Patent EA-004679-B1 (EA)
Title: Method and formulation for treating resistance to antihypertensives and related conditions
Inventor: ZISAPEL NAVA
IPC: A61K31/40
Filed: 2000-01-05
Abstract: 1. A pharmaceutical formulation which comprises, in addition to at least one carrier, diluent or adjuvant: melatonin in an amount effective to ameliorate or prevent symptoms of hypertension developing in a patient who is resistant to the antihypertensive effect of an antihypertensive compound administered in absence of melatonin; and at least one antihypertensive compound in an amount effective to exert an antihypertensive effect in presence of melatonin, in a patient requiring such treatment. 2. A pharmaceutical formulation according to claim 1, which is additionally characterized by at least one of the following features: (i) it is adapted for oral, rectal, parenteral or transdermal administration; (ii) it is in unit dosage form, each unit dosage comprising an amount of melatonin which lies within the range of 2.5-20 mg; (iii) it is in the form of a controlled release formulation, wherein the melatonin is preferably released at a predetermined controlled rate; (iv) it comprises also at least one melatonin receptor modifier and/or melatonin profile modifier; (v) said antihypertensive compound is selected from Diltiazem, Captopril, Atenolol, Benazepril, Enalapril, Valsartan, Metoprolol, Terazosin, Prazosin, Minoxidil, Clonidine, Ramipril and pharmaceutically acceptable salts thereof; (vi) said carrier, diluent or adjuvant includes at least one acrylic resin. 3. Use of melatonin in the manufacture of a medicament for the prevention or treatment of symptoms of hypertension in a patient who is resistant to the antihypertensive effect of an antihypertensive compound administered in absence of melatonin. 4. Use according to claim 3, wherein said medicament takes the form of a pharmaceutical formulation, which includes at least one of the following additional components (a) and (b): (a) at least one carrier, diluent or adjuvant; (b) at least one antihypertensive compound in an amount effective to exert a blood pressure lowering effect in a patient requiring such treatment. 5. Use according to claim 4, wherein said pharmaceutical formulation is additionally characterized by at least one of the following features: (i) it is adapted for oral, rectal, parenteral or transdermal administration; (ii) it is in unit dosage form, each unit dosage comprising an amount of melatonin which lies within the range of 2. 5-20mg; (iii) it is in the form of a controlled release formulation, wherein the melatonin is preferably released at a predetermined controlled rate; (iv) it comprises also at least one melatonin receptor modifier and/or melatonin profile modifier; (v) said antihypertensive compound, when present, is selected from Diltiazem, Captopril, Atenolol, Benazepril, Enalapril, Valsartan, Metoprolol, Terazosin, Prazosin, Minoxidil, Clonidine, Ramipril and pharmaceutically acceptable salts thereof; (vi) said carrier, diluent or adjuvant includes at least one acrylic resin. 6. Use according to claim 3, wherein the formulation is a controlled-release formulation. 7. Use according to claim 6, wherein the formulation the formulation is a controlled-release formulation in particulate form comprising coated particles and the desired controlled-release properties are achieved by at least one of the following features, namely: (a) by variation in the particle size of the melatonin; (b) by use of at least two different coating materials which dissolve at different rates in the human body; and (c) by varying the thickness of coating material (s) whereby the particulate melatonin is coated with different thicknesses of coating material (s) which dissolve at different rates in the human body. 8. Use according to claim 6, wherein the formulation which is additionally characterized by at least one of the following features: (i) it is adapted for oral, rectal, parenteral or transdermal administration; (ii) it is in unit dosage form, each unit dosage comprising an amount of melatonin which lies within the range of 2.5-20 mg; (iii) it is in the form of a controlled release formulation, wherein the melatonin is preferably released at a predetermined controlled rate; (iv) it comprises also at least one melatonin receptor modifier and/or melatonin profile modifier; (v) said antihypertensive compound is selected from Diltiazem, Captopril, Atenolol, Benazepril, Enalapril, Valsartan, Metoprolol, Terazosin, Prazosin, Minoxidil, Clonidine, Ramipril and pharmaceutically acceptable salts thereof; (vi) said carrier, diluent or adjuvant includes at least one acrylic resin. 9. Use of melatonin in the manufacture of a medicament for imparting in a patient at least one effect selected from improvement in mood and daytime vigilance, postponement of the peak level of cortisol in the patient and potential prophylactic protection against the detrimental effects of ischemia on the heart, the medicament being a controlled-release pharmaceutical formulation adapted for oral, parenteral or rectal administration, which comprises melatonin in an amount effective to impart at least one of the above-stated effects. 10. Use according to claim 9, wherein the formulation is further characterized by at least one of the following features: (i) it is a controlled-release formulation which is adapted to release melatonin following administration to a human patient over a predetermined time period; (ii) it is a controlled-release formulation which is adapted to release melatonin according to a profile which simulates the nocturnal profile in plasma of a human having a normal endogenous melatonin nocturnal profile; (iii) it is adapted for oral, rectal, parenteral or transdermal administration; (iv) it is in unit dosage form containing an amount within the range of 1 mg to 80 mg melatonin per dosage unit. 11. Use according to claim 10, wherein the formulation is a controlled-release formulation in particulate form comprising coated particles and the desired controlled-release properties are achieved by at least one of the following features, namely: (a) by variation in the particle size of the melatonin; (b) by use of at least two different coating materials which dissolve at different rates in the human body; and (c) by varying the thickness of coating material (s) whereby the particulate melatonin is coated with different thicknesses of coating material (s) which dissolve at different rates in the human body. 12. Use according to claim 11, wherein the formulation comprises particulate melatonin coated with at least one polymeric coating material. 13. Use according to claim 9, wherein the formulation comprises at least one additional ingredient selected from melatonin receptor modifiers and melatonin profile modifiers. 14. Use according to claim 13, wherein the formulation comprises at least one additional medicament selected from benzodiazepine melatonin receptor modifiers, benzodiazepine melatonin profile modifiers, beta-blockers, calcium channel blockers and serotonin uptake. 15. Use of melatonin according to claim 13 in which said patient is a patient with abnormal nocturnal fall in blood pressure and/or morning increase of blood pressure despite of administering antihypertensive drugs.