Manuel Worcel - Academia.edu (original) (raw)
Papers by Manuel Worcel
La presente invention concerne des methodes de (a) reduction de la mortalite associee a une insuf... more La presente invention concerne des methodes de (a) reduction de la mortalite associee a une insuffisance cardiaque ; (b) amelioration de la consommation d'oxygene ; (c) traitement d'une insuffisance cardiaque ; (d) traitement de l'hypertension ; (e) amelioration de la qualite de vie d'un patient souffrant d'insuffisance cardiaque ; (f) inhibition du remodelage du ventricule gauche ; (g) reduction des hospitalisations liees aux insuffisances cardiaques ; (h) amelioration de la tolerance a l'exercice ; (j) augmentation de la fraction expulsee par le ventricule gauche ; (k) diminution des teneurs en proteine natriuretique de type B ; (l) traitement de maladies renovasculaires ; (m) traitement de maladies renales en phase terminale ;(n) reduction de la cardiomegalie ; (o) traitement de maladies resultant d'un stress oxydant ; (p) traitement de deficiences endotheliales ; (q) traitement de maladies provoquees par des deficiences endotheliales ; ou (r) traiteme...
Background: To characterize the quality of life (QOL) in the African-American Heart Failure Trial... more Background: To characterize the quality of life (QOL) in the African-American Heart Failure Trial (A-HeFT) for factors associated with baseline score, relation of score to prognosis, and response to therapy with a fixed-dose combination of isosorbide dinitrate/hydralazine (FDC I/H). Limited data exist on QOL scores in African-American heart failure patients or on the prognostic value of theses scores in any population. Finally, the effect of FDC I/H on QOL scores, particularly in A-HeFT, is not known. Methods and Results: A-HeFT randomized 1050 African-American patients with New York Heart Association (NYHA) Class III-IV heart failure and systolic dysfunction. QOL measurements using Minnesota Living with Heart Failure Questionnaire (MLHFQ) were done at baseline and 3-month intervals. At baseline, worse MLHFQ scores were associated with younger age, female sex, greater body mass index, nonischemic etiology, high heart rate and NYHA Class, low systolic blood pressure, and chronic obst...
European Journal of Pharmacology, Feb 1, 1988
Trandolapnl (3-100 #g/kg) and enalapnl (10-300 #g/kg) were admlmstered orally to conscious rats A... more Trandolapnl (3-100 #g/kg) and enalapnl (10-300 #g/kg) were admlmstered orally to conscious rats Angtotensmconverting enzyme (CE) acuwty was mtublted m serum, heart ventricle, renal tuner cortex, lung, aorta, adrenal cortex and adrenal medulla, but not m the stnatum InlublUon was maxamal at 2 h and with trandolaprll was maintained for 24 h. Blood pressure and heart rate were not affected by either compound Trandolaprd was 6-10-fold more potent than enalaprd Differences between trandolapnl and enalapnl m CE mlubmon observed m heart ventncle, adrenal cortex and medulla could be due to the presence of more than one type of CE or CE-hke activity.
European Journal of Pharmacology, Mar 1, 1988
Trandolapril (RU 44570), a new non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor chemi... more Trandolapril (RU 44570), a new non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor chemically related to enalapril, and its diacid (RU 44403), were investigated for their ability to inhibit angiotensin-converting enzyme. Trandolapril attenuated angiotensin I (Ang I)-induced pressor responses following i.v. administration to rats and dogs with IDs0 values of 13.1 + 1.3 and 21.1 + 2.3 lag/kg. RU 44403 produced corresponding values of 9.9 + 0.7 and 7.2 + 2.3/~g/kg. Trandolapril (3-300/~g/kg) produced a dose-related attenuation of Ang I-induced pressor responses (IDs0 30 #g/kg) following oral administration to rats. Oral administration of trandolapril (30-1000 /tg/kg) to dogs inhibited Ang I pressor responses for over 6 h. The depressor action of bradykinin in the rat was potentiated by i.v. trandolapril and RU 44403 with EDs0 values of 5.5 + 0.8 and 4.9 + 0.3 /tg/kg respectively. Trandolapril was 2.3-10-fold more potent than enalapril in all experiments, depending on species or route of administration. RU 44403 and MK 422 were approximately equipotent, implying that trandolapril was more readily hydrolysed than enalapril. Trandolapril (0.3-30 mg/kg) produced dose-related, long-lasting (> 24 h) reductions in blood pressure (BP) in spontaneously hypertensive rats (SHR) following oral administration. The anti-hypertensive effect was potentiated significantly in hydrochlorothiazide-pretreated SHR when the plasma renin activity was increased. Enalapril was 10-fold less potent than trandolapril in reducing BP. The anti-hypertensive action of trandolapril (3 mg/kg) was abolished in SHR that were bilaterally nephrectomized 24 h beforehand, but was maintained in SHR pretreated by indomethacin (5 mg/kg p.o.). Trandolapril (1 mg/kg i.v.) produced a modest and transient reduction in BP in anesthetized dogs. Trandolapril produced dose-related (30-1000 ~tg/kg) reductions in BP, total peripheral resistance and heart work in dogs pretreated with hydrochlorothiazide to increase plasma renin activity. Angiotensin-converting enzyme (ACE) inhibition; Trandolapril (RU 44570); Trandolapril-diacid (RU 44403)
Jacc-Heart Failure, Dec 1, 2014
The purpose of this study was to evaluate the influence of the guanine nucleotide-binding protein... more The purpose of this study was to evaluate the influence of the guanine nucleotide-binding proteins (G-proteins), beta-3 subunit (GNB3) genotype on the effectiveness of a fixed-dose combination of isosorbide dinitrate and hydralazine (FDC I/H) in A-HeFT (African American Heart Failure Trial). BACKGROUND GNB3 plays a role in alpha 2-adrenergic signaling. A polymorphism (C825T) exists, and the T allele is linked to enhanced alpha-adrenergic tone and is more prevalent in African Americans. METHODS A total of 350 subjects enrolled in the genetic substudy (GRAHF [Genetic Risk Assessment of Heart Failure in African Americans]) were genotyped for the C825T polymorphism. The impact of FDC I/H on a composite score (CS) that incorporated death, hospital stay for heart failure, and change in quality of life (QoL) and on event-free survival were assessed in GNB3 genotype subsets. RESULTS The GRAHF cohort was 60% male, 25% ischemic, 97% New York Heart Association functional class III, age 57 AE 13 years, with a mean qualifying left ventricular ejection fraction of 0.24 AE 0.06. For GNB3 genotype, 184 subjects were TT (53%), 137 (39%) CT, and 29 (8%) were CC. In GNB3 TT subjects, FDC I/H improved the CS (FDC I/H ¼ 0.50 AE 1.6;
Carolina Digital Repository (University of North Carolina at Chapel Hill), 2004
We examined whether a fixed dose of both isosorbide dinitrate and hydralazine provides additional... more We examined whether a fixed dose of both isosorbide dinitrate and hydralazine provides additional benefit in blacks with advanced heart failure, a subgroup previously noted to have a favorable response to this therapy. methods A total of 1050 black patients who had New York Heart Association class III or IV heart failure with dilated ventricles were randomly assigned to receive a fixed dose of isosorbide dinitrate plus hydralazine or placebo in addition to standard therapy for heart failure. The primary end point was a composite score made up of weighted values for death from any cause, a first hospitalization for heart failure, and change in the quality of life. results The study was terminated early owing to a significantly higher mortality rate in the placebo group than in the group given isosorbide dinitrate plus hydralazine (10.2 percent vs. 6.2 percent, P=0.02). The mean primary composite score was significantly better in the group given isosorbide dinitrate plus hydralazine than in the placebo group (¡0.1±1.9 vs. ¡0.5±2.0, P=0.01; range of possible values,-6 to +2), as were its individual components (43 percent reduction in the rate of death from any cause [hazard ratio, 0.57; P=0.01] 33 percent relative reduction in the rate of first hospitalization for heart failure [16.4 percent vs. 22.4 percent, P=0.001], and an improvement in the quality of life [change in score, ¡5.6±20.6 vs. ¡2.7±21.2, with lower scores indicating better quality of life; P=0.02; range of possible values, 0 to 105]). conclusions The addition of a fixed dose of isosorbide dinitrate plus hydralazine to standard therapy for heart failure including neurohormonal blockers is efficacious and increases survival among black patients with advanced heart failure.
Journal of Cardiac Failure, Aug 1, 2007
Journal of Cardiac Failure, Dec 1, 2009
To characterize the quality of life (QOL) in the African-American Heart Failure Trial (A-HeFT) fo... more To characterize the quality of life (QOL) in the African-American Heart Failure Trial (A-HeFT) for factors associated with baseline score, relation of score to prognosis, and response to therapy with a fixed-dose combination of isosorbide dinitrate/hydralazine (FDC I/H). Limited data exist on QOL scores in African-American heart failure patients or on the prognostic value of theses scores in any population. Finally, the effect of FDC I/H on QOL scores, particularly in A-HeFT, is not known. A-HeFT randomized 1050 African-American patients with New York Heart Association (NYHA) Class III-IV heart failure and systolic dysfunction. QOL measurements using Minnesota Living with Heart Failure Questionnaire (MLHFQ) were done at baseline and 3-month intervals. At baseline, worse MLHFQ scores were associated with younger age, female sex, greater body mass index, nonischemic etiology, high heart rate and NYHA Class, low systolic blood pressure, and chronic obstructive pulmonary disease. Both baseline and change in MLHFQ score were associated with a higher risk for combined all-cause mortality or heart failure hospitalization (baseline P < .0001, change at 3 months P=.001, and at 6 months P=.0008), but not mortality. Treatment with FDC I/H significantly improved MLHFQ score compared with placebo. In A-HeFT, baseline QOL (MLHFQ) scores and change in score were predictive of combined HF morbidity and mortality outcomes. FDC I/H consistently improved QOL scores in A-HeFT compared with placebo.
British Journal of Pharmacology, Nov 1, 1970
Abstract A biological assay, together with determination of radioactivity in the effluent and tis... more Abstract A biological assay, together with determination of radioactivity in the effluent and tissue of isolated perfused hearts and kidneys, and analysis of effluents by chromatography has been used to evaluate the fate of 3 H-angiotensin II on passage through the vascular beds of these organs. Data indicates that the process previously termed “extraction” of angiotensin II, which has been observed in many vascular beds, is due mainly to a rapid enzymatic degradation of the octapeptide into metabolic fragments, of which the heptapeptide, pentapeptide and tetrapeptide have been identified. The kidney has greater angiotensinase activity than the heart.
Clinical Pharmacokinectics, 2007
To investigate whether the apparent discrepancy between the efficacy of the combination of isosor... more To investigate whether the apparent discrepancy between the efficacy of the combination of isosorbide dinitrate (ISDN) and hydralazine demonstrated in the first V-HeFT trial (V-HeFT I) and that in V-HeFT II could be explained by pharmacokinetic differences in the study drug formulations, and to compare the pharmacokinetic profile of the fixed-dose combination of ISDN/hydralazine (FDC ISDN/HYD; BiDil) formulation used in A-HeFT with that of the V-HeFT study drug formulations. A bioequivalence study was performed (n = 18-19 per group) comparing the ISDN and hydralazine formulations used in V-HeFT I, V-HeFT II and A-HeFT in healthy volunteer men and women aged 18-40 years. In phase A of the study, subjects received a reference solution of hydralazine hydrochloride/ISDN (37.5mg/10mg) orally. Slow acetylators were identified and randomised into three groups in phase B to receive a single oral dose of identical amounts of hydralazine hydrochloride/ISDN (37.5mg/10mg) from either (i) a hydralazine capsule plus an ISDN tablet (the V-HeFT I formulation); (ii) a hydralazine tablet plus an ISDN tablet (the V-HeFT II formulation); or (iii) FDC ISDN/HYD (the A-HeFT formulation). Blood/plasma concentrations of hydralazine and ISDN were determined from the blood samples taken between 0 and 36 hours. In phase B, the maximum observed concentrations (C(max)) were 65.9 +/- 53.9, 28.2 +/- 15.8 and 51.5 +/- 54.3 ng/mL of unchanged hydralazine, and 23.1 +/- 12.3, 21.7 +/- 13.4 and 26.7 +/- 18.7 ng/mL of ISDN for the V-HeFT I, V-HeFT II and A-HeFT formulations, respectively. The area under the blood/plasma concentration-time curve (AUC) values were 32.6 +/- 13.4, 23.3 +/- 15.1 and 32.6 +/- 18.5 ng x h/mL of hydralazine, and 24.4 +/- 9.0, 24.8 +/- 8.0 and 23.5 +/- 6.3 ng x h/mL of ISDN for the V-HeFT I, V-HeFT II and A-HeFT formulations, respectively. For comparison of bioequivalence, the C(max) and AUC were normalised to 65kg bodyweight, and point estimates and 90% confidence intervals of the C(max) ratios, AUC ratios and ratios of the AUC in phase B normalised for clearance by the AUC in phase A (AUCR) were calculated. The three formulations were not bioequivalent based on the C(max) and AUC comparisons. The blood concentrations of hydralazine obtained with the tablet formulation tested in V-HeFT II were markedly lower than those obtained with the capsule formulation tested in V-HeFT I or the FDC ISDN/HYD single tablet used in A-HeFT. The apparently modest effect on survival observed in V-HeFT II could be explained in part by the poor hydralazine bioavailability of the tablet preparation used in this trial. ISDN exposures were similar in the two trials. The ISDN-hydralazine formulation used in V-HeFT II was not bioequivalent to the formulation used in V-HeFT I or to the FDC ISDN/HYD that had demonstrated a significant survival benefit in A-HeFT.
British Journal of Pharmacology, Feb 1, 1974
The dose-response curves for angiotensin 1I and four analogues in rat colon and uterus, and in ra... more The dose-response curves for angiotensin 1I and four analogues in rat colon and uterus, and in rabbit aorta, were obtained. 2 The ED50 values of angiotensin II as well as the ED50s and intrinsic activities of angiotensin analogues varied between the three organs. 3 The interaction of two competitive antagonists with angiotensin II receptors was also examined. The KI values obtained with both antagonists on the uterus differed from the values on the other tissues. 4 It is concluded that angiotensin II receptors may be different in the three organs examined.
Springer eBooks, 1972
Formerly (MEYER, PAPADIMITRIOU and WORCEL, 1970),we have shown some results of a study of the act... more Formerly (MEYER, PAPADIMITRIOU and WORCEL, 1970),we have shown some results of a study of the action of five different structure analogues of Valyl-5-angiotensinamide II on the contractility of three smooth muscle preparations. The biological responses of angiotensin and the analogues were then compared by finding the concentration of each that was required in the tissue bath to cause an equal and moderate response of the muscle (at around the ED 50 of Valyl-5-angiotensinamide).
La presente invention concerne des methodes de (a) reduction de la mortalite associee a une insuf... more La presente invention concerne des methodes de (a) reduction de la mortalite associee a une insuffisance cardiaque ; (b) amelioration de la consommation d'oxygene ; (c) traitement d'une insuffisance cardiaque ; (d) traitement de l'hypertension ; (e) amelioration de la qualite de vie d'un patient souffrant d'insuffisance cardiaque ; (f) inhibition du remodelage du ventricule gauche ; (g) reduction des hospitalisations liees aux insuffisances cardiaques ; (h) amelioration de la tolerance a l'exercice ; (j) augmentation de la fraction expulsee par le ventricule gauche ; (k) diminution des teneurs en proteine natriuretique de type B ; (l) traitement de maladies renovasculaires ; (m) traitement de maladies renales en phase terminale ;(n) reduction de la cardiomegalie ; (o) traitement de maladies resultant d'un stress oxydant ; (p) traitement de deficiences endotheliales ; (q) traitement de maladies provoquees par des deficiences endotheliales ; ou (r) traiteme...
Background: To characterize the quality of life (QOL) in the African-American Heart Failure Trial... more Background: To characterize the quality of life (QOL) in the African-American Heart Failure Trial (A-HeFT) for factors associated with baseline score, relation of score to prognosis, and response to therapy with a fixed-dose combination of isosorbide dinitrate/hydralazine (FDC I/H). Limited data exist on QOL scores in African-American heart failure patients or on the prognostic value of theses scores in any population. Finally, the effect of FDC I/H on QOL scores, particularly in A-HeFT, is not known. Methods and Results: A-HeFT randomized 1050 African-American patients with New York Heart Association (NYHA) Class III-IV heart failure and systolic dysfunction. QOL measurements using Minnesota Living with Heart Failure Questionnaire (MLHFQ) were done at baseline and 3-month intervals. At baseline, worse MLHFQ scores were associated with younger age, female sex, greater body mass index, nonischemic etiology, high heart rate and NYHA Class, low systolic blood pressure, and chronic obst...
European Journal of Pharmacology, Feb 1, 1988
Trandolapnl (3-100 #g/kg) and enalapnl (10-300 #g/kg) were admlmstered orally to conscious rats A... more Trandolapnl (3-100 #g/kg) and enalapnl (10-300 #g/kg) were admlmstered orally to conscious rats Angtotensmconverting enzyme (CE) acuwty was mtublted m serum, heart ventricle, renal tuner cortex, lung, aorta, adrenal cortex and adrenal medulla, but not m the stnatum InlublUon was maxamal at 2 h and with trandolaprll was maintained for 24 h. Blood pressure and heart rate were not affected by either compound Trandolaprd was 6-10-fold more potent than enalaprd Differences between trandolapnl and enalapnl m CE mlubmon observed m heart ventncle, adrenal cortex and medulla could be due to the presence of more than one type of CE or CE-hke activity.
European Journal of Pharmacology, Mar 1, 1988
Trandolapril (RU 44570), a new non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor chemi... more Trandolapril (RU 44570), a new non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor chemically related to enalapril, and its diacid (RU 44403), were investigated for their ability to inhibit angiotensin-converting enzyme. Trandolapril attenuated angiotensin I (Ang I)-induced pressor responses following i.v. administration to rats and dogs with IDs0 values of 13.1 + 1.3 and 21.1 + 2.3 lag/kg. RU 44403 produced corresponding values of 9.9 + 0.7 and 7.2 + 2.3/~g/kg. Trandolapril (3-300/~g/kg) produced a dose-related attenuation of Ang I-induced pressor responses (IDs0 30 #g/kg) following oral administration to rats. Oral administration of trandolapril (30-1000 /tg/kg) to dogs inhibited Ang I pressor responses for over 6 h. The depressor action of bradykinin in the rat was potentiated by i.v. trandolapril and RU 44403 with EDs0 values of 5.5 + 0.8 and 4.9 + 0.3 /tg/kg respectively. Trandolapril was 2.3-10-fold more potent than enalapril in all experiments, depending on species or route of administration. RU 44403 and MK 422 were approximately equipotent, implying that trandolapril was more readily hydrolysed than enalapril. Trandolapril (0.3-30 mg/kg) produced dose-related, long-lasting (> 24 h) reductions in blood pressure (BP) in spontaneously hypertensive rats (SHR) following oral administration. The anti-hypertensive effect was potentiated significantly in hydrochlorothiazide-pretreated SHR when the plasma renin activity was increased. Enalapril was 10-fold less potent than trandolapril in reducing BP. The anti-hypertensive action of trandolapril (3 mg/kg) was abolished in SHR that were bilaterally nephrectomized 24 h beforehand, but was maintained in SHR pretreated by indomethacin (5 mg/kg p.o.). Trandolapril (1 mg/kg i.v.) produced a modest and transient reduction in BP in anesthetized dogs. Trandolapril produced dose-related (30-1000 ~tg/kg) reductions in BP, total peripheral resistance and heart work in dogs pretreated with hydrochlorothiazide to increase plasma renin activity. Angiotensin-converting enzyme (ACE) inhibition; Trandolapril (RU 44570); Trandolapril-diacid (RU 44403)
Jacc-Heart Failure, Dec 1, 2014
The purpose of this study was to evaluate the influence of the guanine nucleotide-binding protein... more The purpose of this study was to evaluate the influence of the guanine nucleotide-binding proteins (G-proteins), beta-3 subunit (GNB3) genotype on the effectiveness of a fixed-dose combination of isosorbide dinitrate and hydralazine (FDC I/H) in A-HeFT (African American Heart Failure Trial). BACKGROUND GNB3 plays a role in alpha 2-adrenergic signaling. A polymorphism (C825T) exists, and the T allele is linked to enhanced alpha-adrenergic tone and is more prevalent in African Americans. METHODS A total of 350 subjects enrolled in the genetic substudy (GRAHF [Genetic Risk Assessment of Heart Failure in African Americans]) were genotyped for the C825T polymorphism. The impact of FDC I/H on a composite score (CS) that incorporated death, hospital stay for heart failure, and change in quality of life (QoL) and on event-free survival were assessed in GNB3 genotype subsets. RESULTS The GRAHF cohort was 60% male, 25% ischemic, 97% New York Heart Association functional class III, age 57 AE 13 years, with a mean qualifying left ventricular ejection fraction of 0.24 AE 0.06. For GNB3 genotype, 184 subjects were TT (53%), 137 (39%) CT, and 29 (8%) were CC. In GNB3 TT subjects, FDC I/H improved the CS (FDC I/H ¼ 0.50 AE 1.6;
Carolina Digital Repository (University of North Carolina at Chapel Hill), 2004
We examined whether a fixed dose of both isosorbide dinitrate and hydralazine provides additional... more We examined whether a fixed dose of both isosorbide dinitrate and hydralazine provides additional benefit in blacks with advanced heart failure, a subgroup previously noted to have a favorable response to this therapy. methods A total of 1050 black patients who had New York Heart Association class III or IV heart failure with dilated ventricles were randomly assigned to receive a fixed dose of isosorbide dinitrate plus hydralazine or placebo in addition to standard therapy for heart failure. The primary end point was a composite score made up of weighted values for death from any cause, a first hospitalization for heart failure, and change in the quality of life. results The study was terminated early owing to a significantly higher mortality rate in the placebo group than in the group given isosorbide dinitrate plus hydralazine (10.2 percent vs. 6.2 percent, P=0.02). The mean primary composite score was significantly better in the group given isosorbide dinitrate plus hydralazine than in the placebo group (¡0.1±1.9 vs. ¡0.5±2.0, P=0.01; range of possible values,-6 to +2), as were its individual components (43 percent reduction in the rate of death from any cause [hazard ratio, 0.57; P=0.01] 33 percent relative reduction in the rate of first hospitalization for heart failure [16.4 percent vs. 22.4 percent, P=0.001], and an improvement in the quality of life [change in score, ¡5.6±20.6 vs. ¡2.7±21.2, with lower scores indicating better quality of life; P=0.02; range of possible values, 0 to 105]). conclusions The addition of a fixed dose of isosorbide dinitrate plus hydralazine to standard therapy for heart failure including neurohormonal blockers is efficacious and increases survival among black patients with advanced heart failure.
Journal of Cardiac Failure, Aug 1, 2007
Journal of Cardiac Failure, Dec 1, 2009
To characterize the quality of life (QOL) in the African-American Heart Failure Trial (A-HeFT) fo... more To characterize the quality of life (QOL) in the African-American Heart Failure Trial (A-HeFT) for factors associated with baseline score, relation of score to prognosis, and response to therapy with a fixed-dose combination of isosorbide dinitrate/hydralazine (FDC I/H). Limited data exist on QOL scores in African-American heart failure patients or on the prognostic value of theses scores in any population. Finally, the effect of FDC I/H on QOL scores, particularly in A-HeFT, is not known. A-HeFT randomized 1050 African-American patients with New York Heart Association (NYHA) Class III-IV heart failure and systolic dysfunction. QOL measurements using Minnesota Living with Heart Failure Questionnaire (MLHFQ) were done at baseline and 3-month intervals. At baseline, worse MLHFQ scores were associated with younger age, female sex, greater body mass index, nonischemic etiology, high heart rate and NYHA Class, low systolic blood pressure, and chronic obstructive pulmonary disease. Both baseline and change in MLHFQ score were associated with a higher risk for combined all-cause mortality or heart failure hospitalization (baseline P < .0001, change at 3 months P=.001, and at 6 months P=.0008), but not mortality. Treatment with FDC I/H significantly improved MLHFQ score compared with placebo. In A-HeFT, baseline QOL (MLHFQ) scores and change in score were predictive of combined HF morbidity and mortality outcomes. FDC I/H consistently improved QOL scores in A-HeFT compared with placebo.
British Journal of Pharmacology, Nov 1, 1970
Abstract A biological assay, together with determination of radioactivity in the effluent and tis... more Abstract A biological assay, together with determination of radioactivity in the effluent and tissue of isolated perfused hearts and kidneys, and analysis of effluents by chromatography has been used to evaluate the fate of 3 H-angiotensin II on passage through the vascular beds of these organs. Data indicates that the process previously termed “extraction” of angiotensin II, which has been observed in many vascular beds, is due mainly to a rapid enzymatic degradation of the octapeptide into metabolic fragments, of which the heptapeptide, pentapeptide and tetrapeptide have been identified. The kidney has greater angiotensinase activity than the heart.
Clinical Pharmacokinectics, 2007
To investigate whether the apparent discrepancy between the efficacy of the combination of isosor... more To investigate whether the apparent discrepancy between the efficacy of the combination of isosorbide dinitrate (ISDN) and hydralazine demonstrated in the first V-HeFT trial (V-HeFT I) and that in V-HeFT II could be explained by pharmacokinetic differences in the study drug formulations, and to compare the pharmacokinetic profile of the fixed-dose combination of ISDN/hydralazine (FDC ISDN/HYD; BiDil) formulation used in A-HeFT with that of the V-HeFT study drug formulations. A bioequivalence study was performed (n = 18-19 per group) comparing the ISDN and hydralazine formulations used in V-HeFT I, V-HeFT II and A-HeFT in healthy volunteer men and women aged 18-40 years. In phase A of the study, subjects received a reference solution of hydralazine hydrochloride/ISDN (37.5mg/10mg) orally. Slow acetylators were identified and randomised into three groups in phase B to receive a single oral dose of identical amounts of hydralazine hydrochloride/ISDN (37.5mg/10mg) from either (i) a hydralazine capsule plus an ISDN tablet (the V-HeFT I formulation); (ii) a hydralazine tablet plus an ISDN tablet (the V-HeFT II formulation); or (iii) FDC ISDN/HYD (the A-HeFT formulation). Blood/plasma concentrations of hydralazine and ISDN were determined from the blood samples taken between 0 and 36 hours. In phase B, the maximum observed concentrations (C(max)) were 65.9 +/- 53.9, 28.2 +/- 15.8 and 51.5 +/- 54.3 ng/mL of unchanged hydralazine, and 23.1 +/- 12.3, 21.7 +/- 13.4 and 26.7 +/- 18.7 ng/mL of ISDN for the V-HeFT I, V-HeFT II and A-HeFT formulations, respectively. The area under the blood/plasma concentration-time curve (AUC) values were 32.6 +/- 13.4, 23.3 +/- 15.1 and 32.6 +/- 18.5 ng x h/mL of hydralazine, and 24.4 +/- 9.0, 24.8 +/- 8.0 and 23.5 +/- 6.3 ng x h/mL of ISDN for the V-HeFT I, V-HeFT II and A-HeFT formulations, respectively. For comparison of bioequivalence, the C(max) and AUC were normalised to 65kg bodyweight, and point estimates and 90% confidence intervals of the C(max) ratios, AUC ratios and ratios of the AUC in phase B normalised for clearance by the AUC in phase A (AUCR) were calculated. The three formulations were not bioequivalent based on the C(max) and AUC comparisons. The blood concentrations of hydralazine obtained with the tablet formulation tested in V-HeFT II were markedly lower than those obtained with the capsule formulation tested in V-HeFT I or the FDC ISDN/HYD single tablet used in A-HeFT. The apparently modest effect on survival observed in V-HeFT II could be explained in part by the poor hydralazine bioavailability of the tablet preparation used in this trial. ISDN exposures were similar in the two trials. The ISDN-hydralazine formulation used in V-HeFT II was not bioequivalent to the formulation used in V-HeFT I or to the FDC ISDN/HYD that had demonstrated a significant survival benefit in A-HeFT.
British Journal of Pharmacology, Feb 1, 1974
The dose-response curves for angiotensin 1I and four analogues in rat colon and uterus, and in ra... more The dose-response curves for angiotensin 1I and four analogues in rat colon and uterus, and in rabbit aorta, were obtained. 2 The ED50 values of angiotensin II as well as the ED50s and intrinsic activities of angiotensin analogues varied between the three organs. 3 The interaction of two competitive antagonists with angiotensin II receptors was also examined. The KI values obtained with both antagonists on the uterus differed from the values on the other tissues. 4 It is concluded that angiotensin II receptors may be different in the three organs examined.
Springer eBooks, 1972
Formerly (MEYER, PAPADIMITRIOU and WORCEL, 1970),we have shown some results of a study of the act... more Formerly (MEYER, PAPADIMITRIOU and WORCEL, 1970),we have shown some results of a study of the action of five different structure analogues of Valyl-5-angiotensinamide II on the contractility of three smooth muscle preparations. The biological responses of angiotensin and the analogues were then compared by finding the concentration of each that was required in the tissue bath to cause an equal and moderate response of the muscle (at around the ED 50 of Valyl-5-angiotensinamide).