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Administration time-dependent effects on ambulatory blood pressure of doxazosin gits as added therapy in uncontrolled hypertensive patients
108A
POSTERS: Antihypertensive Drugs
improvement in BP control without metabolic disturbances. The higher the baseline BP values were the greater the lowering effect was. Key Words: Angiotensin Receptor Blocker, Hypertension, Fixed Combination
P-203 EFFECT OF THIOLS ON PEROXYNITRITE: RELATIONSHIP TO BLOOD PRESSURE CHANGES Harvey C Gonick, Stanislav Shelkovnikov. Medicine/Nephrology, West LA VA Hospital, Los Angeles, CA. Of fundamental concern to physiologists is the equation which links the interaction of nitric oxide (NO) and superoxide (O2.⫺) to the formation of peroxynitrite (ONOO) : NO ⫹ O2⫺.fONOO. ONOO is a potent vasodilator, yet its formation is associated with the onset of hypertension. Thiols react with peroxynitrite to form S-nitrosothiols, thus diminishing the concentration of ONOO ( Schrammel A et al: Free Rad Biol Med 34: 1078, 2003). Previous studies have demonstrated that a thiol, dimercaptosuccinic acid (DMSA), can reduce blood pressure in lead-treated rats and prevent the severe vascular and interstitial changes in salt-treated Dahl SS rats (Khalil-Manesh F et al: Environ Res 65:86,1994; Gonick HC et al: Kidney Int 50:1572,1996), while depletion of the intracellular thiol, glutathione, induces hypertension in normal rats (Vaziri ND et al: Hypertension 36:142, 2000). In this study we have compared the ability of three thiols, cysteine, glutathione, and DMSA, to diminish the concentration of ONOO by: 1) a chemical reaction between ONOO, from 5x10⫺6 M to 10⫺4 M, and thiols, 10⫺4 M, using Ellman’s reagent to measure the SH groups of the thiols; 2) an HPLC method to measure the interaction between ONOO, 10⫺4 M, and norepinephrine (NE), 10⫺6 M, with subsequent modification by thiols, 10⫺4 M. Both phosphate buffer, pH 7.4, and Krebs solution were employed.The results in phosphate buffer are listed in the Table. At 10⫺4 M concentration, ONOO destroyed 90 to 100% of NE, but the reaction was modified by addition of thiols, as indicated in the Table. Results in Krebs solution were the same. Thus depletion of ONOO, a vasodilator, was associated with a fall in blood pressure, rather than a rise.Three possible explanations can be offered: 1) a shift in the equation NO ⫹ O2.⫺fONOO to the right would result in a decrease in O2.⫺, a known vasoconstrictor; 2) ONOO stimulates the formation of a vasoconstrictor such as F-2 isoprostanes ( Romeo JC and Reckelhoff JF: Hypertension 34: 143, 1999); or 3) restoration of depleted glutathione levels to normal by thiols. What is clear is that too much emphasis has been placed on an increase in NO accounting for the reduction in blood pressure following thiol administration. Table. Modification of peroxynitrite by thiols Thiols (10ⴚ4 M)
EC50 for ONOO by spectrophotometry
NE by HPLC (control 10ⴚ6 M)
Cysteine Glutathione DMSA
3.3 ⫻ 10⫺5 M 3.5 ⫻ 10⫺5 M 4.5 ⫻ 10⫺5 M
5.0 ⫻ 10⫺7 M 4.2 ⫻ 10⫺7 M 5.6 ⫻ 10⫺7 M
Key Words: Peroxynitrite, Thiols, Blood Pressure
P-204 ALISKIREN, A NOVEL ORALLY EFFECTIVE RENIN INHIBITOR, PROVIDES ANTIHYPERTENSIVE EFFICACY AND PLACEBO-LIKE TOLERABILITY SIMILAR TO AN AT1-RECEPTOR BLOCKER IN HYPERTENSIVE PATIENTS Alan H Gradman, Roland E Schmieder, Robert L Lins, Yanntong Chiang, Martin P Bedigian. The Western Pennsylvania Hospital, Pittsburgh, PA; University of Erlangen-Nurnberg, Erlangen, Germany; A.C.Z.A. Stuivenberg, Antwerp, Belgium; Cardiovascular and Metabolism Clinical Research, Novartis, East Hanover, NJ. Aliskiren is the first in a new class of orally effective, non-peptide renin inhibitors. This dose-finding study compared the antihypertensive effi-
AJH–May 2004 –VOL. 17, NO. 5, PART 2
cacy and safety of aliskiren with placebo and with the AT1-receptor blocker, irbesartan. The study was a randomized, multi-centre, double-blind, placebocontrolled, active comparator 8 week trial in patients with mild-tomoderate hypertension (mean sitting diastolic blood pressure [DBP] ⱖ95 and ⬍110 mmHg). After a 2-week, single-blind placebo run-in, 652 patients were randomized to receive double-blind treatment with either once-daily oral doses of aliskiren (150 mg, 300 mg or 600 mg), irbesartan 150 mg, or placebo. The primary efficacy variable of the study was the change from baseline in trough mean sitting DBP. All doses of aliskiren significantly lowered mean sitting DBP and systolic BP (SBP) compared with placebo. Aliskiren 150 mg, 300 mg, and 600 mg lowered mean sitting DBP by 9.5 ⫾ 8.0, 12.0 ⫾ 8.5 and 11.7 ⫾ 8.8 mmHg respectively versus 6.5 ⫾ 9.0 mmHg for placebo (p⬍ 0.005 versus placebo). Aliskiren 150 mg, 300 mg, and 600 mg lowered mean sitting SBP by 10.8 ⫾ 12.4, 15.5 ⫾ 13.1 and 15.6 ⫾ 14.3 mmHg respectively versus 5.1 ⫾ 16.2 mmHg for placebo (p⬍ 0.001 versus placebo). The antihypertensive effect of aliskiren 150 mg was comparable to that of irbesartan 150 mg (9.0 ⫾ 7.9 and 12.5 ⫾ 14.2 mmHg reduction in mean sitting DBP and SBP respectively for irbesartan). The effects on mean sitting DBP of aliskiren 300 mg and 600 mg were significantly greater than those obtained with irbesartan 150 mg (p⬍ 0.05). Aliskiren was comparable to placebo and irbesartan with respect to overall safety and tolerability. The percentage of patients reporting adverse events (AEs) was 26.8%, 36.2% and 33.1% with aliskiren 150 mg, 300 mg and 600 mg respectively, compared with 36.6% for irbesartan and 32.1% for placebo. The number of patients discontinuing therapy due to AEs was similar in all groups (range 2.2–3.9%). The results of this study show that once-daily oral treatment with aliskiren lowers blood pressure effectively and that aliskiren 150 mg is comparable in efficacy to irbesartan 150 mg, with an overall safety and tolerability profile comparable to irbesartan and placebo in patients with mild-to-moderate hypertension. Key Words: Hypertension, Renin Inhibitor, Angiotensin Receptor Blocker
P-205 ADMINISTRATION TIME-DEPENDENT EFFECTS ON AMBULATORY BLOOD PRESSURE OF DOXAZOSIN GITS AS ADDED THERAPY IN UNCONTROLLED HYPERTENSIVE PATIENTS Ramon C Hermida, Carlos Calvo, Diana E Ayala, Maria J Dominguez, Manuel Covelo, Artemio Mojon, Jose R Fernandez, Jose E Lopez. Bioengineering and Chronobiology Labs., University of Vigo, Vigo, Spain; Hypertension and Vascular Risk Unit, Hospital Clinico Universitario, Santiago de Compostela, Spain. Previous studies have shown that a single nighttime dose of Doxazosin (DOX), an alpha-adrenergic antagonist with demonstrated antihypertensive effects, reduces blood pressure (BP) throughout day and night [Am J Hyp. 1994;7:844 – 847]. However, the potential differing effects of DOX on BP as a function of its time of administration have not yet been reported. Accordingly, we investigated the administration time-dependent effects on the 24-hour pattern of BP of the new DOX gastrointestinal therapeutic system (GITS) formulation given as added therapy in hypertensive patients. We studied 62 patients with uncontrolled grade 1–2 essential hypertension (26 men), 58.3⫾11.0 years of age, who were already taken an average of 2.7 drugs. Patients were randomly assigned to receive 4 mg/day DOX GITS either on awakening or before bedtime. BP was measured by ambulatory monitoring at 20-min intervals from 07:00 to 23:00 hours and at 30-min intervals at night for 48 consecutive hours at baseline and after 3 months of therapeutic intervention. Physical activity was monitored every minute by wrist actigraphy, and the information used to determine diurnal and nocturnal means of BP for each patient according to individual resting time. After DOX GITS on awak-
AJH–May 2004 –VOL. 17, NO. 5, PART 2
ening, there was a small although significant reduction only in the diurnal (3.4 and 2.9 mm Hg for systolic and diastolic BP, P⬍0.036), but not in the nocturnal mean of BP. The antihypertensive efficacy was significantly larger (6.8 and 5.6 mm Hg reduction in the 24-hour mean of systolic and diastolic BP, P⬍0.001) when DOX GITS was administered before bedtime. This BP reduction was similar during daytime and nighttime hours, indicating a larger therapeutic coverage when DOX GITS was administered before bedtime. DOX GITS administered in combination therapy on awakening does not provide a full 24-hour therapeutic coverage, altering the circadian profile of BP to a more nondipping pattern (due to the BP reduction during the day and the lack of effect at night). Nighttime dosing with DOX GITS, however, significantly reduces BP both during diurnal activity and nocturnal resting hours in patients with essential hypertension. These administration time-dependent effects should be taken into consideration when prescribing DOX GITS to uncontrolled hypertensive patients. Key Words: Doxazosin GITS, Chronopharmacology, Circadian
P-206 EFFECTS OF NEBIVOLOL MONOTHERAPY ON AMBULATORY BLOOD PRESSURE IN PATIENTS WITH ESSENTIAL HYPERTENSION Carlos Calvo, Ramon C Hermida, Diana E Ayala, Jose E Lopez, Maria J Dominguez, Manuel Covelo. Hypertension and Vascular Risk Unit, Hospital Clinico Universitario, Santiago de Compostela, Spain; Bioengineering and Chronobiology Labs., University of Vigo, Vigo, Spain Nebivolol is a lipophilic beta-blocker without sympathomimetic activity, but with apparently nitric oxide-mediated vasodilating effects. Previous studies have shown that nebivolol reduces resting blood pressure (BP) as effectively as several other antihypertensive agents (including atenolol, metropolol, lisinopril and nifedipine), but most studies have not provided information of the therapeutic coverage of nebivolol assessed by ambulatory BP monitoring (ABPM). Accordingly, we investigated the effects of nebivolol on the 24-hour BP profile of hypertensive patients. We studied 67 patients with grade 1–2 essential hypertension (34 men), 42.1⫾11.7 years of age, assigned to receive nebivolol monotherapy (5 mg/day) on awakening. BP was measured by ABPM at 20-min intervals from 07:00 to 23:00 hours and at 30-min intervals at night for 48 consecutive hours before and after 3 months of treatment. Physical activity was simultaneously monitored every minute by wrist actigraphy, and the information used to determine diurnal and nocturnal means of BP for each patient according to individual resting time. Nebivolol monotherapy resulted in a highly significant reduction in BP from baseline (11.7 and 10.3 mm Hg reduction in the 24-hour mean of systolic and diastolic BP, respectively; P⬍0.001). The BP reduction was highly significant (after correcting for multiple testing) at each of the 24 hourly means (P⬍0.001). The effects of nebivolol, however, were significantly larger on the diurnal than on the nocturnal mean of BP (P⬍0.001), what resulted in a significant reduction of circadian amplitude (4.3 and 3.5 mm Hg for systolic and diastolic BP; P⬍0.001). There was a significant reduction of heart rate after nebivolol (9.9 beats/min in the 24-hour mean, P⬍0.001). The circadian pattern of wrist activity remained unchanged (24-hour mean of 134 and 132 counts/min before and after treatment, respectively; P⫽0.370). Results indicate that, despite a larger effect in diurnal as compared to nocturnal BP mean, nebivolol efficiently reduces BP for the whole 24 hours of the day. Apart from the expected reduction in heart rate after treatment, this effect of nebivolol on ambulatory BP is independent of any change in physical activity. Accordingly, nebivolol seems appropriate for the management of hypertensive patients with elevated double (pressure-rate) product, a marker of cardiovascular risk. Key Words: Nebivolol, Treatment Efficacy, Circadian
POSTERS: Antihypertensive Drugs
109A
P-207 ADMINISTRATION TIME-DEPENDENT EFFECTS OF PHARMACOLOGIC TREATMENT ON AMBULATORY BLOOD PRESSURE IN PATIENTS WITH REFRACTORY HYPERTENSION Carlos Calvo, Ramon C Hermida, Diana E Ayala, Jose E Lopez, Maria J Dominguez, Manuel Covelo. Hypertension and Vascular Risk Unit, Hospital Clinico Universitario, Santiago de Compostela, Spain; Bioengineering and Chronobiology Labs., University of Vigo, Vigo, Spain. Hypertensive patients with persistently high blood pressure (BP) after treatment with 3 or more antihypertensive drugs represent an important clinical problem due to their high cardiovascular risk and prevalence of target organ damage. Therapeutic strategies in refractory hypertension have currently included adding another drug, increasing the dose of the drugs, or changing drugs in search for a better synergic combination. Most patients, however, receive all their drugs in a single morning dose [J Hypertens. 2002;20:1097–1104]. We have evaluated the impact on the circadian pattern of BP of modifying the time of treatment without increasing the dose neither the number of prescribed drugs. We studied 78 patients with refractory hypertension (45 men), 60.4⫾11.5 years of age, who were receiving 3 antihypertensive drugs in a single morning dose. The patients were randomly assigned to one of two groups according to the modification in their treatment strategy: 1) Changing one drug by a different one (interchange of an alpha-blocker and a CCB), but keeping all 3 drugs in the morning. 2) The same approach but prescribing the new drug to be taken before bedtime. BP was monitored at 20-min intervals from 07:00 to 23:00 hours and at 30-min intervals at night for 48 consecutive hours at baseline and after 3 months of treatment with the new therapeutic scheme. There was a small and non-significant BP reduction when all drugs were still taken after awakening (0.6 and 0.3 mm Hg for systolic and diastolic BP, respectively; P⬎0.744). At baseline, only 27% of the patients in this group were dippers, and this percentage was further reduced to 19% after 3 months of therapy with all drugs on awakening. Results indicate a highly statistically significant BP reduction (7.3 and 4.5 mm Hg for systolic and diastolic BP; P⬍0.001) when one drug was taken before bedtime. This BP reduction was markedly larger in the nocturnal mean of BP. Thus, while only 16% of the patients in this group were dippers at baseline, 52% were already dippers after 3 months of therapy. Results from this prospective trial on patients with refractory hypertension indicate that time of treatment (when to treat) may be more important for BP control and for the proper modeling of the circadian pattern of BP than just changing the drug combination (what to use for treatment). Key Words: Dipper, Chronopharmacology, Refractory Hypertension
P-208 EFFECTS OF MORNING VERSUS EVENING ADMINISTRATION OF VALSARTAN ON AMBULATORY BLOOD PRESSURE IN ELDERLY HYPERTENSIVE PATIENTS Carlos Calvo, Ramon C Hermida, Diana E Ayala, Jose E Lopez, Maria J Dominguez, Manuel Covelo. Hypertension and Vascular Risk Unit, Hospital Clinico Universitario, Santiago de Compostela, Spain; Bioengineering and Chronobiology Labs., University of Vigo, Vigo, Spain. Previous results on the potential differing effects of valsartan as a function of its time of administration indicated that this ARB efficiently reduces blood pressure (BP) throughout the entire 24 hours independent of treatment time [Hypertension. 2003;42:283–290]. However, valsartan administration at bedtime as opposed to upon wakening resulted in a highly significant increase in the day/night BP ratio. This ratio is char-
POSTERS: Antihypertensive Drugs
improvement in BP control without metabolic disturbances. The higher the baseline BP values were the greater the lowering effect was. Key Words: Angiotensin Receptor Blocker, Hypertension, Fixed Combination
P-203 EFFECT OF THIOLS ON PEROXYNITRITE: RELATIONSHIP TO BLOOD PRESSURE CHANGES Harvey C Gonick, Stanislav Shelkovnikov. Medicine/Nephrology, West LA VA Hospital, Los Angeles, CA. Of fundamental concern to physiologists is the equation which links the interaction of nitric oxide (NO) and superoxide (O2.⫺) to the formation of peroxynitrite (ONOO) : NO ⫹ O2⫺.fONOO. ONOO is a potent vasodilator, yet its formation is associated with the onset of hypertension. Thiols react with peroxynitrite to form S-nitrosothiols, thus diminishing the concentration of ONOO ( Schrammel A et al: Free Rad Biol Med 34: 1078, 2003). Previous studies have demonstrated that a thiol, dimercaptosuccinic acid (DMSA), can reduce blood pressure in lead-treated rats and prevent the severe vascular and interstitial changes in salt-treated Dahl SS rats (Khalil-Manesh F et al: Environ Res 65:86,1994; Gonick HC et al: Kidney Int 50:1572,1996), while depletion of the intracellular thiol, glutathione, induces hypertension in normal rats (Vaziri ND et al: Hypertension 36:142, 2000). In this study we have compared the ability of three thiols, cysteine, glutathione, and DMSA, to diminish the concentration of ONOO by: 1) a chemical reaction between ONOO, from 5x10⫺6 M to 10⫺4 M, and thiols, 10⫺4 M, using Ellman’s reagent to measure the SH groups of the thiols; 2) an HPLC method to measure the interaction between ONOO, 10⫺4 M, and norepinephrine (NE), 10⫺6 M, with subsequent modification by thiols, 10⫺4 M. Both phosphate buffer, pH 7.4, and Krebs solution were employed.The results in phosphate buffer are listed in the Table. At 10⫺4 M concentration, ONOO destroyed 90 to 100% of NE, but the reaction was modified by addition of thiols, as indicated in the Table. Results in Krebs solution were the same. Thus depletion of ONOO, a vasodilator, was associated with a fall in blood pressure, rather than a rise.Three possible explanations can be offered: 1) a shift in the equation NO ⫹ O2.⫺fONOO to the right would result in a decrease in O2.⫺, a known vasoconstrictor; 2) ONOO stimulates the formation of a vasoconstrictor such as F-2 isoprostanes ( Romeo JC and Reckelhoff JF: Hypertension 34: 143, 1999); or 3) restoration of depleted glutathione levels to normal by thiols. What is clear is that too much emphasis has been placed on an increase in NO accounting for the reduction in blood pressure following thiol administration. Table. Modification of peroxynitrite by thiols Thiols (10ⴚ4 M)
EC50 for ONOO by spectrophotometry
NE by HPLC (control 10ⴚ6 M)
Cysteine Glutathione DMSA
3.3 ⫻ 10⫺5 M 3.5 ⫻ 10⫺5 M 4.5 ⫻ 10⫺5 M
5.0 ⫻ 10⫺7 M 4.2 ⫻ 10⫺7 M 5.6 ⫻ 10⫺7 M
Key Words: Peroxynitrite, Thiols, Blood Pressure
P-204 ALISKIREN, A NOVEL ORALLY EFFECTIVE RENIN INHIBITOR, PROVIDES ANTIHYPERTENSIVE EFFICACY AND PLACEBO-LIKE TOLERABILITY SIMILAR TO AN AT1-RECEPTOR BLOCKER IN HYPERTENSIVE PATIENTS Alan H Gradman, Roland E Schmieder, Robert L Lins, Yanntong Chiang, Martin P Bedigian. The Western Pennsylvania Hospital, Pittsburgh, PA; University of Erlangen-Nurnberg, Erlangen, Germany; A.C.Z.A. Stuivenberg, Antwerp, Belgium; Cardiovascular and Metabolism Clinical Research, Novartis, East Hanover, NJ. Aliskiren is the first in a new class of orally effective, non-peptide renin inhibitors. This dose-finding study compared the antihypertensive effi-
AJH–May 2004 –VOL. 17, NO. 5, PART 2
cacy and safety of aliskiren with placebo and with the AT1-receptor blocker, irbesartan. The study was a randomized, multi-centre, double-blind, placebocontrolled, active comparator 8 week trial in patients with mild-tomoderate hypertension (mean sitting diastolic blood pressure [DBP] ⱖ95 and ⬍110 mmHg). After a 2-week, single-blind placebo run-in, 652 patients were randomized to receive double-blind treatment with either once-daily oral doses of aliskiren (150 mg, 300 mg or 600 mg), irbesartan 150 mg, or placebo. The primary efficacy variable of the study was the change from baseline in trough mean sitting DBP. All doses of aliskiren significantly lowered mean sitting DBP and systolic BP (SBP) compared with placebo. Aliskiren 150 mg, 300 mg, and 600 mg lowered mean sitting DBP by 9.5 ⫾ 8.0, 12.0 ⫾ 8.5 and 11.7 ⫾ 8.8 mmHg respectively versus 6.5 ⫾ 9.0 mmHg for placebo (p⬍ 0.005 versus placebo). Aliskiren 150 mg, 300 mg, and 600 mg lowered mean sitting SBP by 10.8 ⫾ 12.4, 15.5 ⫾ 13.1 and 15.6 ⫾ 14.3 mmHg respectively versus 5.1 ⫾ 16.2 mmHg for placebo (p⬍ 0.001 versus placebo). The antihypertensive effect of aliskiren 150 mg was comparable to that of irbesartan 150 mg (9.0 ⫾ 7.9 and 12.5 ⫾ 14.2 mmHg reduction in mean sitting DBP and SBP respectively for irbesartan). The effects on mean sitting DBP of aliskiren 300 mg and 600 mg were significantly greater than those obtained with irbesartan 150 mg (p⬍ 0.05). Aliskiren was comparable to placebo and irbesartan with respect to overall safety and tolerability. The percentage of patients reporting adverse events (AEs) was 26.8%, 36.2% and 33.1% with aliskiren 150 mg, 300 mg and 600 mg respectively, compared with 36.6% for irbesartan and 32.1% for placebo. The number of patients discontinuing therapy due to AEs was similar in all groups (range 2.2–3.9%). The results of this study show that once-daily oral treatment with aliskiren lowers blood pressure effectively and that aliskiren 150 mg is comparable in efficacy to irbesartan 150 mg, with an overall safety and tolerability profile comparable to irbesartan and placebo in patients with mild-to-moderate hypertension. Key Words: Hypertension, Renin Inhibitor, Angiotensin Receptor Blocker
P-205 ADMINISTRATION TIME-DEPENDENT EFFECTS ON AMBULATORY BLOOD PRESSURE OF DOXAZOSIN GITS AS ADDED THERAPY IN UNCONTROLLED HYPERTENSIVE PATIENTS Ramon C Hermida, Carlos Calvo, Diana E Ayala, Maria J Dominguez, Manuel Covelo, Artemio Mojon, Jose R Fernandez, Jose E Lopez. Bioengineering and Chronobiology Labs., University of Vigo, Vigo, Spain; Hypertension and Vascular Risk Unit, Hospital Clinico Universitario, Santiago de Compostela, Spain. Previous studies have shown that a single nighttime dose of Doxazosin (DOX), an alpha-adrenergic antagonist with demonstrated antihypertensive effects, reduces blood pressure (BP) throughout day and night [Am J Hyp. 1994;7:844 – 847]. However, the potential differing effects of DOX on BP as a function of its time of administration have not yet been reported. Accordingly, we investigated the administration time-dependent effects on the 24-hour pattern of BP of the new DOX gastrointestinal therapeutic system (GITS) formulation given as added therapy in hypertensive patients. We studied 62 patients with uncontrolled grade 1–2 essential hypertension (26 men), 58.3⫾11.0 years of age, who were already taken an average of 2.7 drugs. Patients were randomly assigned to receive 4 mg/day DOX GITS either on awakening or before bedtime. BP was measured by ambulatory monitoring at 20-min intervals from 07:00 to 23:00 hours and at 30-min intervals at night for 48 consecutive hours at baseline and after 3 months of therapeutic intervention. Physical activity was monitored every minute by wrist actigraphy, and the information used to determine diurnal and nocturnal means of BP for each patient according to individual resting time. After DOX GITS on awak-
AJH–May 2004 –VOL. 17, NO. 5, PART 2
ening, there was a small although significant reduction only in the diurnal (3.4 and 2.9 mm Hg for systolic and diastolic BP, P⬍0.036), but not in the nocturnal mean of BP. The antihypertensive efficacy was significantly larger (6.8 and 5.6 mm Hg reduction in the 24-hour mean of systolic and diastolic BP, P⬍0.001) when DOX GITS was administered before bedtime. This BP reduction was similar during daytime and nighttime hours, indicating a larger therapeutic coverage when DOX GITS was administered before bedtime. DOX GITS administered in combination therapy on awakening does not provide a full 24-hour therapeutic coverage, altering the circadian profile of BP to a more nondipping pattern (due to the BP reduction during the day and the lack of effect at night). Nighttime dosing with DOX GITS, however, significantly reduces BP both during diurnal activity and nocturnal resting hours in patients with essential hypertension. These administration time-dependent effects should be taken into consideration when prescribing DOX GITS to uncontrolled hypertensive patients. Key Words: Doxazosin GITS, Chronopharmacology, Circadian
P-206 EFFECTS OF NEBIVOLOL MONOTHERAPY ON AMBULATORY BLOOD PRESSURE IN PATIENTS WITH ESSENTIAL HYPERTENSION Carlos Calvo, Ramon C Hermida, Diana E Ayala, Jose E Lopez, Maria J Dominguez, Manuel Covelo. Hypertension and Vascular Risk Unit, Hospital Clinico Universitario, Santiago de Compostela, Spain; Bioengineering and Chronobiology Labs., University of Vigo, Vigo, Spain Nebivolol is a lipophilic beta-blocker without sympathomimetic activity, but with apparently nitric oxide-mediated vasodilating effects. Previous studies have shown that nebivolol reduces resting blood pressure (BP) as effectively as several other antihypertensive agents (including atenolol, metropolol, lisinopril and nifedipine), but most studies have not provided information of the therapeutic coverage of nebivolol assessed by ambulatory BP monitoring (ABPM). Accordingly, we investigated the effects of nebivolol on the 24-hour BP profile of hypertensive patients. We studied 67 patients with grade 1–2 essential hypertension (34 men), 42.1⫾11.7 years of age, assigned to receive nebivolol monotherapy (5 mg/day) on awakening. BP was measured by ABPM at 20-min intervals from 07:00 to 23:00 hours and at 30-min intervals at night for 48 consecutive hours before and after 3 months of treatment. Physical activity was simultaneously monitored every minute by wrist actigraphy, and the information used to determine diurnal and nocturnal means of BP for each patient according to individual resting time. Nebivolol monotherapy resulted in a highly significant reduction in BP from baseline (11.7 and 10.3 mm Hg reduction in the 24-hour mean of systolic and diastolic BP, respectively; P⬍0.001). The BP reduction was highly significant (after correcting for multiple testing) at each of the 24 hourly means (P⬍0.001). The effects of nebivolol, however, were significantly larger on the diurnal than on the nocturnal mean of BP (P⬍0.001), what resulted in a significant reduction of circadian amplitude (4.3 and 3.5 mm Hg for systolic and diastolic BP; P⬍0.001). There was a significant reduction of heart rate after nebivolol (9.9 beats/min in the 24-hour mean, P⬍0.001). The circadian pattern of wrist activity remained unchanged (24-hour mean of 134 and 132 counts/min before and after treatment, respectively; P⫽0.370). Results indicate that, despite a larger effect in diurnal as compared to nocturnal BP mean, nebivolol efficiently reduces BP for the whole 24 hours of the day. Apart from the expected reduction in heart rate after treatment, this effect of nebivolol on ambulatory BP is independent of any change in physical activity. Accordingly, nebivolol seems appropriate for the management of hypertensive patients with elevated double (pressure-rate) product, a marker of cardiovascular risk. Key Words: Nebivolol, Treatment Efficacy, Circadian
POSTERS: Antihypertensive Drugs
109A
P-207 ADMINISTRATION TIME-DEPENDENT EFFECTS OF PHARMACOLOGIC TREATMENT ON AMBULATORY BLOOD PRESSURE IN PATIENTS WITH REFRACTORY HYPERTENSION Carlos Calvo, Ramon C Hermida, Diana E Ayala, Jose E Lopez, Maria J Dominguez, Manuel Covelo. Hypertension and Vascular Risk Unit, Hospital Clinico Universitario, Santiago de Compostela, Spain; Bioengineering and Chronobiology Labs., University of Vigo, Vigo, Spain. Hypertensive patients with persistently high blood pressure (BP) after treatment with 3 or more antihypertensive drugs represent an important clinical problem due to their high cardiovascular risk and prevalence of target organ damage. Therapeutic strategies in refractory hypertension have currently included adding another drug, increasing the dose of the drugs, or changing drugs in search for a better synergic combination. Most patients, however, receive all their drugs in a single morning dose [J Hypertens. 2002;20:1097–1104]. We have evaluated the impact on the circadian pattern of BP of modifying the time of treatment without increasing the dose neither the number of prescribed drugs. We studied 78 patients with refractory hypertension (45 men), 60.4⫾11.5 years of age, who were receiving 3 antihypertensive drugs in a single morning dose. The patients were randomly assigned to one of two groups according to the modification in their treatment strategy: 1) Changing one drug by a different one (interchange of an alpha-blocker and a CCB), but keeping all 3 drugs in the morning. 2) The same approach but prescribing the new drug to be taken before bedtime. BP was monitored at 20-min intervals from 07:00 to 23:00 hours and at 30-min intervals at night for 48 consecutive hours at baseline and after 3 months of treatment with the new therapeutic scheme. There was a small and non-significant BP reduction when all drugs were still taken after awakening (0.6 and 0.3 mm Hg for systolic and diastolic BP, respectively; P⬎0.744). At baseline, only 27% of the patients in this group were dippers, and this percentage was further reduced to 19% after 3 months of therapy with all drugs on awakening. Results indicate a highly statistically significant BP reduction (7.3 and 4.5 mm Hg for systolic and diastolic BP; P⬍0.001) when one drug was taken before bedtime. This BP reduction was markedly larger in the nocturnal mean of BP. Thus, while only 16% of the patients in this group were dippers at baseline, 52% were already dippers after 3 months of therapy. Results from this prospective trial on patients with refractory hypertension indicate that time of treatment (when to treat) may be more important for BP control and for the proper modeling of the circadian pattern of BP than just changing the drug combination (what to use for treatment). Key Words: Dipper, Chronopharmacology, Refractory Hypertension
P-208 EFFECTS OF MORNING VERSUS EVENING ADMINISTRATION OF VALSARTAN ON AMBULATORY BLOOD PRESSURE IN ELDERLY HYPERTENSIVE PATIENTS Carlos Calvo, Ramon C Hermida, Diana E Ayala, Jose E Lopez, Maria J Dominguez, Manuel Covelo. Hypertension and Vascular Risk Unit, Hospital Clinico Universitario, Santiago de Compostela, Spain; Bioengineering and Chronobiology Labs., University of Vigo, Vigo, Spain. Previous results on the potential differing effects of valsartan as a function of its time of administration indicated that this ARB efficiently reduces blood pressure (BP) throughout the entire 24 hours independent of treatment time [Hypertension. 2003;42:283–290]. However, valsartan administration at bedtime as opposed to upon wakening resulted in a highly significant increase in the day/night BP ratio. This ratio is char-