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Drugs

, Volume 57, Issue 4, pp 633–651 | Cite as

Nebivolol in the Management of Essential Hypertension

A Review
  • Wendy McNeely
  • Karen L. Goa
Adis Drug Evaluation

Summary

Abstract

Nebivolol is a lipophilic β1-blocker. It is devoid of intrinsic sympathomimetic or membrane stabilising activity but appears to have nitric oxide-mediated vasodilatory effects. Nebivolol is administered as aracemic mixture of equal proportions of d- and l-enantiomers. The drug does not significantly influence glucose or plasma lipid metabolism and appears to have a protective effect on left ventricular function.

At the recommended dosage (5mg once daily) nebivolol reduces resting diastolic blood pressure as effectively as standard therapeutic dosages of atenolol, metoprolol, lisinopril and nifedipine, as shown in comparative trials. Nebivolol reduced blood pressure significantly more than enalapril 10mg daily in the short but not the long term, although the enalapril dose may not have been optimal. Nebivolol has an additive effect in combination with hydrochlorothiazide.

Standing blood pressure and/or mean 24-hour ambulatory blood pressure is significantly and similarly reduced with nebivolol, atenolol or nifedipine. Nebivolol tended to prevent increases in early morning blood pressure better than nifedipine.

Overall response rates to nebivolol therapy (a decrease in sitting/supine diastolic blood pressure to ≤90mm Hg or a 10% or ≥10mm Hg fall in diastolic blood pressure) ranged from 58 to 81% after 4 to 52 weeks’ treatment. In comparative studies, response rates were greater in nebivolol than in enalapril or metoprolol recipients, but not significantly different from those in atenolol or nifedipine recipients.

Nebivolol 5mg once daily is well tolerated in patients with hypertension. Adverse events are infrequent, transient and mild to moderate. Those reported most often include headache, fatigue, paraesthesias and dizziness. Several studies reported no signs of orthostatic hypotension with nebivolol.

Comparative trials revealed no significant differences between the frequency and severity of adverse events in patients receiving nebivolol, atenolol, enalapril or placebo; however, the overall incidence of adverse events was greater with nifedipine or metoprolol. Some atenolol or enalapril, but not nebivolol, recipients reported impotence or decreased libido during therapy.

Conclusion: Current evidence indicates that nebivolol 5mg once daily is a well tolerated β-blocker, which is as effective as once daily atenolol and other classes of antihypertensive agents. It may therefore be recommended as a useful alternative first-line treatment option for the management of patients with mild to moderate uncomplicated essential hypertension.

Pharmacodynamic Profile

Nebivolol is a lipophilic β1-blocker administered clinically as a racemic mixture of equal proportions of its d- and l-enantiomers. The drug is devoid of intrinsic sympathomimetic or membrane stabilising activity but appears to have a nitric oxide-mediated vasodilatory effect. Unlike atenolol, nebivolol causes dose-related endothelium-dependent vasodilation in human dorsal hand or forearm vessels.

Available data suggest that nebivolol has a protective effect on left ventricular function. The drug appears to reduce preload and maintain or decrease afterload. Total peripheral vascular resistance did not increase in any study of nebivolol. Heart rate and left ventricular end-diastolic pressure are decreased, whereas stroke volume is increased and cardiac output is generally maintained, notably in patients with heart failure. Nebivolol reduced left ventricular mass in hypertensive patients with left ventricular hypertrophy.

Decreases in the ratio of pre-ejection period to left ventricular ejection time (PEP/LVET) were the result of significant shortening of PEP and lengthening of LVET periods (p ≤ 0.05 for both) in patients with hypertension treated with nebivolol for 1 year.

Resting heart rates were reduced similarly with nebivolol 5mg and atenolol 50mg once daily, but resting and 24-hour ambulatory heart rates were reduced to a significantly greater extent with nebivolol than with nifedipine 20mg twice daily (p < 0.05) or enalapril 10mg once daily (p < 0.001).

Single or multiple doses of nebivolol reduced exercise-induced tachycardia and attenuated exercise-induced increases in blood pressure in patients and volunteers to a similar or lesser extent than atenolol, propranolol or pindolol. Submaximal endurance time decreased with atenolol but was unchanged with nebivolol.

Nebivolol does not appear to significantly influence glucose or plasma lipid metabolism although there have been rare instances of increases in triglyceride levels. The drug was associated with reductions in plasma renin levels and increased plasma atrial natriuretic peptide levels but did not alter renal haemodynamics in hypertensive patients with or without renal artery stenosis when administered for 4 weeks.

Pharmacokinetic Profile

The metabolism of nebivolol is subject to genetic polymorphism; phenotypically, individuals may be characterised as ‘poor’ (slow) or ‘extensive’ (fast) metabolisers.

After a single 5mg oral dose, peak plasma drug concentrations (Cmax) for unchanged d, l-nebivolol were 1.48 μg/L in fast metabolisers and for active fractions of d- and l-nebivolol plus their corresponding hydroxylated metabolites were 7.3 and 13.1 μg/L, respectively, in hypertensive patients. Repeated doses increased the Cmax values for the individual d- and l-enantiomers and their respective metabolites.

Time to Cmax after oral administration of nebivolol is reported to be about 0.5 to 2.0 hours and is not significantly affected by the presence of food. Generally, steady-state plasma concentrations are achieved within 1 day for nebivolol and within a few days for the active metabolites.

Obesity does not appear to affect the total distribution volumes and total body clearance rates (per kilogram body weight) of unchanged nebivolol (racemate or each enantiomer).

Extensive first-pass metabolism after oral administration of nebivolol produces active β-blocking hydroxy-metabolites. Elimination half-lives for the unchanged compound (racemate or each enantiomer) average about 10 hours, but are reported to increase by up to 5 times in poor metabolisers. Elimination half-lives for the hydroxy-metabolites of both enantiomers average about 24 hours in extensive metabolisers, but are almost doubled in poor metabolisers.

One week after administration, 38 and 48%, respectively, of the nebivolol dose is excreted in urine and faeces; unchanged nebivolol accounts for <0.05% of the amount recovered in the urine.

Plasma concentrations of nebivolol (both enantiomers) and its hydroxy metabolites are elevated in patients with renal disease.

Therapeutic Efficacy

Nebivolol 5mg once daily (the recommended dosage; see Dosage and Administration summary) significantly reduces mean sitting or supine diastolic blood pressure (DBP) [by about 10mm Hg]. Significant reductions are maintained during continued therapy with no sign of rebound hypertension or tolerance. In the following discussion the nebivolol dosage is 5mg once daily.

Nebivolol produced similar reductions in resting DBP to atenolol 50 or 100mg once daily for up to 24 weeks and metoprolol 100mg twice daily for 12 weeks in hypertensive patients with or without comorbidities (concomitant type 2 diabetes mellitus or left ventricular hypertrophy).

In addition, nebivolol reduced sitting DBP in patients with hypertension to a similar extent to nifedipine 20mg twice daily after 12 weeks or lisinopril 40mg once daily after 8 weeks. Nebivolol was more effective than enalapril 10mg once daily (usual dosage is 10 to 20mg once daily) after 4 or 12 weeks but not after 28 weeks of treatment. The drug had an additive effect when combined with hydrochlorothiazide 12.5 or 25mg once daily but not with enalapril.

Nebivolol significantly reduced sitting/supine systolic blood pressure (SBP) compared with baseline or placebo. Standing SBP/DBP was also significantly reduced compared with baseline or placebo and to a similar extent to reductions with atenolol, enalapril or nifedipine.

Nebivolol 5 mg/day and atenolol 100mg once daily, nifedipine 20mg twice daily or lisinopril ≤40mg once daily similarly and significantly reduced mean 24-hour ambulatory blood pressure. However, nebivolol tended to prevent increases in early morning blood pressure better than nifedipine. In addition, nebivolol reduced blood pressure loads by about 50% from baseline.

Trough to peak ratios of about 0.9 for supine or sitting DBP have been reported for nebivolol 5mg once daily, which is the same as that for nifedipine sustained release 20mg twice daily but higher than for enalapril 10mg once daily.

Overall response rates (a decrease in sitting/supine diastolic blood pressure to ≤90mm Hg or a 10% or ≥10mm Hg fall in diastolic blood pressure) to treatment with nebivolol 5mg once daily ranged from 58% after 4 weeks’ therapy to 81% after 52 weeks’ therapy. Response rates in nebivolol recipients were significantly greater than in those receiving enalapril early (≤12 weeks), but not later (7 months), or metoprolol but did not differ between patients receiving nebivolol, atenolol or nifedipine. More nebivolol than nifedipine recipients responded to treatment after 2 weeks.

Tolerability

Nebivolol 5mg once daily is well tolerated in patients with hypertension. Adverse events are typically transient and mild to moderate; the type, severity and frequency are not dose-related. Adverse events experienced most often include headache, fatigue, paraesthesias and dizziness. Importantly, several studies reported no signs of orthostatic hypotension with nebivolol.

In comparative trials the frequency and severity of adverse events reported in patients receiving once daily nebivolol 5mg or atenolol 50mg, enalapril 10mg or placebo were not significantly different. However, the overall incidence of adverse events was greater with nifedipine 20mg twice daily or metoprolol 100mg twice daily than with nebivolol. More atenolol or enalapril than nebivolol recipients reported impotence or decreased libido during therapy. In addition, the incidence of fatigue increased from baseline in atenolol recipients but remained constant in nebivolol recipients during a 4-week treatment period.

Dosage and Administration

The recommended dosage of nebivolol is 5mg once daily taken with or without food, preferably at the same time of day.

Use of the drug in children and patients with hepatic insufficiency is not recommended. A reduced starting dose of 2.5mg (with upward titration where necessary) is recommended in the elderly and in patients with renal insufficiency. Nebivolol may be used alone or in combination with other antihypertensive agents. To date, additive antihypertensive effects have been seen only during combination therapy with hydrochlorothiazide.

Keywords

Diastolic Blood Pressure Adis International Limited Nifedipine Enalapril Atenolol 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Joint National Committee. The sixth report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure. Arch Intern Med 1997 Nov 24; 157: 2413–45CrossRefGoogle Scholar
  2. 2.
    Joint National Committee on Prevention Detection Evaluation and Treatment of High Blood Pressure. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med 1997; 157: 2413–46CrossRefGoogle Scholar
  3. 3.
    Prevention of coronary heart disease in clinical practice. Recommendations of the Second Joint Task Force of European and other Societies on coronary prevention. Eur Heart J 1998 Oct; 19(10): 1434–503CrossRefGoogle Scholar
  4. 4.
    Janssens WJ, Xhonneux R, Janssen PAJ. Animal pharmacology of nebivolol. Drug Invest 1991; 3 Suppl. 1: 13–24Google Scholar
  5. 5.
    Van Bortel LMAB, Kool MJF, Wijnen JAG, et al. β-Adrenoceptor blockade and β1-selectivity of nebivolol and atenolol. Drug Invest 1991; 3 Suppl. 1: 173Google Scholar
  6. 6.
    Leysen JE, Pauwels PJ, Gommeren W, et al. The receptor binding profile of the new antihypertensive agent nebivolol and its stereoisomers compared with various β-adrenergic blockers. Drug Invest 1991; 3 Suppl. 1: 120–1Google Scholar
  7. 7.
    Pauwels PJ, Gommeren W, Van Lommen G, et al. The receptor binding profile of the new antihypertensive agent nebivolol and its stereoisomers compared with various β-adrenergic blockers. Mol Pharmacol 1988 Dec; 34: 843–51PubMedGoogle Scholar
  8. 8.
    Bristow MR, Roden RL, Lowes BO, et al. The role of third-generation beta-blocking agents in chronic heart failure. Clin Cardiol 1998; 21 Suppl. 1: 1.3-1.13CrossRefGoogle Scholar
  9. 9.
    Nebivolol. The first highly selective β1-blocker with NO (nitric oxide) modulating properties. Nebivolol monograph. Churchill Communications Europe, London 1996Google Scholar
  10. 10.
    Cheymol G, Woestenborghs R, Snoeck E, et al. Pharmacokinetic study and cardiovascular monitoring of nebivolol in normal and obese subjects. Eur J Clin Pharmacol 1997 Feb; 51: 493–8PubMedCrossRefGoogle Scholar
  11. 11.
    Van Peer A, Snoeck E, Woestenborghs R, et al. Clinical pharmacokinetics of nebivolol: a review. Drug Invest 1991; 3 Suppl. 1: 25–30Google Scholar
  12. 12.
    Janssens WJ. Pharmacology of nebivolol. J Pharm Belg 1992 Jul–Aug; 47: 323–7PubMedGoogle Scholar
  13. 13.
    Van Neuten L, De Crée J. Nebivolol: comparison of the effects of dl-nebivolol, d-nebivolol, 1-nebivolol, atenolol and placebo on exercise-induced increases in heart rate and systolic blood pressure. Cardiovasc Drugs Ther 1998; 12: 339–44CrossRefGoogle Scholar
  14. 14.
    Lacourcière Y, Poirier L, Lefebvre J. Comparative assessment of antihypertensive efficacy of DL-nebivolol and D-nebivolol in patients with confirmed mild to moderate hypertension. J Cardiovasc Pharmacol 1995 Apr; 25: 619–24PubMedCrossRefGoogle Scholar
  15. 15.
    Stoleru L, Wijns W, van Eyll C, et al. Effects of D-nebivolol and L-nebivolol on left ventricular systolic and diastolic function: comparison with D-L-nebivolol and atenolol. J Cardiovasc Pharmacol 1993 Aug; 22: 183–90PubMedCrossRefGoogle Scholar
  16. 16.
    Duprez D, Lefebvre R, De Backer T, et al. Influence of nebivolol on the cardiovascular hemodynamics during postural changes and isometric exercise. Cardiovasc Drugs Ther 1991 Aug; 5: 709–17PubMedCrossRefGoogle Scholar
  17. 17.
    De-Cree J, Geukens H, Cobo C, et al. Subacute hemodynamic effects of nebivolol in man at rest and during exercise. Angiology 1987 Jun; 38: 440–8PubMedCrossRefGoogle Scholar
  18. 18.
    De Cree J, Cobo C, Geukens H, et al. Comparison of the subacute hemodynamic effects of atenolol, propranolol, pindolol, and nebivolol. Angiology 1990 Feb; 41(2): 95–104PubMedCrossRefGoogle Scholar
  19. 19.
    Coto V, Caponnetto S, Van Nueten L. Left ventricular hypertrophy and systolic function in hypertensive patients during long-term treatment with nebivolol: a randomised, double-blind trial versus atenolol. Clinical trial report NEB-ITA-3, Janssen Research Foundation, Sep 1993Google Scholar
  20. 20.
    Eichstadt H, Kaiser W, Möckel M, et al. Haemodynamic measurements in patients under the beta-1 receptor blocker nebivolol. Perfusion 1997 Dec; 10: 449–54Google Scholar
  21. 21.
    DeCrée J, Van Rooy P, Geukens H, et al. The antihypertensive and cardiac hemodynamic effects of nebivolol. Angiology 1992 May; 43: 369–77PubMedCrossRefGoogle Scholar
  22. 22.
    Marceau M, Lacourcière Y, Cléroux J. Effects of nebivolol and atenolol on regional and systemic hemodynamics at rest and during exercise in hypertensive subjects [abstract]. Am J Hypertens 1998 Apr; 11 (Pt 2): 125CrossRefGoogle Scholar
  23. 23.
    Van Bortel LMAB, Kool MJF, Breed JGS, et al. In contrast to atenolol nebivolol does not increase systemic vascular resistance [abstract no. 240]. Eur Heart J 1993: 21Google Scholar
  24. 24.
    Sanchez RA, Cianciulli T, Dopico AM, et al. Effects of nebivolol on left ventricular function in patients with essential hypertension. Drug Invest 1991; 3 Suppl. 1: 155–60Google Scholar
  25. 25.
    Brune S, Schmidt T, Tebbe U, et al. Hemodynamic effects of nebivolol at rest and on exertion in patients with heart failure. Angiology 1990 Sep; 41: 696–701PubMedCrossRefGoogle Scholar
  26. 26.
    Rousseau M, Chapelle F, Van Eyll C, et al. Medium-term effects of beta-blockade on left ventricular mechanics: a double-blind, placebo-controlled comparison of nebivolol and atenolol in patients with ischemic left ventricular dysfunction. J Card Fail 1996; 2(1): 15–23PubMedCrossRefGoogle Scholar
  27. 27.
    Goldstein M, Vincent J-L, De Smet J-M, et al. Administration of nebivolol after coronary artery bypass in patients with altered left ventricular function. J Cardiovasc Pharmacol 1993 Aug; 22: 253–8PubMedCrossRefGoogle Scholar
  28. 28.
    Wisenbaugh T, Katz I, Davis J, et al. Long-term (3 month) effects of nebivolol on cardiac performance in dilated cardiomyopathy [abstract ni. 458]. J Heart Fail 1993 May; 1 Suppl.Google Scholar
  29. 29.
    De-Cree J, Franken P, Vandevivere J, et al. Hemodynamic effects of nebivolol in men: comparison of radionuclide angiocardiography with systolic time intervals. Angiology 1988 Jun; 39: 526–34PubMedCrossRefGoogle Scholar
  30. 30.
    Uhlir O, Dvorak I, Gregor P, et al. Nebivolol in the treatment of cardiac failure: a double-blind controlled clinical trial. J Card Fail 1997; 3(4): 271–6PubMedCrossRefGoogle Scholar
  31. 31.
    Himmelmann A, Hedner T, Snoeck E, et al. Haemodynamic effects and pharmacokinetics of oral d- and l-nebivolol in hypertensive patients. Eur J Clin Pharmacol 1996 Nov–Dec; 51: 259–64PubMedCrossRefGoogle Scholar
  32. 32.
    Van-Bortel LMAB, Breed JGS, Joosten J, et al. Nebivolol in hypertension: a double-blind placebo-controlled multicenter study assessing its antihypertensive efficacy and impact on quality of life. J Cardiovasc Pharmacol 1993 Jun; 21: 856–62PubMedCrossRefGoogle Scholar
  33. 33.
    Chan TYK, Woo KS, Nicholls MG. The application of nebivolol in essential hypertension: a double-blind, randomized, placebo-controlled study. Int J Cardiol 1992 Jun; 35: 387–95PubMedCrossRefGoogle Scholar
  34. 34.
    van Nueten L, Dupont AG, Vertommen C, et al. A dose-response trial of nebivolol in essential hypertension. J Hum Hypertens 1997; 11: 139–44PubMedCrossRefGoogle Scholar
  35. 35.
    van Nueten L, van Grieken M, Dom J, et al. Nebivolol versus nifedipine LA in the treatment of hypertension [abstract no. 2060]. 15th Scientific Meeting of the International Society of Hypertension 1994 Mar 20–24; Melbourne, Australia. 110Google Scholar
  36. 36.
    Fogari R, Zoppi A, Lazzari P, et al. Comparative effects of nebivolol and atenolol on blood pressure and insulin sensitivity in hypertensive subjects with type II diabetes. J Hum Hypertens 1997 Nov; 11: 753–7PubMedCrossRefGoogle Scholar
  37. 37.
    van Nueten L, Taylor FR, Robertson JIS. Nebivolol vs atenolol and placebo in essential hypertension: a double-blind randomised trial. J Hum Hypertens 1998; 12: 135–40PubMedCrossRefGoogle Scholar
  38. 38.
    van Nueten L, Schelling A, Vertommen C, et al. Nebivolol vs enalapril in the treatment of essential hypertension: a double-blind randomised trial. J Hum Hypertens 1997; 11: 813–9PubMedCrossRefGoogle Scholar
  39. 39.
    Lacourcière Y, Poirier L, Lefebvre J, et al. Comparative effects of a new cardioselective beta-blocker nebivolol and nifedipine sustained-release on 24-hour ambulatory blood pressure and plasma lipoproteins. J Clin Pharmacol 1992 Jul; 32: 660–6PubMedGoogle Scholar
  40. 40.
    Lacourcière Y, Arnott W. Placebo-controlled comparison of the effects of nebivolol and low-dose hydrochlorothiazide as monotherapies and in combination on blood pressure and lipid profile in hypertensive patients. J Hum Hypertens 1994 Apr; 8: 283–8PubMedGoogle Scholar
  41. 41.
    Derman WE, Dunbar F, Haus M, et al. Chronic β-blockade does not influence muscle power output during high-intensity exercise of short-duration. Eur J Appl Physiol 1993 Nov; 67: 415–9CrossRefGoogle Scholar
  42. 42.
    De Cree J, Geukens H, Leempoels J, et al. Haemodynamic effects in man during exercise of a single oral dose of narbivolol (R67555), a new beta-1-adrenoceptor blocking agent: a comparative study with atenolol, pindolol and propranolol. Drug Dev Res 1986; 8: 109–17CrossRefGoogle Scholar
  43. 43.
    Van Bortel LMAB, de Hoon JNJM, Kool MJF, et al. Pharmacological properties of nebivolol in man. Eur J Clin Pharmacol 1997; 51: 379–84PubMedCrossRefGoogle Scholar
  44. 44.
    Van Bortel LMAB, van Baak M. Exercise tolerance with nebivolol and atenolol. Cardiovasc Drugs Ther 1992; 6: 239–47PubMedCrossRefGoogle Scholar
  45. 45.
    Gao Y, Nagao T, Bond RA, et al. Nebivolol induces endothelium-dependent relaxations of canine coronary arteries. J Cardiovasc Pharmacol 1991 Jun; 17: 964–9PubMedCrossRefGoogle Scholar
  46. 46.
    Ritter J. A study to investigate the vasodilator effect of nebivolol racemate and isomers on forearm blood flow in healthy volunteers. Clinical research report trial NEB-GBR-31, January, 1996, Janssen Research FoundationGoogle Scholar
  47. 47.
    Hashimoto M, Tanabe Y, Gamoh S, et al. Nebivolol, a new β1 antagonist, can induce endothelium-dependent relaxations of porcine coronary artery by release of nitric oxide from the endothelial cells [abstract]. Jpn J Pharmacol 1996; 71 Suppl. I: 224Google Scholar
  48. 48.
    Cockcroft JR, Chowienczyk PJ, Brett SE, et al. Nebivolol vasodilates human forearm vasculature: evidence for an L-arginine/NO-dependent mechanism. J Pharmacol Exp Ther 1995 Sep; 274: 1067–71PubMedGoogle Scholar
  49. 49.
    Bowman AJ, Chen CPL-H, Ford GA. Nitric oxide mediated venodilator effects of nebivolol. Br J Clin Pharmacol 1994 Sep; 38: 199–204PubMedCrossRefGoogle Scholar
  50. 50.
    Ritter JM, Chowienczyk PJ, Dawes M, et al. Attività vasodilatatoria del nebivololo, nuovo β-bloccante cardioselecttivo, in pazienti con ipertensione arteriosa essenziale [abstract]. Presented at the XV National Congress of the Italian Society for Arterial Hypertension, 1998 6–9 Oct, Rome [in German]Google Scholar
  51. 51.
    Lacourcière Y, Poirier L, Nadeau A. Comparative effects of atenolol and nebivolol on blood pressure and insulin sensitivity in hypertensive patients with glucose intolerance [abstract]. Am J Hypertens 1997 Apr; 10 (Pt 2): 115CrossRefGoogle Scholar
  52. 52.
    Van Nueten L, Aerts T, Vertommen C, et al. Overview of the therapeutic efficacy and safety of nebivolol in the treatment of hypertension. Clinical research report, Janssen Research Foundation, Dec 1994Google Scholar
  53. 53.
    Blankestijn PJ, van den Meiracker AH, Man in’t Veld AJ, et al. Nebivolol, an acute and long term study in essential hypertension. Drug Invest 1991; 3 Suppl. 1: 152–4Google Scholar
  54. 54.
    Janssens WJ, Snoeck E. Pharmacology and pharmacokinetics of nebivolol. Presented at the symposium on endothelium in hypertension. New Therapeutic Trends, Berlin, Germany; 1997 Mar 1; 10-3Google Scholar
  55. 55.
    Kamali F, Howes A, Thomas SHL, et al. Apharmacokinetic and pharmacodynamic interaction study between nebivolol and the H2-receptor antagonists cimetidine and ranitidine. Br J Clin Pharmacol 1997 Feb; 43: 201–4PubMedCrossRefGoogle Scholar
  56. 56.
    Mullier JP. Pharmacokinetics and safety of nebivolol in patients with liver disease receiving a single oral dose of 5 mg nebivolol. Clinical research report NEB-BEL-54, Janssen Pharmaceutica N.V 1996Google Scholar
  57. 57.
    Herlitz H, Alfredsson A. Pharmacokinetics of nebivolol in hypertensive patients with and without renal insufficiency. Clinical research report NEB-SWE-8, Dec 1994, Janssen Research FoundationGoogle Scholar
  58. 58.
    Italian product approvals. Scrip 1997 Mar 4(2211): 20Google Scholar
  59. 59.
    Van Nueten L, Lacourciére Y, Vyssoulis G, et al. Nebivolol versus nifedipine in the treatment of essential hypertension: a double-blind, randomized comparative trial. Am J Ther 1998; 5: 237–43PubMedCrossRefGoogle Scholar
  60. 60.
    Lacourcière Y, Lefebvre J, Poirier L. Treatment of ambulatory hypertensives with nebivolol or hydrochlorothiazide alone and in combination. A randomized, double-blind, placebo-controlled, factorial-design trial. Am J Hypertens 1994 Feb; 7: 137–45Google Scholar
  61. 61.
    Uhlír O, Fejfusa M, Havránek K, et al. Nebivolol versus metoprolol in the treatment of hypertension. Drug Invest 1991; 3 Suppl. 1: 107–10Google Scholar
  62. 62.
    Lacourcière Y, Lefebvre J, Poirer L, et al. A double-blind crossover comparison of nebivolol and lisinopril in the treatment of ambulatory hypertension. Am J Ther 1994; 1: 74–80PubMedCrossRefGoogle Scholar
  63. 63.
    Chalmers JP, Van Nueten L. Effect of single and combination therapy with nebivolol and enalapril and comparison with placebo in the treatment of essential hypertension. Clinical trial report NEB-AUS-5, Janssen Research Foundation, Oct 1994Google Scholar
  64. 64.
    Van Nueten L, Nielsen R, Vertommen C, et al. Nebivolol versus enalapril in essential hypertension: a long-term double-blind comparative trial. Data on file, Janssen Research FoundationGoogle Scholar
  65. 65.
    Elliott HL. Trough to peakratio: current status and applicability. J Hum Hypertens 1998 Jan; 12: 55–9PubMedCrossRefGoogle Scholar
  66. 66.
    Millar JA. Shortcomings in the trough to peak ratio as a guide to the dose interval for antihypertensive drugs. J Hum Hypertens 1998 Jan; 12: 37–44PubMedCrossRefGoogle Scholar
  67. 67.
    Wing LMH, Tonkin AL, Beilby JJ, et al. Nebivolol and enalapril are not additive in combination in the treatment of essential hypertension [abstract]. J Hypertens 1994 Mar; 12 Suppl. 3: 70Google Scholar
  68. 68.
    Kaplan NM, Gifford Jr RW. Choice of initial therapy for hypertension. JAMA 1996 May 22–29; 275: 1577–80PubMedCrossRefGoogle Scholar
  69. 69.
    Freis ED, Papademetriou V. Current drug treatment and treatment patterns with antihypertensive drugs. Drugs 1996 Jul; 52: 1–16PubMedCrossRefGoogle Scholar
  70. 70.
    Mancia G, Grassi G. Antihypertensive treatment: past, present and future. J Hypertens 1998 Jan; 16 Suppl. 1: 1–7CrossRefGoogle Scholar
  71. 71.
    Chalmers J, Zanchetti A. The 1996 report of a World Health Organization expert comittee on hypertension control. J Hypertens 1996 Aug; 14: 929–33PubMedGoogle Scholar
  72. 72.
    Chalmers J. Treatment guidelines in hypertension: current limitations and future solutions. J Hypertens 1996 Nov; 14 Suppl. 4: S3–8CrossRefGoogle Scholar
  73. 73.
    Chalmers J. First-line drugs: the position of the World Health Organization-International Society of Hypertension. J Hypertens 1993 Dec; 11 Suppl. 5: S381–3CrossRefGoogle Scholar

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© Adis International Limited 1999

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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