BLOOD PRESSURE
1992; 1: 162-1 67
Effect of Ketoprofen on Blood Pressure, Endocrine and Renal Responses to Chronic Dosing with Captopril in Patients with Essential Hypertension JEAN R. CUSSON,' PATRICK D U SOUICH,2 PATRICK LE MORVAN,3 GAETAN THIBAULT,' ROBERT PHILLIPS,3 ALAIN MILOT' and PIERRE LAROCHELLE'
'
'
From Institut de recherches cliniques de Montrial, Universiti de Montrial, and Rhdne-Poulenc Rorer, Canada Inc., Canada
Blood Press Downloaded from informahealthcare.com by University of North Carolina on 12/06/14 For personal use only.
Cusson JR, Souich P du, Le Morvan P, Thibault G , Phillips R, Milot A, Larochelle P. Effect of ketoprofen on blood pressure, endocrine and renal responses to chronic dosing with captopril in patients with essential hypertension. Blood Pressure 1992; 1: 162-167.
The effects of non-steroidal anti-inflammatory drugs (NSAIDs) on the blood pressure and renal function of essential hypertensive patients depend on the specific type of NSAID and antihypertensive drug administered. Twelve patients with essential hypertension, aged 35 to 59 years, stabilized (blood pressure less than 140/90 mmHg) with captopril, received ketoprofen (100 mg bid for 7 days) or matching placebo in a randomized double-blind cross-over fashion. A 3-week wash-out period was included between treatment periods. Blood pressure on the first and last days of the placebo treatment period (137 k 7(SD)/80 f.8 and 139& 1 1/8 1 k 9 mmHg) was similar to respective values during ketoprofen therapy (136 k 10/79 7 and 143k 10/81 9 mmHg). The mean differencesin systolic and diastolic blood pressures, at the end of the treatment periods, between ketoprofen and placebo were 4 (95% confidence intervals - 5, + 13) and 0 (- 8, + 8) mmHg, respectively.Ketoprofen had no effect on 24-h urinary sodium excretion (160 k 3 3 and 147+39 mmo1/24 h for ketoprofen and placebo, respectively). Ketoprofen was without effect on glomerular filtration rate, renal plasma Row and filtration fraction. In conclusion, our data suggest that ketoprofen is a safe choice when short-term treatment with a NSAID is indicated in an essential hypertensive patient treated with a converting enzyme inhibitor such as captopril. Key words: non-steroidal anti-injammatory drugs, essential hypertension, aldosterone, angiotensin converting enzyme inhibition, natriuresis.
INTRODUCTION Non-steroidal anti-inflammatory drugs (NSAIDs) have the potential to reduce the effect of antihypertensive drugs. This has been shown for the interaction of indomethacin and many antihypertensive agents including angiotensin converting enzyme (ACE) inhibitors [ 1-71; the mechanism of this interaction involves the inhibition of prostaglandin (PG) synthesis by NSAIDs [8]. This could be particularly important when captopril is used as an antihypertensive drug because captopril stimulates prostaglandin synthesis [9]. However, it has also been shown previously that all NSAIDs do not necessarily interact similarly with antihypertensive drugs [I 01. Sulindac and acetylsalicylic acid have been reported to have no effect in this situation [I 1-12]. Oates [lo] recently suggested that all other NSAIDs might reduce the effect of antihypertensive drugs unless proven otherwise. Limited and conflicting data have been published with regard to NSAIDs of the propionic acid type [7]. The main purpose of this study was therefore to evaluate whether ketoprofen increased blood pressure in essential hypertensive patients treated with captopril. In addition, renal function and hormonal parameters were monitored.
MATERIAL AND METHODS Subjects and protocol Twelve patients with essential hypertension participated in this double-blind, randomized, placebo-controlled, cross-over study where the effects of the addition of ketoprofen versus placebo on the blood pressure response and the renal function of hypertensive patients under chronic dosing of captopril were investigated. The study was approved by the local ethics committee. Male or female patients between the ages of 18 and 60 years with uncomplicated (WHO stage I) essential hypertension were included in the study. Systolic and diastolic blood pressure values, under pharmacological treatment, had to be lower than 140 and 90 mmHg on admission to the study. The diagnosis of hypertension had beeen made between 1 and 26 years prior to the study, and blood pressure under drug-free conditions had been greater than 140/95 mmHg in all subjects; indeed 11 of the 18 patients initially invited to participate in the study had blood pressure levels greater than 170/100 recorded in their charts at the Hypertension Clinic, and up to 230/130 mmHg. Exclusion criteria were: women of child bearing potential, secondary
Blood Press Downloaded from informahealthcare.com by University of North Carolina on 12/06/14 For personal use only.
Ketoprofen treatment in captopril-treated hypertensives
hypertension, history of adverse effects or allergy to the study drugs or to NSAIDs, significant liver dysfunction, diabetes, gastric or duodenal ulcer, abnormal hemostasis, history of alcohol or drug abuse, and previous history of non-compliance. Patients with musculoskeletal conditions requiring NSAIDs were not excluded. The use of any concomitant medication was prohibited during the course of the study except for acetaminophen if needed for pain. Initially, 18 patients were recruited but only 12 completed the study. One patient withdrew from the study because of a skin rash. This adverse event occurred before the administration of ketoprofen and was attributed to captopril. Another patient was excluded when he complained of retrosternal chest pain. Three patients were excluded because they did not meet the blood pressure stability criteria before the main phase. Finally, one had a white blood cell count of less than 3.5 x 109/Land was excluded in the preliminary phase. The study consisted of a preliminary phase and a treatment phase. First, patients were stabilized on captopril (Capoten Squibb Canada) monotherapy in three equal daily doses (08 :00, 15 :00,23 :00). When, at three consecutive weekly visits diastolic blood pressure was stabilized, patients could be included in the treatment phase of the protocol. Diastolic blood pressure was considered stabilized if at these 3 visits the diastolic blood pressure readings were within 10 mmHg. The captopril treatment was maintained for a period of 5 weeks. On the first and last weeks of this period, all subjects would receive, in two daily doses, either enteric coated tablets of ketoprofen 100 mg (Orudism), or matching placebo in a randomized fashion under double-blind conditions. The patients therefore took 200 mg/d of ketoprofen, the dose recommended by the manufacturer in rheumatoid arthritis. Compliance was assessed by pill counts. During the 3-week wash-out period, patients remained only on captopril therapy. On the first and last days of each 1-week experimental treatment period, data on blood pressure, renal function and plasma levels of some hormones involved in blood pressure homeostasis, were obtained to determine a first dose and 1-week treatment effects. Blood pressure was evaluated during the stabilization period on captopril monotherapy and at the beginning and at the end of the two treatment periods with either ketoprofen or placebo. Blood pressure was measured by a direct oscillometric recording device (Dynamap, Critikon) on the same arm, after at least 5 min in supine resting position. Prior to the morning dose of captopril, the mean of three blood pressure readings was used as the baseline value for that day. @,
163
Blood was sampled for a complete blood count and a biochemical profile during the screening phase, prior to the first week of experimental treatment and at the follow-up visit 2-3 weeks after the end of the study. An additional biochemical profile was also done at each visit during the study. Urinanalysis was also done at the screening phase, and prior and at the end of the study whereas the 24-h urinary protein excretion was measured at each visit during the actual study. All patients were instructed to follow a diet containing approximately 150 and 100 mmol of sodium and potassium per day, respectively. For renal function studies, the patients came to the Physiology room at 07:30 after an overnight fast. At 08:00, a baseline blood sample was drawn and subjects then received one tablet of test medication (ketoprofen or placebo) along with the morning dose of captopril and 240 ml of water. While remaining supine and after a light breakfast, constant infusions of inulin at 32 mg/min (following a bolus dose of 50 mg/kg) and of PAH at 12 mg/min (following a bolus dose of 8 mg/kg) were started for a duration of 90 min. Blood was sampled at the end of the infusion to determine the plasma concentrations of both inulin and PAH. The aim was to obtain steadystate levels of inulin and PAH of about 12 and 150 mg/ mL respectively. Using this method, steady-state levels are achieved relatively rapidly [ 13,141. The clearances of inulin and PAH were calculated as the ratio of the infusion rate over the steady-state plasma concentration according to the constant infusion pharmacokinetic model [ 151. The PAH clearance is an estimate of the renal plasma flow (RPF) and inulin clearance is an estimate of glomerular filtration rate (GFR) [16]. The filtration fraction (FF) was calculated as the ratio of GFR/RPF. Patients also received 100 ml of water every 30 min during the clearance procedures. Plasma levels of peripheral renin activity (PRA) [ 171, aldosterone [18], C-terminal (CT-ANF) and N-terminal (NT-ANF) fragments of atrial natriuretic factor [19] and cyclic guanosine monophosphate (cGMP) [20] were determined on the last day of each treatment period, at 0,90,150 and 360 min following the morning dose of captopril. Statistical Analysis
Data are presented as means fstandard deviation. Mean differences are given with 95% confidence intervals. In order to demonstrate a difference of 6 mmHg for diastolic blood pressure, the main variable, 12 subjects needed to be included in this study according to sample size calculation based on a bilateral LI of 0.05 and a unilateral fi of 0.80. The results, presented as means and standard deviations, were analyzed by
164
J . R. Cusson et al.
Blood Press Downloaded from informahealthcare.com by University of North Carolina on 12/06/14 For personal use only.
analysis of variance (ANOVA). After testing for homoscedasticity (Bartlett’s test), analysis of differences between the sequences was performed using ANOVA for repeated measures for blood pressure and heart rate data at baseline and on each first day of the test periods. Data obtained between periods were analyzed according to a 2 x 2 Latin square design for repeated measures within periods. RESULTS The 12 patients (6 females and 6 males) had a mean age of 50 years (range 35-59), a mean height of 166 cm (range 154-1 79), and a mean weight of 77 kg (range 5596). Seven were controlled with a dose of 37.5 mg t.i.d., 4 on 25 mg t.i.d. and one on 12.5 mg t.i.d. EfSect of ketoprofen on blood pressure and heart rate Compared to placebo, ketoprofen did not significantly alter systolic ( p = 0.44) nor diastolic ( p = 0.72) blood pressure (Table I). The mean difference in systolic and diastolic blood pressures, at the end of the treatment periods, between ketoprofen and placebo were 4 (95% confidence intervals - 5 , 13) and 0 (- 8, 8) mmHg, respectively. There was a period effect for diastolic as it was slightly increased in the second period independently of the type of treatment (p=O.O43). Heart rate was similarly unaffected by ketoprofen.
+
+
Effect of ketoprofen on blood pressure, heart rate and hormonal responses to captopril Changes in blood pressure and heart rate were also monitored during 360 min following captopril dosing
on the last day of each treatment period. All decreased significantly ( p < 0.01) following captopril and these blood pressure and heart rate reductions, presented for all patients together, were unaffected by ketoprofen treatment (Table 11). Actually, blood pressure decreased by about 10/4 mmHg 90 min post captopril, under both placebo and ketoprofen. Changes in plasma levels of PRA, aldosterone, CTANF, NT-ANF and cGMP were also measured following the morning dose of captopril on the last day of each treatment period. Following captopril, PRA increased and plasma aldosterone decreased (Table 111). After ketoprofen, the captopril-induced increase in PRA (+0.9 k0.8 ng/mL/h), was reduced compared to that observed following placebo (+2.1 k 2.1 ng/mL/h) treatment. However, this difference did not reach statistical significance ( p = 0.06). The captoprilinduced reduction in aldosterone was unchanged by ketoprofen (see Table 111). In addition, the urinary excretion of aldosterone during the period following captopril was unaffected by ketoprofen (placebo: 68.2k43.1, ketoprofen: 56.3 k 51.7 ng/360 min, p=0.28). There were no particular trends in plasma levels of CT-ANF, NT-ANF and cGMP (not shown).
EfSects of ketoprofen on renal function
Baseline 24-h urinary volume, potassium and creatinine excretion rates on the first day of each treatment period were similar (not shown) but there was a slightly lower baseline 24-h urinary sodium excretion rate prior to the first day of ketoprofen therapy versus that prior to the first day of placebo (135 f50 vs 176+65 mmo1/24 h, a difference of 41 ( - 8 to +90) mmo1/24 h, p = 0 . 0 5 5 ) .
Table I. EfSect of one-week treatment with ketoprofen on blood pressure and heart rate prior to the morning dose of captopril SBP: systolic blood pressure; DBP: diastolic blood pressure; HR: heart rate; K : ketoprofen; P: placebo. DATA are means fSD. ~
Day 0
Day 7
SBP (mmHg)
DBP (mmHg)
HR (min-I)
SBP (mmHg)
DBP (mmHg)
HR (min-I)
Sequence I (n=6) K P
134+ 10 137f9
78k7 82+8
6 4 5 10 66k9
I43 7 l38+ 10
81 + 6 83+9
63+12 67+6
Sequence 2 (n = 6) P K
137f5 137+ 10
77f7 80+8
68+ 12 71515
I41 f 12 I43 f 14
79+ 10 81 f 12
69f 14 66+ I5
All patients ( n = 12) P K
13757 136f 10
80+8 79+7
67+ 10 67+ 13
139f11 I43 10
81 + 9 81 f 9
68f 11 64+ 13
+
+
Ketoprofen treatment in captopril-treated hypertensives
165
Table 11. E$ect of ketoprofen on blood pressure and heart rate responses to captopril on the 7th day P placebo; K: ketoprofen; S B P systolic blood pressure; DBP: diastolic blood pressure; M B P mean blood pressure; HR: heart rate. DATA are means SD.
*
Time (min) after captopril administration 0
60
90
120
150
180
240
360
139f11 143+ 10
133f 14* 129f 17**
129+15** 132f 16**
130+ 14* 135+ 16
129k 17** 133f 18*
l35+ 18 135f17
128f 17** 130+ 13**
134f I6 138f 12
81 + 9 81 + 9
75f9** 74f11*
77+ 10* 77+11*
78+11 8 0 2 12
79f11 78+13
78f12 81 f 12
76f12 77f 10
7 8 5 10 81 f 10
94+ lo** 92f 12**
94 I 1 ** 95f 12*
95+11* 98f 12
95 f 12* 97f 14
97f 13 99f 13
93 & 12* 94f lo**
67+7 64f 10
64+8 66f11
62+7** 63+ 10
62&8** 60 10*
61 +_ 10* 60 f 8*
67f8 64f8
SBP (mmHg) P K
DBP (mmHg) Blood Press Downloaded from informahealthcare.com by University of North Carolina on 12/06/14 For personal use only.
P K
MBP (mmHg) 101+ 8 102f9
P K
+
96+11* loof 10
HR (min-') P
68f11 64f 13
K
*,**
: ~ ( 0 . 0 5 0.01 , vs
+
67f8 64+9
time=O min.
Table 111. Egects of ketoprofen on hormonal responses to captopril dosing on the 7th day P: placebo; K : ketoprofen; P R A : peripheral renin activity; DATA are means fSD. Time (min) after captopril administration 0
90
150
360
0.97 f 0.70 0.55 +0.42*
3.06k7.10 1.40f2.807
1.83f2.60 1.08f 1.607
I .OO f 0.71 0.56 k 0.52*
6.2 f I .8 7.9 k 6.5
5.4f 2.2 5.2f3.3
PRA (ng/ml/h) P K
Aldosterone (ng/100 ml) P K ~~
t; *: 0.05
5.7f2.5 6.4f3.3
6.8 1.7 5.5k3.0
~~
< p
1992; 1: 162-1 67
Effect of Ketoprofen on Blood Pressure, Endocrine and Renal Responses to Chronic Dosing with Captopril in Patients with Essential Hypertension JEAN R. CUSSON,' PATRICK D U SOUICH,2 PATRICK LE MORVAN,3 GAETAN THIBAULT,' ROBERT PHILLIPS,3 ALAIN MILOT' and PIERRE LAROCHELLE'
'
'
From Institut de recherches cliniques de Montrial, Universiti de Montrial, and Rhdne-Poulenc Rorer, Canada Inc., Canada
Blood Press Downloaded from informahealthcare.com by University of North Carolina on 12/06/14 For personal use only.
Cusson JR, Souich P du, Le Morvan P, Thibault G , Phillips R, Milot A, Larochelle P. Effect of ketoprofen on blood pressure, endocrine and renal responses to chronic dosing with captopril in patients with essential hypertension. Blood Pressure 1992; 1: 162-167.
The effects of non-steroidal anti-inflammatory drugs (NSAIDs) on the blood pressure and renal function of essential hypertensive patients depend on the specific type of NSAID and antihypertensive drug administered. Twelve patients with essential hypertension, aged 35 to 59 years, stabilized (blood pressure less than 140/90 mmHg) with captopril, received ketoprofen (100 mg bid for 7 days) or matching placebo in a randomized double-blind cross-over fashion. A 3-week wash-out period was included between treatment periods. Blood pressure on the first and last days of the placebo treatment period (137 k 7(SD)/80 f.8 and 139& 1 1/8 1 k 9 mmHg) was similar to respective values during ketoprofen therapy (136 k 10/79 7 and 143k 10/81 9 mmHg). The mean differencesin systolic and diastolic blood pressures, at the end of the treatment periods, between ketoprofen and placebo were 4 (95% confidence intervals - 5, + 13) and 0 (- 8, + 8) mmHg, respectively.Ketoprofen had no effect on 24-h urinary sodium excretion (160 k 3 3 and 147+39 mmo1/24 h for ketoprofen and placebo, respectively). Ketoprofen was without effect on glomerular filtration rate, renal plasma Row and filtration fraction. In conclusion, our data suggest that ketoprofen is a safe choice when short-term treatment with a NSAID is indicated in an essential hypertensive patient treated with a converting enzyme inhibitor such as captopril. Key words: non-steroidal anti-injammatory drugs, essential hypertension, aldosterone, angiotensin converting enzyme inhibition, natriuresis.
INTRODUCTION Non-steroidal anti-inflammatory drugs (NSAIDs) have the potential to reduce the effect of antihypertensive drugs. This has been shown for the interaction of indomethacin and many antihypertensive agents including angiotensin converting enzyme (ACE) inhibitors [ 1-71; the mechanism of this interaction involves the inhibition of prostaglandin (PG) synthesis by NSAIDs [8]. This could be particularly important when captopril is used as an antihypertensive drug because captopril stimulates prostaglandin synthesis [9]. However, it has also been shown previously that all NSAIDs do not necessarily interact similarly with antihypertensive drugs [I 01. Sulindac and acetylsalicylic acid have been reported to have no effect in this situation [I 1-12]. Oates [lo] recently suggested that all other NSAIDs might reduce the effect of antihypertensive drugs unless proven otherwise. Limited and conflicting data have been published with regard to NSAIDs of the propionic acid type [7]. The main purpose of this study was therefore to evaluate whether ketoprofen increased blood pressure in essential hypertensive patients treated with captopril. In addition, renal function and hormonal parameters were monitored.
MATERIAL AND METHODS Subjects and protocol Twelve patients with essential hypertension participated in this double-blind, randomized, placebo-controlled, cross-over study where the effects of the addition of ketoprofen versus placebo on the blood pressure response and the renal function of hypertensive patients under chronic dosing of captopril were investigated. The study was approved by the local ethics committee. Male or female patients between the ages of 18 and 60 years with uncomplicated (WHO stage I) essential hypertension were included in the study. Systolic and diastolic blood pressure values, under pharmacological treatment, had to be lower than 140 and 90 mmHg on admission to the study. The diagnosis of hypertension had beeen made between 1 and 26 years prior to the study, and blood pressure under drug-free conditions had been greater than 140/95 mmHg in all subjects; indeed 11 of the 18 patients initially invited to participate in the study had blood pressure levels greater than 170/100 recorded in their charts at the Hypertension Clinic, and up to 230/130 mmHg. Exclusion criteria were: women of child bearing potential, secondary
Blood Press Downloaded from informahealthcare.com by University of North Carolina on 12/06/14 For personal use only.
Ketoprofen treatment in captopril-treated hypertensives
hypertension, history of adverse effects or allergy to the study drugs or to NSAIDs, significant liver dysfunction, diabetes, gastric or duodenal ulcer, abnormal hemostasis, history of alcohol or drug abuse, and previous history of non-compliance. Patients with musculoskeletal conditions requiring NSAIDs were not excluded. The use of any concomitant medication was prohibited during the course of the study except for acetaminophen if needed for pain. Initially, 18 patients were recruited but only 12 completed the study. One patient withdrew from the study because of a skin rash. This adverse event occurred before the administration of ketoprofen and was attributed to captopril. Another patient was excluded when he complained of retrosternal chest pain. Three patients were excluded because they did not meet the blood pressure stability criteria before the main phase. Finally, one had a white blood cell count of less than 3.5 x 109/Land was excluded in the preliminary phase. The study consisted of a preliminary phase and a treatment phase. First, patients were stabilized on captopril (Capoten Squibb Canada) monotherapy in three equal daily doses (08 :00, 15 :00,23 :00). When, at three consecutive weekly visits diastolic blood pressure was stabilized, patients could be included in the treatment phase of the protocol. Diastolic blood pressure was considered stabilized if at these 3 visits the diastolic blood pressure readings were within 10 mmHg. The captopril treatment was maintained for a period of 5 weeks. On the first and last weeks of this period, all subjects would receive, in two daily doses, either enteric coated tablets of ketoprofen 100 mg (Orudism), or matching placebo in a randomized fashion under double-blind conditions. The patients therefore took 200 mg/d of ketoprofen, the dose recommended by the manufacturer in rheumatoid arthritis. Compliance was assessed by pill counts. During the 3-week wash-out period, patients remained only on captopril therapy. On the first and last days of each 1-week experimental treatment period, data on blood pressure, renal function and plasma levels of some hormones involved in blood pressure homeostasis, were obtained to determine a first dose and 1-week treatment effects. Blood pressure was evaluated during the stabilization period on captopril monotherapy and at the beginning and at the end of the two treatment periods with either ketoprofen or placebo. Blood pressure was measured by a direct oscillometric recording device (Dynamap, Critikon) on the same arm, after at least 5 min in supine resting position. Prior to the morning dose of captopril, the mean of three blood pressure readings was used as the baseline value for that day. @,
163
Blood was sampled for a complete blood count and a biochemical profile during the screening phase, prior to the first week of experimental treatment and at the follow-up visit 2-3 weeks after the end of the study. An additional biochemical profile was also done at each visit during the study. Urinanalysis was also done at the screening phase, and prior and at the end of the study whereas the 24-h urinary protein excretion was measured at each visit during the actual study. All patients were instructed to follow a diet containing approximately 150 and 100 mmol of sodium and potassium per day, respectively. For renal function studies, the patients came to the Physiology room at 07:30 after an overnight fast. At 08:00, a baseline blood sample was drawn and subjects then received one tablet of test medication (ketoprofen or placebo) along with the morning dose of captopril and 240 ml of water. While remaining supine and after a light breakfast, constant infusions of inulin at 32 mg/min (following a bolus dose of 50 mg/kg) and of PAH at 12 mg/min (following a bolus dose of 8 mg/kg) were started for a duration of 90 min. Blood was sampled at the end of the infusion to determine the plasma concentrations of both inulin and PAH. The aim was to obtain steadystate levels of inulin and PAH of about 12 and 150 mg/ mL respectively. Using this method, steady-state levels are achieved relatively rapidly [ 13,141. The clearances of inulin and PAH were calculated as the ratio of the infusion rate over the steady-state plasma concentration according to the constant infusion pharmacokinetic model [ 151. The PAH clearance is an estimate of the renal plasma flow (RPF) and inulin clearance is an estimate of glomerular filtration rate (GFR) [16]. The filtration fraction (FF) was calculated as the ratio of GFR/RPF. Patients also received 100 ml of water every 30 min during the clearance procedures. Plasma levels of peripheral renin activity (PRA) [ 171, aldosterone [18], C-terminal (CT-ANF) and N-terminal (NT-ANF) fragments of atrial natriuretic factor [19] and cyclic guanosine monophosphate (cGMP) [20] were determined on the last day of each treatment period, at 0,90,150 and 360 min following the morning dose of captopril. Statistical Analysis
Data are presented as means fstandard deviation. Mean differences are given with 95% confidence intervals. In order to demonstrate a difference of 6 mmHg for diastolic blood pressure, the main variable, 12 subjects needed to be included in this study according to sample size calculation based on a bilateral LI of 0.05 and a unilateral fi of 0.80. The results, presented as means and standard deviations, were analyzed by
164
J . R. Cusson et al.
Blood Press Downloaded from informahealthcare.com by University of North Carolina on 12/06/14 For personal use only.
analysis of variance (ANOVA). After testing for homoscedasticity (Bartlett’s test), analysis of differences between the sequences was performed using ANOVA for repeated measures for blood pressure and heart rate data at baseline and on each first day of the test periods. Data obtained between periods were analyzed according to a 2 x 2 Latin square design for repeated measures within periods. RESULTS The 12 patients (6 females and 6 males) had a mean age of 50 years (range 35-59), a mean height of 166 cm (range 154-1 79), and a mean weight of 77 kg (range 5596). Seven were controlled with a dose of 37.5 mg t.i.d., 4 on 25 mg t.i.d. and one on 12.5 mg t.i.d. EfSect of ketoprofen on blood pressure and heart rate Compared to placebo, ketoprofen did not significantly alter systolic ( p = 0.44) nor diastolic ( p = 0.72) blood pressure (Table I). The mean difference in systolic and diastolic blood pressures, at the end of the treatment periods, between ketoprofen and placebo were 4 (95% confidence intervals - 5 , 13) and 0 (- 8, 8) mmHg, respectively. There was a period effect for diastolic as it was slightly increased in the second period independently of the type of treatment (p=O.O43). Heart rate was similarly unaffected by ketoprofen.
+
+
Effect of ketoprofen on blood pressure, heart rate and hormonal responses to captopril Changes in blood pressure and heart rate were also monitored during 360 min following captopril dosing
on the last day of each treatment period. All decreased significantly ( p < 0.01) following captopril and these blood pressure and heart rate reductions, presented for all patients together, were unaffected by ketoprofen treatment (Table 11). Actually, blood pressure decreased by about 10/4 mmHg 90 min post captopril, under both placebo and ketoprofen. Changes in plasma levels of PRA, aldosterone, CTANF, NT-ANF and cGMP were also measured following the morning dose of captopril on the last day of each treatment period. Following captopril, PRA increased and plasma aldosterone decreased (Table 111). After ketoprofen, the captopril-induced increase in PRA (+0.9 k0.8 ng/mL/h), was reduced compared to that observed following placebo (+2.1 k 2.1 ng/mL/h) treatment. However, this difference did not reach statistical significance ( p = 0.06). The captoprilinduced reduction in aldosterone was unchanged by ketoprofen (see Table 111). In addition, the urinary excretion of aldosterone during the period following captopril was unaffected by ketoprofen (placebo: 68.2k43.1, ketoprofen: 56.3 k 51.7 ng/360 min, p=0.28). There were no particular trends in plasma levels of CT-ANF, NT-ANF and cGMP (not shown).
EfSects of ketoprofen on renal function
Baseline 24-h urinary volume, potassium and creatinine excretion rates on the first day of each treatment period were similar (not shown) but there was a slightly lower baseline 24-h urinary sodium excretion rate prior to the first day of ketoprofen therapy versus that prior to the first day of placebo (135 f50 vs 176+65 mmo1/24 h, a difference of 41 ( - 8 to +90) mmo1/24 h, p = 0 . 0 5 5 ) .
Table I. EfSect of one-week treatment with ketoprofen on blood pressure and heart rate prior to the morning dose of captopril SBP: systolic blood pressure; DBP: diastolic blood pressure; HR: heart rate; K : ketoprofen; P: placebo. DATA are means fSD. ~
Day 0
Day 7
SBP (mmHg)
DBP (mmHg)
HR (min-I)
SBP (mmHg)
DBP (mmHg)
HR (min-I)
Sequence I (n=6) K P
134+ 10 137f9
78k7 82+8
6 4 5 10 66k9
I43 7 l38+ 10
81 + 6 83+9
63+12 67+6
Sequence 2 (n = 6) P K
137f5 137+ 10
77f7 80+8
68+ 12 71515
I41 f 12 I43 f 14
79+ 10 81 f 12
69f 14 66+ I5
All patients ( n = 12) P K
13757 136f 10
80+8 79+7
67+ 10 67+ 13
139f11 I43 10
81 + 9 81 f 9
68f 11 64+ 13
+
+
Ketoprofen treatment in captopril-treated hypertensives
165
Table 11. E$ect of ketoprofen on blood pressure and heart rate responses to captopril on the 7th day P placebo; K: ketoprofen; S B P systolic blood pressure; DBP: diastolic blood pressure; M B P mean blood pressure; HR: heart rate. DATA are means SD.
*
Time (min) after captopril administration 0
60
90
120
150
180
240
360
139f11 143+ 10
133f 14* 129f 17**
129+15** 132f 16**
130+ 14* 135+ 16
129k 17** 133f 18*
l35+ 18 135f17
128f 17** 130+ 13**
134f I6 138f 12
81 + 9 81 + 9
75f9** 74f11*
77+ 10* 77+11*
78+11 8 0 2 12
79f11 78+13
78f12 81 f 12
76f12 77f 10
7 8 5 10 81 f 10
94+ lo** 92f 12**
94 I 1 ** 95f 12*
95+11* 98f 12
95 f 12* 97f 14
97f 13 99f 13
93 & 12* 94f lo**
67+7 64f 10
64+8 66f11
62+7** 63+ 10
62&8** 60 10*
61 +_ 10* 60 f 8*
67f8 64f8
SBP (mmHg) P K
DBP (mmHg) Blood Press Downloaded from informahealthcare.com by University of North Carolina on 12/06/14 For personal use only.
P K
MBP (mmHg) 101+ 8 102f9
P K
+
96+11* loof 10
HR (min-') P
68f11 64f 13
K
*,**
: ~ ( 0 . 0 5 0.01 , vs
+
67f8 64+9
time=O min.
Table 111. Egects of ketoprofen on hormonal responses to captopril dosing on the 7th day P: placebo; K : ketoprofen; P R A : peripheral renin activity; DATA are means fSD. Time (min) after captopril administration 0
90
150
360
0.97 f 0.70 0.55 +0.42*
3.06k7.10 1.40f2.807
1.83f2.60 1.08f 1.607
I .OO f 0.71 0.56 k 0.52*
6.2 f I .8 7.9 k 6.5
5.4f 2.2 5.2f3.3
PRA (ng/ml/h) P K
Aldosterone (ng/100 ml) P K ~~
t; *: 0.05
5.7f2.5 6.4f3.3
6.8 1.7 5.5k3.0
~~
< p
