPARED WITH ATENOLOL IN PATIENTS WITH MILD-TO-MODERATE HYPERTENSION:
Br J Pharmacol. 2008 Jun 16;
Ngala RA, O'Dowd J, Wang SJ, Agarwal A, Stocker C, Cawthorne MA, Arch JR
Background and purpose:Picomolar concentrations of the beta(3)-adrenoceptor agonist BRL37344 stimulate 2-deoxyglucose uptake in soleus muscle via undefined receptors. Higher concentrations alter uptake, apparently via beta(2)-adrenoceptors. Effects of BRL37344 and beta(2)-adrenoceptor agonists are compared.Experimental approach:Mouse soleus muscles were incubated with 2-deoxy[1-(14)C]-glucose, [1-(14)C]-palmitate or [2-(14)C]-pyruvate, and BRL37344, beta(2)-adrenoceptor agonists and selective beta-adrenoceptor antagonists. Formation of 2-deoxy[1-(14)C]-glucose-6-phosphate or (14)CO(2) was measured. 2-Deoxy[1-(14)C]-glucose uptake and beta-adrenoceptor mRNA were measured in C2C12 cells.Key results:10 pM BRL37344, 10 pM clenbuterol and 100 pM salbutamol stimulated 2-deoxyglucose uptake in soleus muscle by 33-54%. The effect of BRL37344 was prevented by 1 muM atenolol but not by 300 nM CGP20712A or IC3118551, or 1 muM SR59230A; that of clenbuterol was prevented by ICI118551 but not atenolol. 10 nM BRL37344 st4mulated 2-deoxyglucose uptake, whereas 100 nM clenbuterol and salbutamol inhibited uptake. These effects were blocked by ICI118551. Similar results were obtained in C2C12 cells, in which only beta(2)-adrenoceptor mRNA could be detected by RT-PCR. 10 nM BRL37344 and 10 pM clenbuterol stimulated muscle palmitate oxidation. In the presence of palmitate, BRL37344 no longer stimulated 2-deoxyglucose uptake and the effect of clenbuterol was not significant.Conclusions and implications:Stimulation of glucose uptake by 10 pM BRL37344 and clenbuterol involves different atypical pharmacologies. Nanomolar concentrations of BRL37344 and clenbuterol, probably acting via beta(2)-adrenoceptors, have opposite effects on glucose uptake. The agonists preferentially stimulate fat rather than carbohydrate oxidation, but stimulation of endogenous fat oxidation cannot explain why 100 nM clenbuterol inhibited 2-deoxyglucose uptake.British Journal of Pharmacology advance online publication, 16 June 2008; doi:10.1038/bjp.2008.244.
J Hypertens. 2008 Jul; 26(7): 1463-1471
Matsui Y, Eguchi K, Shibasaki S, Ishikawa J, Hoshide S, Pickering TG, Shimada K, Kario K,
OBJECTIVES: Doxazosin is reported to increase the incidence of congestive heart failure. The benefits of doxazosin, for controlling morning blood pressure as well as its effect on the left ventricular structure and function, are herein examined. METHODS: In this study, 223 morning hypertensive patients were randomized into either the doxazosin group, with a once-daily bedtime dose of doxazosin, or the control group, who continued their current medication. Atenolol was added to the doxazosin group when needed. The effect of doxazosin was evaluated by measurement of echocardiographic parameters and B-type natriuretic peptide. RESULTS: The left ventricular wall thickness decreased, but the left ventricular diastolic diameter in the doxazosin group increased from the baseline. The changes in the left ventricular mass index were similar between the groups, whereas the relative wall thickness in the doxazosin group decreased more than that in the control group. The left ventricular diastolic function could deteriorate in the doxazosin group. In the doxazosin group, an increase in the left ventricular diameter was only seen in the patient who did not take diuretics throughout the study. The office and home blood pressure in the doxazosin group decreased more than that in the control group, whereas the B-type natriuretic peptide increased in the doxazosin group. Three cases of congestive heart failure were observed in the doxazosin group, but none in the control group. CONCLUSION: Although a bedtime dose of doxazosin can significantly lower the blood pressure, it can also increase left ventricular diameter, thus increasing the risk of congestive heart failure. However, the prior use of diuretics can prevent the unfavorable effects of doxazosin on the left ventricular structure.
Olmesartan medoxomil : a review of its use in the management of hypertension.
Drugs. 2008; 68(9): 1239-72
Scott LJ, McCormack PL
Olmesartan medoxomil (Olmetec((R)), Benicar((R))) is an angiotensin II type 1 (AT(1)) receptor antagonist (angiotensin receptor blocker [ARB]) that inhibits the actions of angiotensin II on the renin-angiotensin-aldosterone system, which plays a key role in the pathogenesis of hypertension. Oral olmesartan medoxomil 10-40 mg once daily is recommended for the treatment of adult patients with hypertension. In those with inadequate BP control using monotherapy, fixed-dose olmesartan medoxomil/hydrochlorothiazide (HCTZ) [Olmetec plus((R)), Benicar-HCT((R))] combination therapy may be initiated.Extensive clinical evidence from several large well designed trials and the clinical practice setting has confirmed the antihypertensive efficacy and good tolerability profile of oral olmesartan medoxomil, as monotherapy or in combination with HCTZ, in patients with hypertension, including elderly patients with isolated systolic hypertension (ISH). Notably, BP control is sustained throughout the 24-hour dosage interval, including during the last 4 hours of this period. In clinical trials, olmesartan medoxomil monotherapy provided better antihypertensive efficacy than losartan, candesartan cilexetil or irbesartan monotherapy, and was at least as effective as valsartan treatment, with a faster onset of action than other ARBs in terms of reductions from baseline in diastolic BP (DBP) and, in most instances, systolic BP (SBP). Combination therapy with olmesartan medoxomil plus HCTZ was superior to that with benazepril plus amlodipine, as effective as that with losartan plus HCTZ, noninferior to that with atenolol plus HCTZ, but less effective than that with telmisartan plus HCTZ, in individual trials. Data from ongoing clinical outcome trials are required to more fully determine the relative position of olmesartan medoxomil therapy in the management of hypertension. In the meantime, the consistent antihypertensive efficacy during the entire 24-hour dosage interval and good tolerability profile of olmesartan medoxomil, with or without HCTZ, make it a valuable option for the treatment of adult patients with hypertension, including the elderly.
Kardiologiia. 2008; 48(5): 60-1
Tatarchenko IP, Pozdniakova NV, Biriuchenko MV
In vitro and in vivo transdermal studies of atenolol using iontophoresis.
Acta Pol Pharm. 2008 Jan-Feb; 65(1): 29-36
Inal O, Kiliçarslan M, Ari N, Baykara T
Matrix formulations of Eudragit E 100: NE 40D polymers (100:0, 70:30, 60:40, 50:50% w/w) with 20% w/w of triacetine and 5% w/w of atenolol were prepared by film casting method with different solvents (methanol, 2-propanol and acetone). In vitro release of atenolol from the films were studied by vertical Franz diffusion cells in HEPES buffer (pH 7.4) for 78 h. Direct currents of 0.1 and 0.5 mA/cm2 were applied for 6 h to the formulations with Ag/AgCl electrodes. Also, transdermal application for the Eudragit E 100: NE 40 D (70:30% w/w) formulation was compared by iontophoresis or oleic acid (2.5% w/v) with control group on Wistar rats. As a result, the in vitro release rate of atenolol from films were increased with iontophoresis by increasing the current density (from 0.240 to 0.424 mg/cm2 for 70:3% w/w formulation) and also increased with the amount of Eudragit NE 40D (from 0.646 to 1.30 mg/cm2 at the end of 78 h). It is obtained from the in vivo studies that oleic acid provided a higher plasma and skin concentration (0.825 mg/mL and 12.5 mg/cm2, respectively) than iontophoresis treatment (0.399 mg/mL and 1.81 mg/cm2, respectively) due to the different mechanisms. However, the results showed that iontophoresis is a good alternative for enhancing the transdermal delivery of atenolol.
Eur J Pharmacol. 2008 Apr 25;
Mikami M, Goubaeva F, Song JH, Lee HT, Yang J
The beta-adrenoceptor blockers exhibit a well-characterized anti-apoptotic property in the heart and kidney while less is known about the effect of this class of drugs on neuronal apoptosis. We studied the effects of three beta-adrenoceptor blockers propranolol (1-(isoproplyamino)-3-(naphthalene-1-yloxy)propan-2-ol), atenolol (2-[4-[2-hydroxy-3-(1-methylethylamino)propoxyl]phenyl]ehanamide), and ICI 118551 (1-[2,3-(dihydro-7-methyl-1H-iden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol), against staurosporine-induced apoptosis in SH-SY5Y human neuroblastoma cells. Staurosporine increased caspase 3-like activity, DNA fragmentation, PARP cleavage, and the number of TUNEL positive cells consistent with the induction of apoptosis. Propranolol and ICI 118551, but not atenolol, demonstrated a concentration-dependent inhibition of caspase 3-like activity. Propranolol and ICI 118551 directly inhibited the enzymatic activity of recombinant caspase 9 while atenolol did not; however, none of the beta-adrenoceptor blockers that were examined directly blocked caspases 2 or 3 activity. In isolated mitochondria, propranolol and ICI 118551 inhibited staurosporine-induced cytochrome c release while atenolol did not. We conclude that propranolol and ICI 118551 protect SH-SY5Y cells against staurosporine-induced apoptosis through a dual action on the mitochondria and on caspase 9 in a cell type and an apoptotic paradigm where the conventional inhibitors of mitochondrial permeability transition such as cyclosporin A and bongkrekic acid demonstrate no protection.
Am J Emerg Med. 2008 Jun; 26(5): 578-84
Bassiakou E, Xanthos T, Koudouna E, Goulas S, Prapa V, Papadimitriou D, Rokas G, Papadimitriou L
STUDY OBJECTIVES: The aim of the present study was to assess whether a beta-adrenergic blocking agent such as atenolol, administered during cardiopulmonary resuscitation, would improve initial resuscitation success. METHODS: Ventricular fibrillation was induced in 20 Landrace/Large White piglets, which were left untreated for 8 minutes before attempted resuscitation with precordial compression, mechanical ventilation, and electrical defibrillation. Animals were randomized into 2 groups (10 animals each) to receive saline as placebo (20 mL dilution, bolus) + epinephrine (0.02 mg/kg) (group A) or atenolol (0.05 mg/kg per 20 mL dilution, bolus) + epinephrine (0.02 mg/kg) (group B) during cardiopulmonary resuscitation. Electrical defibrillation was attempted after 10 minutes of ventricular fibrillation. RESULTS: Nine animals in group B restored spontaneous circulation in comparison to only 4 in group A. Aortic systolic and diastolic pressures as well as coronary perfusion pressure were significantly increased during cardiopulmonary resuscitation in group B. Furthermore, postresuscitation heart rate of the atenolol-treated group was significantly decreased. CONCLUSIONS: A beta-adrenergic blocking agent, when administered during cardiopulmonary resuscitation, significantly improves initial resuscitation success and increases blood and coronary perfusion pressures during cardiopulmonary resuscitation.
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.