В ряде последних крупных рандомизированных исследований была четко продемонстрирована важность антигипертензивной терапии для профилактики сердечно-сосудистой смертности. Антагонисты кальция занимают достойное место в арсенале терапевтических средств для контроля факторов сердечно-сосудистого риска. Несмотря на недавние споры о побочных эффектах и проблемах, связанных с безопасностью применения блокаторов кальциевых каналов, они, по-прежнему, играют важную роль в лечении артериальной гипертензии. В то время как ранние разработки фокусировались на повышении мощности и селективности блокаторов кальциевых каналов, большинство последних разработок касается получения препаратов с медленным началом и большей продолжительностью действия. Последним из полученных препаратов в данном направлении является лерканидипин. Этот представитель блокаторов кальциевых каналов объединяет в себе практически все благоприятные эффекты. С фармакологической точки зрения препарат обладает высокой липофильностью, что обусловливает его большую продолжительность действия и возможность применения 1 раз в день. Он обладает уникальным связывающим профилем, гарантирующим перманентное блокирующее действие на кальциевые каналы, не связанное с его концентрацией в плазме крови. Процентная доля пациентов, ответивших на терапию, находится между 70 и 90%. Идеальная дозировка составляет 10–20 мг/сут. Нежелательные явления возникают редко, и пожилые пациенты имеют ряд положительных моментов при использовании данного препарата. Тысячи пациентов в Европе уже с успехом получают лерканидипин. В частности, нежелательное действие на сердечно-сосудистую систему дигидропиридинов I поколения, таких как нифедипин, на фоне терапии лерканидипином фактически отсутствует.
Recently several large endpoint studies have clearly established the importance of antihypertensive treatment in the prevention of cardiovascular death. Calcium antagonists clearly have their place within the therapeutic efforts aimed at cardiovascular risk control. Despite former debates on side effects and safety problems calcium channel blockers thus still hold an important position in the treatment of systemic hypertension. While earlier developments have focused on increasing potency and selectivity of calcium channel blockers, the most recent developments have brought about drugs with a particularly slow onset and long duration of action. The latest designer-drug in this context is lercanidipine. This particular calcium channel blocker combines practically all desired effects. Pharmacologically the drug has a high lipophilicity which enables a long duration and a single-dose use. It has a unique binding profile which guarantees constant calcium antagonistic action independent of serum concentration changes. The proportion of responding patients lies between 70 and 90%. The ideal dosage is 10 to 20 mg per day. Adverse effects are few and elderly patients profit from the drug. Thousands of patients throughout Europe have so far been treated with lercanidipine successfully. In particular, the cardiovascular side effects seen with earlier dihydropyridines such as nifedipine are virtually absent with lercanidipine.
1. Uemura K, Pisa Z. Trends in cardiovascular disease mortality in industrialised countries since 1950. World Health Stat Q 1988; 41: 155–68.
2. Marques-Vidal P, Tuomilehto J. Hypertension awareness, treatment and control in the community: is the «rule of halves» still valid? J Hum Hypertens 1997; 11: 213–20.
3. Murray CJL, Lopez AD. The global burden of disease. a comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020. World Health Organisation, Geneva, 1996.
4. MacMahon S, Peto R, Cutler J et al. Blood pressure, stroke, and coronary disease. Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990; 335: 765–74.
5. Eastern Stroke and Coronary Heart Disease Collaborative Research Group. Blood pressure, cholesterol and stroke in Eastern Asia. Lancet 1998; 352: 1801–7.
6. Prospective Studies Collaboration. Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 45,000 people in 45 prospective cohorts. Lancet 1995; 346: 1647–53.
7. Klag MJ, Whelton PK, Randall BL et al. Blood pressure and end-stage renal disease in men. N Engl J Med 1996; 334: 13–8.
8. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317: 703–13.
9. Staessen JA, Fagard R, Thijs L et al., for the Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997; 350: 757–64.
10. World Health Organization-International Society of Hypertension Guidelines for the Management of Hypertension. J Hypertens 1999; 17: 151–83.
11. Pahor M, Guralnik JM, Furberg CD et al. Risk of gastrointestinal haemorrhage with calcium antagonists in hypertensive persons over 67 years old. Lancet 1996; 347: 1061–5.
12. Pahor M, Guralnik JM, Ferrucci L et al. Calcium-channel blockade and incidence of cancer in aged populations. Lancet 1996; 348: 493–7.
13. Furberg CD, Psaty BM, Meyer JV. Nifedipine: dose-related increase in mortality in patients with coronary heart disease. Circulation 1995; 92: 1326–31.
14. Psaty BM, Heckbert SR, Koepsell TD et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA 1995; 274: 620–5.
15. Gong L, Zhang W, Zhu Y et al. Shanghai Trial of Nifedipine in the Elderly (STONE). J Hypertens 1996; 14: 1237–45.
16. Gasser R. Calcium antagonists: pharmacological agents in search of new clinical indications. Angiology 1990; 41: 36–41.
17. Goa KL, Sorkin EM. Nitrendipine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the treatment of hypertension. Drugs 1987; 33: 123–55.
18. Meredith PA, Elliott HL. Amlodipine: clincial relevance of a unique pharmacokinetic profile. J Cardiovasc Pharmacol 1993; 22 (Suppl. A): S6–8.
19. Triggle DJ. Pharmacologic and therapeutic differences among calcium channel antagonists: profile of mibefradil, a new calcium antagonist. Am J Cardiol 1996; 78 (Suppl. 9A): 7–12.
20. Brohani NO, Mercuri M, Borhani PA et al. Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS). A randomized controlled trial. JAMA 1996; 276: 785–91.
21. Herbette L. Lipophilic design of dihydropyridine calcium channel blockers: enhanced membrane properties. 3rd European Meeting on Calcium Antagonists. Symposium Lipophilic dihydropyridines: a new generation of calcium channel blockers. Amsterdam, October 31, 1997 (Abstract).
22. Leonardi A, Nardi D, Pennini R et al. New 1,4-dihydropyridines with antihypertensive activity. IX International Symposium on Medical Chemistry, Berlin, September 14–18, 1986.
23. Nardi D, Leonardi A, Cerri A et al. Asymmetric N-(3,3 diphenylpropyl)aminoalkyl esters of 4-aryl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acids with antihypertensive activity. J Mol Cell Cardiol 1995; 27: A385.
24. Fleckenstein A, Frey M, Zorn J, Fleckenstein-Grun G. Amlodipine, a new 1,4-dihydropyridine calcium antagonist with a particularly strong antihypertensive profile. Am J Cardiol 1989; 64: 21I–34I.
25. Abernethy DR, Gutkowaka J, Winterbottom LM. Effects of amlodipine, a long acting dihydropyridine calcium antagonist in aging hypertension: pharmacodynamics in relation to disposition. Clin Pharmacol Ther 1990; 48; 76–86.
26. Herbette LG, Vecchiarelli M, Sartani A, Leonardi A. Lercanidipine: short plasma half-life, long duration of action and high cholesterol tolerance. Updated molecular model to rationalize its pharmacokinetic properties. Blood Pressure 1998; 7 (Suppl. 2): 10–17.
27. Mason RP, Campbell S, Wang S, Herbette LG. A comparison of bilayer location and binding for the charged 1,4-dihydropyridine Ca2+ channel antagonist amlodipine with uncharged drugs of this class in cardiac and model membranes. Mol Pharmacol 1989; 36: 634–40.
28. Zimmerman BG. Peripheral neurogenic factors in acute and chronic alterations of arterial pressure. Circ Res 1983; 53: 121–30.
29. Ganten D. Role of animal models in hypertension research. Hypertension 1987; 9: 12–4.
30. Guarneri L, Angelico P, Ibba M et al. Pharmacological in vitro studies of the new 1,4-dihydropyridine calcium antagonist lercanidipine. Arzneim Forsch/Drug Res 1996; 46: 15–24.
31. Leonardi A, Poggesi E, Taddei C et al. In vitro calcium-antagonistic activity of lercanidipine and its enantiomers. J Cardiovasc Pharmacol 1997; 29 (Suppl. 1): S10–8.
32. Sironi G, Montagna E, Greto L et al. Antihypertensive effects of lercanidipine in experimental hypertensive rats and dogs. Arzneim Forsch/Drug Res 1996; 46: 145–52.
33. Sironi G, Colombo D, Greto L et al. Antihypertensive activity of lercanidipine and its enantiomers in animal models. J Cardiovasc Pharmacol 1997; 29 (Suppl. 1): S33–40.
34. Sironi G, Montagna E, Greto L et al. Hemodynamic effects of lercanidipine in anaesthetized open-chest dogs. Arzneim Forsch/Drug Res 1996; 46: 256–61.
35. Testa R, Leonardi A, Tajana A et al. Lercanidipine (Rec 15/2375): a novel 1,4-dihydropyridine calcium antagonist for hypertension. Cardiovasc Drug Rev 1997; 15: 187–219.
36. Herbette LG, Vecchiarelli M, Leonardi A. Lercanidipine: short plasma half-life, long duration of action «A molecular model to rationalize its pharmacokinetic properties». J Cardiovasc Pharmacol 1997; 29 (Suppl. 1): S19–24.
37. Circo A. Active dose findings for lercanidipine in a double-blind, placebocontrolled design in patients with mild to moderate hypertension. J Cardiovasc Pharmacol 1997; 29 (Suppl. 2): S22–6.
38. Ninci MA, Magliocca R, Malliani A. Efficacy and tolerability of lercanidipine in elderly patients with mild to moderate hypertension in a placebo-controlled, double-blind study. J Cardiovasc Pharmacol 1997; 29 (Suppl. 2): S41–5.
39. Morisco C, Trimarco B. Efficacy and tolerability of lercanidipine in comparison to and in combination with atenolol in patients with mild to moderate hypertension in a double-blind controlled study. J Cardiovasc Pharmacol 1997; 29 (Suppl. 2): S26–30.
40. Policicchio D, Magliocca R, Malliani A. Efficacy and tolerability of lercanidipine in patients with mild to moderate essential hypertension: a comparative study with slow-release nifedipine. J Cardiovasc Pharmacol 1997; 29 (Suppl. 2): S31–5.
41. Barbagallo Sangiorgi G, Putignano E, Calcara L, Barbagallo M. Efficacy and tolerability of lercanidipine vs. captopril in patients with mild to moderate hypertension in a double-blind controlled study. J Cardiovasc Pharmacol 1997; 29 (Suppl. 2): S36–9.
42. Ninci MA, Magliocca R, Malliani A. Efficacy and tolerability of lercanidipine in elderly patients with mild to moderate hypertension in a placebo-controlled, double-blind study. J Cardiovasc Pharmacol 1997; 29 (Suppl. 2): S40–4.
43. Meredith PA, Reid L. Differences between calcium antagonists: duration of action and trough to peak ratio. J Hypertens 1993: 11 (Suppl. 1): S21–6.
44. Lipicky RS. Trough/peak ratio: the rationale behind the United States Food and Drug Administration recommendations. J Hypertens 1994; 12 (Suppl. 8): S17–9.
45. Barbagallo Sangiorgi G. A study of the efficacy and tolerability of Lercanidipine as sole treatment in elderly patients with isolated systolic hypertension. A multicenter double blind comparison with placebo. (Data on file).
46. Paterna S, Licata A, Arnone S et al. Lercanidipine in two different dosage regimens as a sole treatment for severe essential hypertension. J Cardiovasc Pharmacol 1997; 29 (Suppl. 2): S50–3.
47. Rengo F, Romis L. Activity of lercanidipine in double-blind comparison with nitrendipine in combination treatment of patients with resistant essential hypertension. J Cardiovasc Pharmacol 1997; 29 (Suppl. 2): S54–8.
48. Cafiero M, Giasi M. Long-term (12 month) treatment with lercanidipine in patients with mild to moderate hypertension. J Cardiovasc Pharmacol 1987; 9 (Suppl. 2): S46–50.
49. Rossoni G, Bernareggi M, De Gennaro Colonna V et al. Lercanidipine protects the heart from low flow ischemia damage and antagonizes the vasopressor activity of endothelin-1. J Cardiovasc Pharmacol 1997; 29 (Suppl. 1): S41–7.
50. Bernocchi P, Ceconi C, Cargnoni A et al. Effects of lercanidipine on Fe2+-induced mitochondrial lipid peroxidation. J Cardiovasc Pharmacol 1997; 29 (Suppl. 1): S63–8.
51. Corsini A, Bonifatti M, Quarato P et al. Effect of the new calcium antagonist lercanidipine and its enantiomers on the migration and proliferation of arterial myocytes. J Cardiovasc Pharmacol 1996; 28: 687–94.
52. Floras JS. Antihypertensive treatment, myocardial infarction and nocturnal myocardial ischaemia. Lancet 1988; 2: 994–6.
________________________________________________
1. Uemura K, Pisa Z. Trends in cardiovascular disease mortality in industrialised countries since 1950. World Health Stat Q 1988; 41: 155–68.
2. Marques-Vidal P, Tuomilehto J. Hypertension awareness, treatment and control in the community: is the «rule of halves» still valid? J Hum Hypertens 1997; 11: 213–20.
3. Murray CJL, Lopez AD. The global burden of disease. a comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020. World Health Organisation, Geneva, 1996.
4. MacMahon S, Peto R, Cutler J et al. Blood pressure, stroke, and coronary disease. Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990; 335: 765–74.
5. Eastern Stroke and Coronary Heart Disease Collaborative Research Group. Blood pressure, cholesterol and stroke in Eastern Asia. Lancet 1998; 352: 1801–7.
6. Prospective Studies Collaboration. Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 45,000 people in 45 prospective cohorts. Lancet 1995; 346: 1647–53.
7. Klag MJ, Whelton PK, Randall BL et al. Blood pressure and end-stage renal disease in men. N Engl J Med 1996; 334: 13–8.
8. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317: 703–13.
9. Staessen JA, Fagard R, Thijs L et al., for the Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997; 350: 757–64.
10. World Health Organization-International Society of Hypertension Guidelines for the Management of Hypertension. J Hypertens 1999; 17: 151–83.
11. Pahor M, Guralnik JM, Furberg CD et al. Risk of gastrointestinal haemorrhage with calcium antagonists in hypertensive persons over 67 years old. Lancet 1996; 347: 1061–5.
12. Pahor M, Guralnik JM, Ferrucci L et al. Calcium-channel blockade and incidence of cancer in aged populations. Lancet 1996; 348: 493–7.
13. Furberg CD, Psaty BM, Meyer JV. Nifedipine: dose-related increase in mortality in patients with coronary heart disease. Circulation 1995; 92: 1326–31.
14. Psaty BM, Heckbert SR, Koepsell TD et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA 1995; 274: 620–5.
15. Gong L, Zhang W, Zhu Y et al. Shanghai Trial of Nifedipine in the Elderly (STONE). J Hypertens 1996; 14: 1237–45.
16. Gasser R. Calcium antagonists: pharmacological agents in search of new clinical indications. Angiology 1990; 41: 36–41.
17. Goa KL, Sorkin EM. Nitrendipine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the treatment of hypertension. Drugs 1987; 33: 123–55.
18. Meredith PA, Elliott HL. Amlodipine: clincial relevance of a unique pharmacokinetic profile. J Cardiovasc Pharmacol 1993; 22 (Suppl. A): S6–8.
19. Triggle DJ. Pharmacologic and therapeutic differences among calcium channel antagonists: profile of mibefradil, a new calcium antagonist. Am J Cardiol 1996; 78 (Suppl. 9A): 7–12.
20. Brohani NO, Mercuri M, Borhani PA et al. Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS). A randomized controlled trial. JAMA 1996; 276: 785–91.
21. Herbette L. Lipophilic design of dihydropyridine calcium channel blockers: enhanced membrane properties. 3rd European Meeting on Calcium Antagonists. Symposium Lipophilic dihydropyridines: a new generation of calcium channel blockers. Amsterdam, October 31, 1997 (Abstract).
22. Leonardi A, Nardi D, Pennini R et al. New 1,4-dihydropyridines with antihypertensive activity. IX International Symposium on Medical Chemistry, Berlin, September 14–18, 1986.
23. Nardi D, Leonardi A, Cerri A et al. Asymmetric N-(3,3 diphenylpropyl)aminoalkyl esters of 4-aryl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acids with antihypertensive activity. J Mol Cell Cardiol 1995; 27: A385.
24. Fleckenstein A, Frey M, Zorn J, Fleckenstein-Grun G. Amlodipine, a new 1,4-dihydropyridine calcium antagonist with a particularly strong antihypertensive profile. Am J Cardiol 1989; 64: 21I–34I.
25. Abernethy DR, Gutkowaka J, Winterbottom LM. Effects of amlodipine, a long acting dihydropyridine calcium antagonist in aging hypertension: pharmacodynamics in relation to disposition. Clin Pharmacol Ther 1990; 48; 76–86.
26. Herbette LG, Vecchiarelli M, Sartani A, Leonardi A. Lercanidipine: short plasma half-life, long duration of action and high cholesterol tolerance. Updated molecular model to rationalize its pharmacokinetic properties. Blood Pressure 1998; 7 (Suppl. 2): 10–17.
27. Mason RP, Campbell S, Wang S, Herbette LG. A comparison of bilayer location and binding for the charged 1,4-dihydropyridine Ca2+ channel antagonist amlodipine with uncharged drugs of this class in cardiac and model membranes. Mol Pharmacol 1989; 36: 634–40.
28. Zimmerman BG. Peripheral neurogenic factors in acute and chronic alterations of arterial pressure. Circ Res 1983; 53: 121–30.
29. Ganten D. Role of animal models in hypertension research. Hypertension 1987; 9: 12–4.
30. Guarneri L, Angelico P, Ibba M et al. Pharmacological in vitro studies of the new 1,4-dihydropyridine calcium antagonist lercanidipine. Arzneim Forsch/Drug Res 1996; 46: 15–24.
31. Leonardi A, Poggesi E, Taddei C et al. In vitro calcium-antagonistic activity of lercanidipine and its enantiomers. J Cardiovasc Pharmacol 1997; 29 (Suppl. 1): S10–8.
32. Sironi G, Montagna E, Greto L et al. Antihypertensive effects of lercanidipine in experimental hypertensive rats and dogs. Arzneim Forsch/Drug Res 1996; 46: 145–52.
33. Sironi G, Colombo D, Greto L et al. Antihypertensive activity of lercanidipine and its enantiomers in animal models. J Cardiovasc Pharmacol 1997; 29 (Suppl. 1): S33–40.
34. Sironi G, Montagna E, Greto L et al. Hemodynamic effects of lercanidipine in anaesthetized open-chest dogs. Arzneim Forsch/Drug Res 1996; 46: 256–61.
35. Testa R, Leonardi A, Tajana A et al. Lercanidipine (Rec 15/2375): a novel 1,4-dihydropyridine calcium antagonist for hypertension. Cardiovasc Drug Rev 1997; 15: 187–219.
36. Herbette LG, Vecchiarelli M, Leonardi A. Lercanidipine: short plasma half-life, long duration of action «A molecular model to rationalize its pharmacokinetic properties». J Cardiovasc Pharmacol 1997; 29 (Suppl. 1): S19–24.
37. Circo A. Active dose findings for lercanidipine in a double-blind, placebocontrolled design in patients with mild to moderate hypertension. J Cardiovasc Pharmacol 1997; 29 (Suppl. 2): S22–6.
38. Ninci MA, Magliocca R, Malliani A. Efficacy and tolerability of lercanidipine in elderly patients with mild to moderate hypertension in a placebo-controlled, double-blind study. J Cardiovasc Pharmacol 1997; 29 (Suppl. 2): S41–5.
39. Morisco C, Trimarco B. Efficacy and tolerability of lercanidipine in comparison to and in combination with atenolol in patients with mild to moderate hypertension in a double-blind controlled study. J Cardiovasc Pharmacol 1997; 29 (Suppl. 2): S26–30.
40. Policicchio D, Magliocca R, Malliani A. Efficacy and tolerability of lercanidipine in patients with mild to moderate essential hypertension: a comparative study with slow-release nifedipine. J Cardiovasc Pharmacol 1997; 29 (Suppl. 2): S31–5.
41. Barbagallo Sangiorgi G, Putignano E, Calcara L, Barbagallo M. Efficacy and tolerability of lercanidipine vs. captopril in patients with mild to moderate hypertension in a double-blind controlled study. J Cardiovasc Pharmacol 1997; 29 (Suppl. 2): S36–9.
42. Ninci MA, Magliocca R, Malliani A. Efficacy and tolerability of lercanidipine in elderly patients with mild to moderate hypertension in a placebo-controlled, double-blind study. J Cardiovasc Pharmacol 1997; 29 (Suppl. 2): S40–4.
43. Meredith PA, Reid L. Differences between calcium antagonists: duration of action and trough to peak ratio. J Hypertens 1993: 11 (Suppl. 1): S21–6.
44. Lipicky RS. Trough/peak ratio: the rationale behind the United States Food and Drug Administration recommendations. J Hypertens 1994; 12 (Suppl. 8): S17–9.
45. Barbagallo Sangiorgi G. A study of the efficacy and tolerability of Lercanidipine as sole treatment in elderly patients with isolated systolic hypertension. A multicenter double blind comparison with placebo. (Data on file).
46. Paterna S, Licata A, Arnone S et al. Lercanidipine in two different dosage regimens as a sole treatment for severe essential hypertension. J Cardiovasc Pharmacol 1997; 29 (Suppl. 2): S50–3.
47. Rengo F, Romis L. Activity of lercanidipine in double-blind comparison with nitrendipine in combination treatment of patients with resistant essential hypertension. J Cardiovasc Pharmacol 1997; 29 (Suppl. 2): S54–8.
48. Cafiero M, Giasi M. Long-term (12 month) treatment with lercanidipine in patients with mild to moderate hypertension. J Cardiovasc Pharmacol 1987; 9 (Suppl. 2): S46–50.
49. Rossoni G, Bernareggi M, De Gennaro Colonna V et al. Lercanidipine protects the heart from low flow ischemia damage and antagonizes the vasopressor activity of endothelin-1. J Cardiovasc Pharmacol 1997; 29 (Suppl. 1): S41–7.
50. Bernocchi P, Ceconi C, Cargnoni A et al. Effects of lercanidipine on Fe2+-induced mitochondrial lipid peroxidation. J Cardiovasc Pharmacol 1997; 29 (Suppl. 1): S63–8.
51. Corsini A, Bonifatti M, Quarato P et al. Effect of the new calcium antagonist lercanidipine and its enantiomers on the migration and proliferation of arterial myocytes. J Cardiovasc Pharmacol 1996; 28: 687–94.
52. Floras JS. Antihypertensive treatment, myocardial infarction and nocturnal myocardial ischaemia. Lancet 1988; 2: 994–6.