Volume Number
121 2. Part 2
Pharmacology
bronchodilating properties in experimental models of bronchoconstriction. Celiprolol is not a cardiodepressant but augments global cardiac function. It also has beneficial effects in the ischemic myocardium. These properties distinguish it from other antihypertensive agents.
I.
8 REFERENCES
1. Barrett
2.
3I
4.
51
6.
JA, Smith RD, Wolf PS, Pruss TP. Beta-l antagonist and cardiostimulatory effects of celiprolol in anesthetized dogs. Drug Dev Res 1986;9:159-69. Jolly SR, Van Inwegen R, Schwa1 A, et al. Comparison of l- and d-celiprolol in ganglionic-blocked dogs. Drug Dev Res 1988; 14:45-58. Smith RD, Wolf PS. Celiprolol. In: Scriabine A, ed. New drugs annual: Cardiovascular drugs. vol. 2. New York: Raven Press, 1984:19-:15. Van Inwegen R, Khandwala R, Ingram R, et al. Effects of celiprolol on the interactions of serotonin (5HT) and post-synaptic alphas receptors in isolated cat tracheal rings [Abstract]. Fed Proc 1984;43:2689. Thulesius 0, Gjores JE, Berlin E. Vasodilating properties of beta-adrenoceptor blocker with intrinsic sympathomimetic activity. Br J Clin Pharmacol 1982;13:2293-308. Rodenburg JM. Messina EJ, Kaley G, et al. Peripheral
Clinical
safety
and efficacy
9
10.
11.
12.
13.
of celiprolol
microvascular effect of the beta-l receptor blocking agent: celiprolol in rats [Abstract]. Fed Proc 1986;45:582. Brodde OE, Schmuth R, Brickmann M, et al. Beta-adrenoceptor antagonist (non-selective as well as beta-l selective) with partial agonist activity decreased beta-2 adrenoceptor density in human lymphocytes: evidence for a beta-2 agonist component of the partial agonist activity. Naunyn Schmiedebergs Arch Pharmacol 1986;332:130-8. Daul A, Wang XL, Borchard 0, et al. Differential changes in lymphocyte beta 2.adrenoceptor density in beta-blocker administration: role of intrinsic sympathomimetic activity. J Cardiovasc Pharmacol 1986;8(suppl 4):593-6. Reynolds EE, Molinoff PB. Downregulation of beta adrenergic receptors in S49 lymphoma cells induced by atypical agonists. J Pharmacol Exp Ther 1986;239:654-60. Neve KA, Barrett JA, Molinoff PB. Selective regulation of beta-l and beta-2 adrenergic receptor by atypical agonists. J Pharmacol Exp Ther 1985;235:657-64. Wolf PS, Smith RD, Kwandewala A, et al. Celiprolol-pharmacological profile in an unconventional beta blocker. Br J Clin Pratt 1985;39(suppl 40):5-11. Nganele DM, Deleonardis VM, Hintze TH. Celiprolol: a positive inotropic beta-adrenoceptor blocking agent in conscious dogs. Br J Pharmacol 1988;93:501-8. Barrett JA, Magistro AM, Smith RD, et al. Celiprolol, a compound which attenuates myocardial acidosis and improves regional segmental function following ischemia in dogs: a comparison with propranolol. Pharmacology 1989;39:1-10.
of celiprolol
The management of essential hypertension requires therapeutic selections that are not only effective in reducing diastolic blood pressure but are also tailored to the individual patient, with minimal effect on patient demographics, concurrent illnesses, and cardiovascular risk factors. Celiprolol hydrochloride is a new highly cardioselective vasodilating p-adrenoceptor antagonist that has been proven effective and safe for the treatment of essential hypertension. It is comparable to other therapies in blood pressure control while demonstrating an excellent safety profile, favorable hemodynamic activity, and minimal effects on other cardiovascular risk factors. Celiprolol may offer the physician a unique therapeutic alternative. (AM HEART J 1991;121:683-7.)
Kim D. Lamon,
MD, PhD Horsham, Pa.
The complications of untreated essential hypertension, including stroke, heart failure, sudden death, renal failure, retinal damage, angina, myocardial infarction, and peripheral vascular disease, are now
From the Department Pdenc Rarer Central
(,fClinical
Research and Regulatory,
Reprint requeals: Kim D. Lamon, MD, PhD, latory Affairs. Khfine-Poulenc Rarer Central ter Dr., Horsham, PA 1900”. 4/0125424
Affairs,
Rhb-
Research. Clinical Research,
Research and 800 Business
ReguCen-
well recognized. This has led to a change in the management of hypertension-away from stepped-care therapy to an approach that tailors therapy to the individual and considers patient demographics, concurrent diseases, and other cardiovascular risk factors. The pharmaceutical industry has responded to these changing needs with the discovery of new chemical entities (NCEs), the formulations of which are based on our current understanding of the pathophysiology of hypertension, and with the de683
664
Lamon
Table
I.
American
Classification
RESULTS
of P-blockers
Nonselective
Selectice
(61 + 821
Ifid
Nonvasodilating Propranolol Oxprenolol Nadolol
Nonvasodilating Metoprolol Acebutolol Bisoprolol Atenolol Vasodilating Celiprolol
Vasodilating Labetalol Dilevalol Pindolol Carvedilol
Table
II. Effectiveness
of celiprolol in various classesof hy-
pertension
Classificationof hypertension
Isolated systolic (n = 2341 Mild (n = 877) Moderate (n = 8041 Severe (n = 3961 Average decrease in systolic iSIP) readings at the end of treatment 2311 patients with hypertension.‘6
Full in SBP (mm Hg)
Fall in DBP (mm Hd
-24 -22 -24 -31
-4 -10 -14 -23
and diastolic are compared
February 1991 Heart Journal
blood pressure with baseline
(DAP) when readings in
velopment of innovative chemical extensions (ICES) of current drug classesthat are designed to maximize efficacy and favorably affect cardiovascular risk factors while minimizing side effects and adverse effects on quality of life. Celiprolol is a new highly cardioselective P-adrenergic antagonist1 developed in response to these changing needs in the management of essential hypertension, This ICE is an important addition to the therapeutic armamentarium because of its pharmacology, mechanism of action, safety profile, effects on cardiovascular risk factors, and efficacy in comparison to other antihypertensive therapies. This article will assessthe therapeutic index of celiprolol based on review of controlled clinical trials involving thousands of patients worldwide. METHODS
The data presented here are basedon published reports of the clinical safety and efficacy of celiprolol or from data compiled and submitted to regulatory agencies. In all instances,clinical trials were conducted in accordancewith the ethical standards of the committee on human experimentation at the participating institution or in accordance with the Helsinki Declaration of 1975 and as amendedin 1989.
The efficacy of celiprolol in the treatment of hypertension has been well established2-” and appears to be based on its unique pharmacologic profile,7m1S’ which combines in a single molecule selective &-antagonism and Pa-agonism. The PI-antagonism confers activity in the treatment of hypertension and angina, whereas the &agonism appears to be responsible for the low incidence of bradycardia, favorable hemodynamic effects, vasodilating activity, favorable bronchopulmonary profile, and low incidence of adverse experiences. The combined Pi-antagonist and &-agonist properties separate celiprolol from other /3-adrenergic agonists currently in use (Table I). In a large-scale clinical trial evaluating 2311 patients with various classes of hypertension,lG celiprolol produced clinically significant reductions in systolic and diastolic blood pressure in all subpopulations (Table II). Although the magnitude of the response was somewhat larger in this postmarketing surveillance trial than that observed in smaller, double-blind, placebo-controlled trials, the effectiveness of the drug across all classesof hypertension is clear. Celiprolol is administered once daily at doses ranging from 200 mg to 600 mg. Evaluation of its effectiveness by ambulatory blood pressure monitoring throughout a 24-hour dosing cycle was conducted in 84 patients with mild to moderate hypertension (data on file). After 3 weeks of placebo therapy to document hypertension, the qualifying patients were than randomly assigned to receive either placebo or 400 mgl day celiprolol for an additional 4 weeks of doubleblind therapy. Patients randomized to placebo showed the expected diurnal variation in ambulatory diastolic blood pressure, with excellent reproducibility of results when baseline and post-treatment recordings were compared (Fig. 1). Patients randomized to celiprolol showed a good antihypertensive response after 4 weeks of therapy, with a greater effect observed during the waking hours and a more modest effect during sleep (Fig. 2). These results with ambulatory blood pressure recordings confirm the findings with standard cuff measurements that celiprolol is effective in the once-daily treatment of hypertension. In numerous clinical trials, celiprolol has been shown to be equivalent in efficacy to other antihypertensive agents, while demonstrating differences in hemodynamic effects and/or response to exercise testing when compared with nadolol,i7 propranolol,‘” atenolol,‘g, 2overapamil,21 and enalapril.“2 Typical of these results are the findings in a study comparing the effects of celiprolol with metoprolol on blood
Volume Number
121 2. Part 2
safety and efficacy of celiprolol
Treatment
665
- Placebo --VP--
Baseline Pclsttreatment
D$i%tOiC
pressure (mm Hg)
Hour
postdose
Fig. I. Ambulatory diastolic blood pressure: Hourly averages (baseline versus post-treatment). Patients randomized to placebo after 3-week placebo lead-in. Hourly diastolic ambulatory blood pressure readings at baseline (--o--) and after 4 weeks of double-blind placebo therapy (--A--).
Treatment
- Celiprolol
400 qd
v-
100 Diastolic blood pressure (mm Hg)
Baseline Posttreatment
9o
-_-“_
80
0
1
2
_ ^--__- ^...^..-..-.-.-
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Hour postdose
Fig. 2. Ambulatory diastolic blood pressure: Hourly averages (baseline versus post-treatment). Patients randomized to celiprolol, 400 mg/day, after 3-week placebo lead-in. Hourly diastolic ambulatory blood pressure readings at baseline (--o--) and after 4 weeks of double-blind celiprolol therapy (--A--).
pressure and hemodynamics in patients with essential hypertension. 23In this trial both drugs were effective in the control of blood pressure (Fig. 3). However, metoprolol produced significant decreases in heart rate and cardiac output that were not observed with celiprolol, whereas celiprolol produced a significant reduction in total peripheral resistance (Fig. 4). Evaluation of the overall safety of celiprolol also reveals a favorable profile. Of 2884 patients who participated in double-blind, placebo-controlled, clinical trials, no individual adverse experience was reported to have an incidence of >lO % (data on file). The most frequently occurring individual adverse experiences were headache, upper respiratory infection, dizziness, and fatigue/tiredness, but the overall incidence of each experience was low and essentially the same as that observed in the placebo group (Fig. 5). Similar results have been reported previously.24 Finally, initial reports from the literature suggest
that the pharmacologic profile of celiprolol may have favorable effects on cardiovascular risk factors. Celiprolol has been shown to significantly reduce left ventricular hypertrophy25p 26and has demonstrated a beneficial effect on plasma lipids,27 especially when compared with propranolo128 and other P-adrenergic antagonists.2g If these results are confirmed in largescale studies, the already favorable profile of the drug will improve substantially. CONCLUSIONS
Selection of an antihypertensive agent requires an understanding of the agent’s pharmacologic profile, safety profile, and efficacy compared with other available drugs. Patient demographics, concomitant diseases, and other cardiovascular risk factors may also play a role in the therapeutic selection. Taking all of these factors into account allows physicians to match individual patient needs to the
666
Lamon
American
February 1991 Heart Journal
Fig. 3. Comparison of celiprolol and metoprolol: Effects on blood pressure and cardiac output. Effects of metoprolol and celiprolol compared with placebo on standing diastolic blood pressure (BP) and cardiac outnut in natients with essential hypertension. (*Difference from placebo, p < 0.05.) (From J Clin Pharmacol 1987;27:593-600.)
L
Total peripheral resistance (dyne sec/cms)
Heart rate @Pm)
7c I-
1 , -
1500
6CI
-
1400
55 I
-
1300
Placebo
Metoproloi
Place&
Celiprolol
50 I-
Pli lcebd
Metoprolol
Placebo
Celiprolol
Fig. 4. Comparison of celiprolol and metoprolol: Effects on total peripheral resistance and heart rate. Effects of metoprolol and celiprolol compared with placebo on total peripheral resistance and heart rate in patients with essential hypertension. (*Difference from placebo, p < 0.05.) (From J Clin Pharmacol 1987;27:593-600.)
10 9 8 7 6 0%
5 4 3 2 1 n Headache
Ed Celiprolol Fig.
ported
5. Incidence of most frequently by 2884 patients participating
Dizziness
upper resp. infection
I
Fatigue/ tiredness
Placebo
occurring adverse experiences. Incidence of adverse experiences in double-blind, placebo-controlled clinical trials.
re-
Volume Number
121 2. Part 2
therapeutic selection to maximize overall therapeutic benefit. Celiprolol, a new highly cardioselective vasodilatory /3-adrenergic antagonist, has been shown to be effective in the management of essential hypertension. The combination of PI -antagonist and P-agonist properties provides a balanced activity and an excellent safety profile, and therefore may offer a unique alternative to the physician for the management of patients with essential hypertension. REFERENCES
1. Pruss TP, Khandwala A, Wolf I’S, et al. Celiprolol: a new beta adrenoceptor antagonist with novel ancillary properties. J Cardiovasc Pharmacol 1986;8(suppl 4):S29-32. 2. Frishman WH, Flamenbaum W, Schoenbereer J, et al. Celiprolol in systemic hypertension. Am J Cardiol 1989;63:839-42. 3. Capone P, Mayo1 R. A placebo-controlled double-blind multicenter study of celiprolol in the treatment of mild and moderate hypertension. J Cardiovasc Pharmacol 1986;8(suppl 4):S119-21. 4. Leary P, Mayo1 R, Capone P. A comparison of celiprolol and propranolol in the treatment of hypertension in one hundred and seventy-nine subjects. Br J Clin Pratt 1985;39(suppl 40):70-2. 5. Parati (;. Pomidossi G, Casadei R, et al. Evaluation of the antihvpertensive effect of celiprolol by ambulatory blood pressure-monitoring. Am J Car&o1 1988;61:27C33C, 6. Riddell JG. Shanks RG. Broaden RN. Celiorolol: a oreliminary review of its pharmacodynamic and pharmacbkinetic properties and its therapeutic use in hypertension and angina pectoris. Drugs 1987;34:438-58. 7. Opie LH. Qualities of an ideal beta-adrenoceptor antagonist and comparison of existing agents with a new cardioselective hydrophilic vasodilator beta-adrenoceptor antagonist, celiprolol. Am J Cardiol 1988;61:8C-13C. 8. Kimura S, DeQuattro V, Hernandez P, Lee D. Celiprolol’s effects on blood pressure, plasmin renin, aldosterone, and catecholamines in hypertensives suggest mixed beta receptor agonist-antagonist action [Abstract]. Clin Pharmacol Ther 1988;43:183. 9. Brodde OE, Schemuth R, Brinkmann M, et al. Beta-adrenoceptor antagonists (nonselective as well as betai-selective) with partial agonistic activity decreased beta-adrenoceptor density in human lymphocytes: evidence for a betaz-agonistic component of the partial agonistic activity. Naunyn Schmiedebergs Arch Pharmacol 1986;333:130-8. 10. Frishman WH, Teicher M. Beta-adrenergic blockade: an update. Cardiology 1985;72:380-96. 11. Donaldson RM, Williams LA, Lee EH. Acute hemodynamic effects of celiprolol. Am J Cardiol 1988;61:49C51C.
Safety and efficacy of celiprolol
687
12. Mancia G. The central and peripheral hemodynamics of celiprolol. AM HEART J 1988;116:1405-11. dM, Wilson J, Dargie HJ. Improved left ventric13. McLenachan ular function during exercise: a comparison of celiprolol and atenolol. AM HEART ,J 1988;116:1435-6. 14. Mimran A, Ducarliar G. Systemic and regional haemodynamic profile of diuretics and alpha and beta-blockers. A review comoarinr acute and chronic effects. Drugs 1988:35:60-g. 15. Dorow P.‘Celiprolo-review of airway studies. Am .J Cardiol 1988;61:“3C6C. 16. Hotfmann W, Hotfmann H. Results of the Austrian celiprolol postmarketing surveillance study. J Cardiovasc Pharmacol 1986;8(suppl 4):S88-90. 17. Mancia G, Grassi G, Parati G, et al. Effects of celiprolol on reflex control of the cardiovascular system in essential hypertension J Cardiovasc Pharmacol 1986;8(suppl 4l:S67-74. S, Beattie A, Silke B. Celiprolol in the treatment of 18. Taylor hypertension: a comparison with propranolol. J Cardiovasc Pharmacol 1986;8(suppl 4):S127-31. 19. Silke B, Rosenthal F, Taylor S. A randomized double-blind study of atenolol and celiprolol in mild to moderate hypertension. J Cardiovasc Pharmacol 1986;8(suppl 4):S122-6. 20. Rosenthal F, Silke B, Capone, P. A comparison of celiprolol and atenolol in the treatment of hypertension. Br J Clin Pratt 1985;39(suppl 401:76-7. 21. McInnes GT, McLenachan JM, Henderson E, et al. Celiprolol and verapamil in the treatment of essential hypertension. AM HEAKT J 1988;116:1437-8. 22. Ghiringhelli S, Cozzi E, Tsialtas D. Comparison of the antihypertensive effects of celiprolol and enalapril. J Int Med Res 1988;16(suppl 1):73A-9A. 23. Trimarco B, Lembo G, DeLuca N, et al. Effects of celiprolol on systemic and forearm circulation in hypertensive patients: a double-blind cross-over study versus metoprolol. J Clin Pharmacol 1987;27:593-600. 24. Lamon KD. Safety profile of celiprolol. AM HEART J 1988; 116:1438-40. “5. Herrmann JM, Bischof F, Von Heymann F, et al. Reduction of left ventricular hypertrophy in hypertensive patients after treatment with celiprolol. Am J Cardiol 1988;61:55C6C. 26. Trimarco B, Lembo G, DeLuca N, et al. Long-term reduction of peripheral resistance with celiprolol and effects on left ventricular mass. J Int Med Res 1988;16(suppl 11:62A-72A. 27. Herrmann JM, Mayer EO. A long-term study of the effects of celiprolol on blood pressure and lipid-associated risk factors. AM HEART J 1988;116:1416-21. 28. Sirtori CR, Johnson B, Vaccarino V, et al. Lipid effects of celiprolol, a new cardioselective &blocker, versus propranolol. Clin Pharmacol Ther 1989;45:617-26. 29. Fogari R, Zoppi A, Pasotti C, et al. Plasma lipids during chronic antihypertensive therapy with different &blockers. J Cardiovasc Pharmacol 1989;14(suppl 7):S28-32.
121 2. Part 2
Pharmacology
bronchodilating properties in experimental models of bronchoconstriction. Celiprolol is not a cardiodepressant but augments global cardiac function. It also has beneficial effects in the ischemic myocardium. These properties distinguish it from other antihypertensive agents.
I.
8 REFERENCES
1. Barrett
2.
3I
4.
51
6.
JA, Smith RD, Wolf PS, Pruss TP. Beta-l antagonist and cardiostimulatory effects of celiprolol in anesthetized dogs. Drug Dev Res 1986;9:159-69. Jolly SR, Van Inwegen R, Schwa1 A, et al. Comparison of l- and d-celiprolol in ganglionic-blocked dogs. Drug Dev Res 1988; 14:45-58. Smith RD, Wolf PS. Celiprolol. In: Scriabine A, ed. New drugs annual: Cardiovascular drugs. vol. 2. New York: Raven Press, 1984:19-:15. Van Inwegen R, Khandwala R, Ingram R, et al. Effects of celiprolol on the interactions of serotonin (5HT) and post-synaptic alphas receptors in isolated cat tracheal rings [Abstract]. Fed Proc 1984;43:2689. Thulesius 0, Gjores JE, Berlin E. Vasodilating properties of beta-adrenoceptor blocker with intrinsic sympathomimetic activity. Br J Clin Pharmacol 1982;13:2293-308. Rodenburg JM. Messina EJ, Kaley G, et al. Peripheral
Clinical
safety
and efficacy
9
10.
11.
12.
13.
of celiprolol
microvascular effect of the beta-l receptor blocking agent: celiprolol in rats [Abstract]. Fed Proc 1986;45:582. Brodde OE, Schmuth R, Brickmann M, et al. Beta-adrenoceptor antagonist (non-selective as well as beta-l selective) with partial agonist activity decreased beta-2 adrenoceptor density in human lymphocytes: evidence for a beta-2 agonist component of the partial agonist activity. Naunyn Schmiedebergs Arch Pharmacol 1986;332:130-8. Daul A, Wang XL, Borchard 0, et al. Differential changes in lymphocyte beta 2.adrenoceptor density in beta-blocker administration: role of intrinsic sympathomimetic activity. J Cardiovasc Pharmacol 1986;8(suppl 4):593-6. Reynolds EE, Molinoff PB. Downregulation of beta adrenergic receptors in S49 lymphoma cells induced by atypical agonists. J Pharmacol Exp Ther 1986;239:654-60. Neve KA, Barrett JA, Molinoff PB. Selective regulation of beta-l and beta-2 adrenergic receptor by atypical agonists. J Pharmacol Exp Ther 1985;235:657-64. Wolf PS, Smith RD, Kwandewala A, et al. Celiprolol-pharmacological profile in an unconventional beta blocker. Br J Clin Pratt 1985;39(suppl 40):5-11. Nganele DM, Deleonardis VM, Hintze TH. Celiprolol: a positive inotropic beta-adrenoceptor blocking agent in conscious dogs. Br J Pharmacol 1988;93:501-8. Barrett JA, Magistro AM, Smith RD, et al. Celiprolol, a compound which attenuates myocardial acidosis and improves regional segmental function following ischemia in dogs: a comparison with propranolol. Pharmacology 1989;39:1-10.
of celiprolol
The management of essential hypertension requires therapeutic selections that are not only effective in reducing diastolic blood pressure but are also tailored to the individual patient, with minimal effect on patient demographics, concurrent illnesses, and cardiovascular risk factors. Celiprolol hydrochloride is a new highly cardioselective vasodilating p-adrenoceptor antagonist that has been proven effective and safe for the treatment of essential hypertension. It is comparable to other therapies in blood pressure control while demonstrating an excellent safety profile, favorable hemodynamic activity, and minimal effects on other cardiovascular risk factors. Celiprolol may offer the physician a unique therapeutic alternative. (AM HEART J 1991;121:683-7.)
Kim D. Lamon,
MD, PhD Horsham, Pa.
The complications of untreated essential hypertension, including stroke, heart failure, sudden death, renal failure, retinal damage, angina, myocardial infarction, and peripheral vascular disease, are now
From the Department Pdenc Rarer Central
(,fClinical
Research and Regulatory,
Reprint requeals: Kim D. Lamon, MD, PhD, latory Affairs. Khfine-Poulenc Rarer Central ter Dr., Horsham, PA 1900”. 4/0125424
Affairs,
Rhb-
Research. Clinical Research,
Research and 800 Business
ReguCen-
well recognized. This has led to a change in the management of hypertension-away from stepped-care therapy to an approach that tailors therapy to the individual and considers patient demographics, concurrent diseases, and other cardiovascular risk factors. The pharmaceutical industry has responded to these changing needs with the discovery of new chemical entities (NCEs), the formulations of which are based on our current understanding of the pathophysiology of hypertension, and with the de683
664
Lamon
Table
I.
American
Classification
RESULTS
of P-blockers
Nonselective
Selectice
(61 + 821
Ifid
Nonvasodilating Propranolol Oxprenolol Nadolol
Nonvasodilating Metoprolol Acebutolol Bisoprolol Atenolol Vasodilating Celiprolol
Vasodilating Labetalol Dilevalol Pindolol Carvedilol
Table
II. Effectiveness
of celiprolol in various classesof hy-
pertension
Classificationof hypertension
Isolated systolic (n = 2341 Mild (n = 877) Moderate (n = 8041 Severe (n = 3961 Average decrease in systolic iSIP) readings at the end of treatment 2311 patients with hypertension.‘6
Full in SBP (mm Hg)
Fall in DBP (mm Hd
-24 -22 -24 -31
-4 -10 -14 -23
and diastolic are compared
February 1991 Heart Journal
blood pressure with baseline
(DAP) when readings in
velopment of innovative chemical extensions (ICES) of current drug classesthat are designed to maximize efficacy and favorably affect cardiovascular risk factors while minimizing side effects and adverse effects on quality of life. Celiprolol is a new highly cardioselective P-adrenergic antagonist1 developed in response to these changing needs in the management of essential hypertension, This ICE is an important addition to the therapeutic armamentarium because of its pharmacology, mechanism of action, safety profile, effects on cardiovascular risk factors, and efficacy in comparison to other antihypertensive therapies. This article will assessthe therapeutic index of celiprolol based on review of controlled clinical trials involving thousands of patients worldwide. METHODS
The data presented here are basedon published reports of the clinical safety and efficacy of celiprolol or from data compiled and submitted to regulatory agencies. In all instances,clinical trials were conducted in accordancewith the ethical standards of the committee on human experimentation at the participating institution or in accordance with the Helsinki Declaration of 1975 and as amendedin 1989.
The efficacy of celiprolol in the treatment of hypertension has been well established2-” and appears to be based on its unique pharmacologic profile,7m1S’ which combines in a single molecule selective &-antagonism and Pa-agonism. The PI-antagonism confers activity in the treatment of hypertension and angina, whereas the &agonism appears to be responsible for the low incidence of bradycardia, favorable hemodynamic effects, vasodilating activity, favorable bronchopulmonary profile, and low incidence of adverse experiences. The combined Pi-antagonist and &-agonist properties separate celiprolol from other /3-adrenergic agonists currently in use (Table I). In a large-scale clinical trial evaluating 2311 patients with various classes of hypertension,lG celiprolol produced clinically significant reductions in systolic and diastolic blood pressure in all subpopulations (Table II). Although the magnitude of the response was somewhat larger in this postmarketing surveillance trial than that observed in smaller, double-blind, placebo-controlled trials, the effectiveness of the drug across all classesof hypertension is clear. Celiprolol is administered once daily at doses ranging from 200 mg to 600 mg. Evaluation of its effectiveness by ambulatory blood pressure monitoring throughout a 24-hour dosing cycle was conducted in 84 patients with mild to moderate hypertension (data on file). After 3 weeks of placebo therapy to document hypertension, the qualifying patients were than randomly assigned to receive either placebo or 400 mgl day celiprolol for an additional 4 weeks of doubleblind therapy. Patients randomized to placebo showed the expected diurnal variation in ambulatory diastolic blood pressure, with excellent reproducibility of results when baseline and post-treatment recordings were compared (Fig. 1). Patients randomized to celiprolol showed a good antihypertensive response after 4 weeks of therapy, with a greater effect observed during the waking hours and a more modest effect during sleep (Fig. 2). These results with ambulatory blood pressure recordings confirm the findings with standard cuff measurements that celiprolol is effective in the once-daily treatment of hypertension. In numerous clinical trials, celiprolol has been shown to be equivalent in efficacy to other antihypertensive agents, while demonstrating differences in hemodynamic effects and/or response to exercise testing when compared with nadolol,i7 propranolol,‘” atenolol,‘g, 2overapamil,21 and enalapril.“2 Typical of these results are the findings in a study comparing the effects of celiprolol with metoprolol on blood
Volume Number
121 2. Part 2
safety and efficacy of celiprolol
Treatment
665
- Placebo --VP--
Baseline Pclsttreatment
D$i%tOiC
pressure (mm Hg)
Hour
postdose
Fig. I. Ambulatory diastolic blood pressure: Hourly averages (baseline versus post-treatment). Patients randomized to placebo after 3-week placebo lead-in. Hourly diastolic ambulatory blood pressure readings at baseline (--o--) and after 4 weeks of double-blind placebo therapy (--A--).
Treatment
- Celiprolol
400 qd
v-
100 Diastolic blood pressure (mm Hg)
Baseline Posttreatment
9o
-_-“_
80
0
1
2
_ ^--__- ^...^..-..-.-.-
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Hour postdose
Fig. 2. Ambulatory diastolic blood pressure: Hourly averages (baseline versus post-treatment). Patients randomized to celiprolol, 400 mg/day, after 3-week placebo lead-in. Hourly diastolic ambulatory blood pressure readings at baseline (--o--) and after 4 weeks of double-blind celiprolol therapy (--A--).
pressure and hemodynamics in patients with essential hypertension. 23In this trial both drugs were effective in the control of blood pressure (Fig. 3). However, metoprolol produced significant decreases in heart rate and cardiac output that were not observed with celiprolol, whereas celiprolol produced a significant reduction in total peripheral resistance (Fig. 4). Evaluation of the overall safety of celiprolol also reveals a favorable profile. Of 2884 patients who participated in double-blind, placebo-controlled, clinical trials, no individual adverse experience was reported to have an incidence of >lO % (data on file). The most frequently occurring individual adverse experiences were headache, upper respiratory infection, dizziness, and fatigue/tiredness, but the overall incidence of each experience was low and essentially the same as that observed in the placebo group (Fig. 5). Similar results have been reported previously.24 Finally, initial reports from the literature suggest
that the pharmacologic profile of celiprolol may have favorable effects on cardiovascular risk factors. Celiprolol has been shown to significantly reduce left ventricular hypertrophy25p 26and has demonstrated a beneficial effect on plasma lipids,27 especially when compared with propranolo128 and other P-adrenergic antagonists.2g If these results are confirmed in largescale studies, the already favorable profile of the drug will improve substantially. CONCLUSIONS
Selection of an antihypertensive agent requires an understanding of the agent’s pharmacologic profile, safety profile, and efficacy compared with other available drugs. Patient demographics, concomitant diseases, and other cardiovascular risk factors may also play a role in the therapeutic selection. Taking all of these factors into account allows physicians to match individual patient needs to the
666
Lamon
American
February 1991 Heart Journal
Fig. 3. Comparison of celiprolol and metoprolol: Effects on blood pressure and cardiac output. Effects of metoprolol and celiprolol compared with placebo on standing diastolic blood pressure (BP) and cardiac outnut in natients with essential hypertension. (*Difference from placebo, p < 0.05.) (From J Clin Pharmacol 1987;27:593-600.)
L
Total peripheral resistance (dyne sec/cms)
Heart rate @Pm)
7c I-
1 , -
1500
6CI
-
1400
55 I
-
1300
Placebo
Metoproloi
Place&
Celiprolol
50 I-
Pli lcebd
Metoprolol
Placebo
Celiprolol
Fig. 4. Comparison of celiprolol and metoprolol: Effects on total peripheral resistance and heart rate. Effects of metoprolol and celiprolol compared with placebo on total peripheral resistance and heart rate in patients with essential hypertension. (*Difference from placebo, p < 0.05.) (From J Clin Pharmacol 1987;27:593-600.)
10 9 8 7 6 0%
5 4 3 2 1 n Headache
Ed Celiprolol Fig.
ported
5. Incidence of most frequently by 2884 patients participating
Dizziness
upper resp. infection
I
Fatigue/ tiredness
Placebo
occurring adverse experiences. Incidence of adverse experiences in double-blind, placebo-controlled clinical trials.
re-
Volume Number
121 2. Part 2
therapeutic selection to maximize overall therapeutic benefit. Celiprolol, a new highly cardioselective vasodilatory /3-adrenergic antagonist, has been shown to be effective in the management of essential hypertension. The combination of PI -antagonist and P-agonist properties provides a balanced activity and an excellent safety profile, and therefore may offer a unique alternative to the physician for the management of patients with essential hypertension. REFERENCES
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