FR2805993A1 - Treatment or prevention of tolerance to nitro compound vasodilators, comprises administration of melatonin or melatoninergic ligands, especially useful in chronic treatment of cardiac disorders such as angina - Google Patents
Treatment or prevention of tolerance to nitro compound vasodilators, comprises administration of melatonin or melatoninergic ligands, especially useful in chronic treatment of cardiac disorders such as angina Download PDFInfo
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- FR2805993A1 FR2805993A1 FR0002952A FR0002952A FR2805993A1 FR 2805993 A1 FR2805993 A1 FR 2805993A1 FR 0002952 A FR0002952 A FR 0002952A FR 0002952 A FR0002952 A FR 0002952A FR 2805993 A1 FR2805993 A1 FR 2805993A1
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- tolerance
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
- A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
Description
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La nitroglycérine et d'autres composés nitrés ont été utilisés dans le traitement de l'ischémie myocardique depuis plus d'un siècle. Ils sont utilisés pour traiter les patients atteints d'un angor stable ou instable, d'infarctus du myocarde ou d'insuffisance cardiaque. L'efficacité des nitrates dans l'ischémie myocardique est due essentiellement à leurs effets vasodilatateurs (Parker J.D. and Parker J.O. Nitrate therapy for stable angine pectoris. Nitroglycerin and other nitro compounds have been used in the treatment of myocardial ischemia for over a century. They are used to treat patients with stable or unstable angina, myocardial infarction or heart failure. The effectiveness of nitrates in myocardial ischemia is mainly due to their vasodilator effects (Parker J.D. and Parker J.O. Nitrate therapy for stable angina pectoris.
N. Engl. J. Med. 338 :520-531, En dilatant les veines, la nitroglycérine et les autres nitrates induisent une diminution du retour veineux au c#ur réduisant ainsi la pré-charge et les besoins du myocarde en oxygène. La dilatation des artères réduit la post-charge, un autre paramètre déterminant dans la consommation en oxygène du myocarde. Les nitrates sont aussi de puissants coronarodilatateurs permettant ainsi d'améliorer l'apport en oxygène du myocarde. N. Engl. J. Med. 338: 520-531, By dilating the veins, nitroglycerin and the other nitrates induce a reduction of the venous return to the heart thus reducing the preload and the needs of the myocardium for oxygen. The dilation of the arteries reduces afterload, another determining parameter in the oxygen consumption of the myocardium. Nitrates are also powerful coronarodilators, thereby improving the oxygen supply to the myocardium.
Bien que l'efficacité des nitrates soit largement reconnue dans le traitement des cardiopathies d'origine ischémique, l'exposition continue ou fréquente aux composés nitrés entraîne rapidement une diminution de leur efficacité, limitant ainsi leur utilisation à long terme (Abrams, J. et al. Tolérance: An historical overview. Am. J. Cardiol. 81(1A): 3A-14A, 1998). La perte des effets hémodynamiques et anti-angineux observée lors de traitement prolongé constitue le phénomène de tolérance aux nitrés. Although the efficacy of nitrates is widely recognized in the treatment of ischemic heart disease, continuous or frequent exposure to nitrates quickly leads to a reduction in their effectiveness, thus limiting their long-term use (Abrams, J. and al. Tolerance: An historical overview. Am. J. Cardiol. 81 (1A): 3A-14A, 1998). The loss of hemodynamic and antianginal effects observed during prolonged treatment constitutes the phenomenon of tolerance to nitrates.
Le phénomène de tolérance aux dérivés nitrés a rapidement été reconnu après l'utilisation de la nitroglycérine en clinique mais l'utilisation massive de cette thérapie durant les deux dernières décennies a focalisé l'attention sur ce phénomène. The phenomenon of tolerance to nitrates was quickly recognized after the use of nitroglycerin in the clinic, but the widespread use of this therapy during the last two decades has focused attention on this phenomenon.
En effet, le problème de la tolérance aux dérivés nitrés a été amplifié dans les années 1980 après l'introduction des patchs transdermiques à la nitroglycérine. Alors qu'il était anticipé que cette nouvelle forme de dosage en application continue permettrait à la protection antiangineuse de couvrir les 24 heures, il apparut rapidement à partir d'études cliniques versus placebo qu'une tolérance aux dérivés nitrés se développait rapidement dans ces conditions (Parker J. O. and H. L. Fung. Transdermal nitroglycerin in angina pectoris. Am. J. Cardiol. In fact, the problem of tolerance to nitrates was amplified in the 1980s after the introduction of nitroglycerin transdermal patches. While it was anticipated that this new dosage form in continuous application would allow antianginal protection to cover 24 hours, it quickly appeared from clinical studies versus placebo that a tolerance to nitrates developed quickly under these conditions (Parker JO and HL Fung. Transdermal nitroglycerin in angina pectoris. Am. J. Cardiol.
54 :471-476, 1984; Reichek et al. Antianginal effects of nitroglycerin patches. Am. J. 54: 471-476, 1984; Reichek et al. Antianginal effects of nitroglycerin patches. Am. J.
Cardiol. 54:1-7, 1984 ; Steering Committee Transdermal Nitroglycerin Coopérative Study. Cardiol. 54: 1-7, 1984; Steering Committee Transdermal Nitroglycerin Cooperative Study.
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Acute and chronic antianginal efficacy of continuous twenty-four hour application of transdermal nitroglycerin. Am. J. Cardiol. 68 :1263-1273, De plus, un certain nombre d'études cliniques contrôlées ont permis de montrer que cette tolérance n'était pas seulement limitée à la thérapie par patchs mais qu'elle se développait aussi après administration orale ou intraveineuse de composés nitrés (Zimrin, D. et al Antianginal effect of intravenous nitroglycerin over 24 hours. Circulation 77:1376-1384,
1988 ; Thadani, U. and R. J Lipicky. Short and long-acting oral nitrates for stable angina pectoris. Cardiovasc. Drugs Ther 8:611-623, 1994). Acute and chronic antianginal efficacy of continuous twenty-four hour application of transdermal nitroglycerin. Am. J. Cardiol. 68: 1263-1273, In addition, a number of controlled clinical studies have shown that this tolerance is not only limited to patch therapy but also develops after oral or intravenous administration of nitro compounds. (Zimrin, D. et al Antianginal effect of intravenous nitroglycerin over 24 hours. Circulation 77: 1376-1384,
1988; Thadani, U. and R. J Lipicky. Short and long-acting oral nitrates for stable angina pectoris. Cardiovasc. Drugs Ther 8: 611-623, 1994).
Les mécanismes impliqués dans le développement de la tolérance aux dérivés nitrés ne sont pas encore élucidés. Parmi les différentes approches pour prévenir ce phénomène, l'utilisation de patchs à dosages excentriques permettant des expositions à de faibles doses de dérivés nitrés pendant chaque période de 24 heures a été largement décrite (Parker J.D. and Parker J. O. Nitrate therapy for stable angine pectoris. N. Engl. J. Med. 338:520-531,
1998 ; Abrams, J. et al. Tolérance : An historical overview. Am. J. Cardiol. 81(1A):3A-
14A, 1998). L'inconvénient majeur de cette approche est que les patients se trouvent pendant les périodes de sous-dosages ou d'absence de nitrates exposés à un risque augmenté d'ischémie myocardique. En conséquence, ils peuvent présenter durant ces périodes une fréquence accrue des crises angineuses voire subir un infarctus du myocarde. The mechanisms involved in the development of tolerance to nitrates have not yet been elucidated. Among the various approaches to prevent this phenomenon, the use of patches with eccentric dosages allowing exposure to low doses of nitrates during each 24 hour period has been widely described (Parker JD and Parker JO Nitrate therapy for stable angina pectoris. N. Engl. J. Med. 338: 520-531,
1998; Abrams, J. et al. Tolerance: An historical overview. Am. J. Cardiol. 81 (1A): 3A-
14A, 1998). The major disadvantage of this approach is that patients are found during periods of underdosing or absence of nitrates exposed to an increased risk of myocardial ischemia. Consequently, they can present during these periods an increased frequency of anginal attacks or even undergo a myocardial infarction.
Parmi les agents pharmacologiques testés tels que des diurétiques, des inhibiteurs de l'enzyme de conversion de l'angiotensine I, des composés contenant un groupement sulfhydryl, aucun ne s'est révélé actif dans la prévention de la tolérance aux dérivés nitrés (Parker J. D. and Parker J. O. Nitrate therapy for stable angine pectoris. N. Engl. J. Med. Among the pharmacological agents tested such as diuretics, angiotensin I converting enzyme inhibitors, compounds containing a sulfhydryl group, none was found to be active in the prevention of tolerance to nitrates (Parker JD and Parker JO Nitrate therapy for stable angina pectoris. N. Engl. J. Med.
338 :520-531, 1998 ; Abrams, J. et al. Tolérance : An historical overview. Am. J. Cardiol. 338: 520-531, 1998; Abrams, J. et al. Tolerance: An historical overview. Am. J. Cardiol.
81(IA):3A-14A, 1998). 81 (IA): 3A-14A, 1998).
Par conséquent, le développement de nouvelles stratégies pour prévenir la tolérance aux dérivés nitrés constitue un enjeu thérapeutique important. Therefore, the development of new strategies to prevent tolerance to nitrates is an important therapeutic issue.
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Une des particularités de la tolérance aux dérivés nitrés est une diminution des effets vasorelaxants de ces composés (Herman, A.G. and Bogaert M.G. : Organic nitrates : tolérance at the level of the vascular smooth muscle. Arch. Int. Pharmacodyn. 192:200-2, 1971 ; Needleman P. and Johnson E.M. Jr : Mechanism of tolérance development to organic nitrates. J. Pharmacol. Exp. Ther. 184 :709-15, Thadani U. et al. Tolérance to the circulatory effects of oral isosorbide dinitrate : of development of tolérance and cross tolérance to glyceryl trinitrate. Circulation 1980 ; 61:526-35). L'utilisation d'un agent pharmacologique qui permettrait de restaurer une réponse normale aux agents nitrés s'opposerait au développement de la tolérance. One of the peculiarities of tolerance to nitrates is a reduction in the vasorelaxing effects of these compounds (Herman, AG and Bogaert MG: Organic nitrates: tolerance at the level of the vascular smooth muscle. Arch. Int. Pharmacodyn. 192: 200-2 , 1971; Needleman P. and Johnson EM Jr: Mechanism of tolerance development to organic nitrates. J. Pharmacol. Exp. Ther. 184: 709-15, Thadani U. et al. Tolerance to the circulatory effects of oral isosorbide dinitrate: of development of tolerance and cross tolerance to glyceryl trinitrate. Circulation 1980; 61: 526-35). The use of a pharmacological agent which would restore a normal response to nitrates would oppose the development of tolerance.
La demanderesse a ainsi découvert que la mélatonine et les ligands mélatoninergiques étaient utiles dans la prévention et/ou dans le traitement du développement de la tolérance aux dérivés nitrés. The Applicant has thus discovered that melatonin and melatoninergic ligands are useful in the prevention and / or in the treatment of the development of tolerance to nitrates.
Il a en effet été montré par des études in vitro menées sur vaisseaux isolés que les ligands mélatoninergiques sont capables, en étant co-incubés avec la nitroglycérine ou d'autres composés nitrés, de maintenir les effets vasodilatateurs de ces composés et par conséquent de s'opposer au développement de la tolérance aux dérivés nitrés observée en absence de ligands mélatoninergiques. It has indeed been shown by in vitro studies carried out on isolated vessels that the melatoninergic ligands are capable, by being co-incubated with nitroglycerin or other nitro compounds, of maintaining the vasodilatory effects of these compounds and consequently of s oppose the development of tolerance to nitrates observed in the absence of melatoninergic ligands.
L'invention concerne donc l'utilisation de la mélatonine et des ligands mélatoninergiques, agonistes ou antagonistes, pour l'obtention de compositions pharmaceutiques destinées à la prévention et /ou au traitement du développement de la tolérance aux dérivés nitrés. The invention therefore relates to the use of melatonin and melatoninergic ligands, agonists or antagonists, for obtaining pharmaceutical compositions intended for the prevention and / or treatment of the development of tolerance to nitrates.
L'invention concerne en particulier l'utilisation de la mélatonine et des ligands mélatoninergiques, agonistes ou antagonistes, en coadministration avec un dérivé nitré dans le traitement aigu et surtout chronique de l'ischémie myocardique, des cardiopathies d'origine ischémiques, de l'angor stable ou instable, et de l'infarctus du myocarde, cette coadministration pouvant être réalisée conjointement au sein d'une seule composition pharmaceutique ou séparément dans deux compositions pharmaceutiques différentes. The invention relates in particular to the use of melatonin and of melatoninergic ligands, agonists or antagonists, in co-administration with a nitro derivative in the acute and especially chronic treatment of myocardial ischemia, of heart diseases of ischemic origin, of stable or unstable angina, and myocardial infarction, this coadministration can be carried out jointly within a single pharmaceutical composition or separately in two different pharmaceutical compositions.
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Plus particulièrement, l'invention concerne l'utilisation, pour l'obtention de compositions pharmaceutiques destinées à la prévention et/ou au traitement du développement de la tolérance aux dérivés nitrés, de la mélatonine et des ligands mélatoninergiques comme par exemple les ligands : - de formule (I)
tels que décrits dans la demande de brevet EP447285, - de formule (II)
tels que décrits dans la demande de brevet EP506539, - de formule (III)
tels que décrits dans la demande de brevet EP530087, - de formule (IV)
tels que décrits dans la demande de brevet EP527687, More particularly, the invention relates to the use, for obtaining pharmaceutical compositions intended for the prevention and / or treatment of the development of tolerance to nitrates, of melatonin and of melatoninergic ligands such as for example ligands: - of formula (I)
as described in patent application EP447285, - of formula (II)
as described in patent application EP506539, - of formula (III)
as described in patent application EP530087, - of formula (IV)
as described in patent application EP527687,
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- de formule (V)
tels que décrits dans la demande de brevet EP562956, - de formule (VI)
tels que décrits dans la demande de brevet EP591057, - de formule (VII)
tels que décrits dans la demande de brevet EP662471, - de formule (VIII)
tels que décrits dans la demande de brevet EP708099, - of formula (V)
as described in patent application EP562956, - of formula (VI)
as described in patent application EP591057, - of formula (VII)
as described in patent application EP662471, - of formula (VIII)
as described in patent application EP708099,
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- de formule (IX)
tels que décrits dans la demande de brevet EP709371, - de formule (X)
tels que décrits dans la demande de brevet EP745583, - de formule (XI)
tels que décrits dans la demande de brevet EP721938, - de formule (XII)
tels que décrits dans la demande de brevet EP721947, - of formula (IX)
as described in patent application EP709371, - of formula (X)
as described in patent application EP745583, - of formula (XI)
as described in patent application EP721938, - of formula (XII)
as described in patent application EP721947,
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- de formule (XIII)
tels que décrits dans la demande de brevet EP737670, - de formule (XIV)
tels que décrits dans la demande de brevet EP737685, - de formule (XV)
tels que décrits dans la demande de brevet EP745584, - de formule (XVI)
tels que décrits dans la demande de brevet EP745586, - of formula (XIII)
as described in patent application EP737670, - of formula (XIV)
as described in patent application EP737685, - of formula (XV)
as described in patent application EP745584, - of formula (XVI)
as described in patent application EP745586,
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- de formule (XVII)
tels que décrits dans la demande de brevet EP873993, - de formule (XVIII)
tels que décrits dans la demande de brevet W098/52935, - ou de formule (XIX)
tels que décrits dans la demande de brevet EP919541, - ou de formule (XX)
tels que décrits dans la demande de brevet EP926145, - ou de formule (XXI)
R - A - R' (XXI) tels que décrits dans les demandes de brevet W09958495 et W09958496, - of formula (XVII)
as described in patent application EP873993, - of formula (XVIII)
as described in patent application W098 / 52935, - or of formula (XIX)
as described in patent application EP919541, - or of formula (XX)
as described in patent application EP926145, - or of formula (XXI)
R - A - R '(XXI) as described in patent applications W09958495 and W09958496,
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- ou de formule (XXII)
tels que décrits dans la demande de brevet W09936392. - or of formula (XXII)
as described in patent application W09936392.
L'invention concerne également l'utilisation, pour l'obtention de compositions pharmaceutiques destinées à la prévention du développement de la tolérance aux dérivés nitrés d'autres ligands mélatoninergiques que ceux représentés par les formules (I) à (XXII) comme par exemple les composés décrits dans les demandes WO 9838991, EP 747346, WO 9825606, EP 706994, EP 747345, EP 745597, WO 9738682, WO 9529173, WO 9517405, WO 9743272, WO 9705098, WO 9608466, WO 9732871, WO 9706140, WO 9527712, EP 281242 ou EP 655243. The invention also relates to the use, for obtaining pharmaceutical compositions intended for the prevention of the development of tolerance to nitrates derivatives of other melatoninergic ligands than those represented by the formulas (I) to (XXII) such as for example the compounds described in applications WO 9838991, EP 747346, WO 9825606, EP 706994, EP 747345, EP 745597, WO 9738682, WO 9529173, WO 9517405, WO 9743272, WO 9705098, WO 9608466, WO 9732871, WO 9706140, WO 9527712 EP 281242 or EP 655243.
Un aspect avantageux de l'invention concerne l'utilisation, pour l'obtention de compositions pharmaceutiques destinées à la prévention et/ou au traitement du développement de la tolérance aux dérivés nitrés de ligands mélatoninergiques agonistes. An advantageous aspect of the invention relates to the use, for obtaining pharmaceutical compositions intended for the prevention and / or treatment of the development of tolerance to nitrates derivatives of melatoninergic agonist ligands.
Un autre aspect avantageux de l'invention concerne l'utilisation, pour l'obtention de compositions pharmaceutiques destinées à la prévention et/ou au traitement du développement de la tolérance aux dérivés nitrés de ligands mélatoninergiques antagonistes. Another advantageous aspect of the invention relates to the use, for obtaining pharmaceutical compositions intended for the prevention and / or treatment of the development of tolerance to nitrates derivatives of antagonistic melatoninergic ligands.
Encore plus préférentiellement, l'invention concerne l'utilisation, pour l'obtention de compositions pharmaceutiques destinées à la prévention et/ou au traitement du développement de la tolérance aux dérivés nitrés du 7V-[2-(7-méthoxy-l- naphtyl)éthyl]acétamide, du N-[2-(5-éthyl-1-benzothiphèn-3-yl)éthyl]acétamide, du N-[2- Even more preferably, the invention relates to the use, for obtaining pharmaceutical compositions intended for the prevention and / or treatment of the development of tolerance to nitro derivatives of 7V- [2- (7-methoxy-1-naphthyl ) ethyl] acetamide, N- [2- (5-ethyl-1-benzothiphen-3-yl) ethyl] acetamide, N- [2-
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(8,9-dihydro-7H-furo[3,2-J]chromèn- 1 -yl)éthyllacétamide, et du 4-(2,3-dihydro-1,4- benzodioxin-5-yl) -N-methylbutanamide.
(8,9-dihydro-7H-furo [3,2-J] chromen-1-yl) ethyllacetamide, and 4- (2,3-dihydro-1,4-benzodioxin-5-yl) -N-methylbutanamide .
L'invention s'étend également aux compositions pharmaceutiques contenant de la mélatonine ou un ou plusieurs ligands mélatoninergiques, agonistes ou antagonistes, en combinaison avec un ou plusieurs excipients pharmaceutiquement acceptables, utiles dans la prévention et/ou dans le traitement du développement de la tolérance aux dérivés nitrés. The invention also extends to pharmaceutical compositions containing melatonin or one or more melatoninergic ligands, agonists or antagonists, in combination with one or more pharmaceutically acceptable excipients, useful in the prevention and / or in the treatment of tolerance development nitrates.
L'invention s'étend également aux compositions pharmaceutiques contenant de la mélatonine ou un ou plusieurs ligands mélatoninergiques, agonistes ou antagonistes, de formules (I) à (XXII) telles que définies précédemment en combinaison avec un ou plusieurs excipients pharmaceutiquement acceptables, utiles dans la prévention et/ou dans le traitement du développement de la tolérance aux dérivés nitrés. The invention also extends to pharmaceutical compositions containing melatonin or one or more melatoninergic ligands, agonists or antagonists, of formulas (I) to (XXII) as defined above in combination with one or more pharmaceutically acceptable excipients, useful in prevention and / or in the treatment of the development of tolerance to nitrates.
L'invention comprend également les compositions pharmaceutiques contenant de la mélatonine ou un ou plusieurs ligands mélatoninergiques, agonistes ou antagonistes en combinaison avec un dérivé nitré et un ou plusieurs excipients pharmaceutiquement acceptables utiles dans le traitement aigu et surtout chronique de l'ischémie myocardique, des cardiopathies d'origine ischémiques, de l'angor stable ou instable, de l'infarctus du myocarde et de l'insuffisance cardiaque. The invention also includes pharmaceutical compositions containing melatonin or one or more melatoninergic ligands, agonists or antagonists in combination with a nitro derivative and one or more pharmaceutically acceptable excipients useful in the acute and especially chronic treatment of myocardial ischemia, ischemic heart disease, stable or unstable angina, myocardial infarction and heart failure.
Parmi les compositions pharmaceutiques selon l'invention, on pourra citer plus particulièrement celles qui conviennent pour l'administration orale, parentérale, nasale, per ou transcutanée, rectale, perlinguale, oculaire ou respiratoire et notamment les comprimés simples ou dragéifiés, les comprimés sublinguaux, les sachets, les paquets, les gélules, les glossettes, les tablettes, les suppositoires, les crèmes, les pommades, les gels dermiques, les patchs, et les ampoules buvables ou injectables. Among the pharmaceutical compositions according to the invention, mention may be made more particularly of those which are suitable for oral, parenteral, nasal, per or transcutaneous, rectal, perlingual, ocular or respiratory administration and in particular simple or coated tablets, sublingual tablets, sachets, packages, capsules, lollipops, tablets, suppositories, creams, ointments, dermal gels, patches, and oral or injectable ampoules.
La posologie varie selon le sexe, l'âge et le poids du patient, la voie d'administration, la nature de l'indication thérapeutique, ou des traitements éventuellement associés et s'échelonne entre 0,1 mg et 1 g par 24 heures en 1 ou plusieurs prises. The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, or possibly associated treatments and ranges between 0.1 mg and 1 g per 24 hours in 1 or more takes.
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L'activité pharmacologique de la mélatonine et des ligands mélatoninergiques est illustrée dans l'exemple suivant : Des segments d'artères coronaires de porc sont étudiés in vitro en chambre d'organes dans une solution physiologique oxygénée et leurs tensions isométriques sont enregistrées. The pharmacological activity of melatonin and the melatoninergic ligands is illustrated in the following example: Pork coronary artery segments are studied in vitro in an organ chamber in a physiological oxygen solution and their isometric tensions are recorded.
La tolérance aux dérivés nitrés est induite par une incubation des vaisseaux dans la nitroglycérine (10 M) pendant 90 minutes. Les vaisseaux sont ensuite rincés avec une solution physiologique toutes les 10 minutes pendant une heure. Sur certains segments, les composés de l'invention ligands mélatoninergiques CI 0-9 à 10-7M) sont co-incubés avec la nitroglycérine pendant 90 minutes. Tolerance to nitrates is induced by incubating the vessels in nitroglycerin (10 M) for 90 minutes. The vessels are then rinsed with physiological solution every 10 minutes for an hour. On certain segments, the compounds of the invention melatoninergic ligands CI 0-9 to 10-7M) are co-incubated with nitroglycerin for 90 minutes.
L'effet vasodilatateur de la nitroglycérine (10-9 à 10-4M) est ensuite étudié sur des segments pré-constrictés par un analogue du thromboxane A2, U 46619 (3.10-9M). Lorsque l'effet constricteur du U 46619 a atteint son maximum, la nitroglycérine est ajoutée dans la chambre à organes de façon cumulative. The vasodilator effect of nitroglycerin (10-9 to 10-4M) is then studied on pre-constricted segments by an analog of thromboxane A2, U 46619 (3.10-9M). When the constricting effect of U 46619 has reached its maximum, nitroglycerin is added to the organ chamber cumulatively.
La nitroglycérine induit une vasodilatation concentration dépendante des artères coronaires. La courbe concentration-réponse à la nitroglycérine est déplacée vers la droite pour les artères coronaires pré-incubées avec la nitroglycérine ("tolérantes"). En effet, pour avoir un même effet vasodilatateur de la nitroglycérine, il faudra des concentrations plus élevées pour les segments pré-incubés. Ce phénomène est caractéristique de la tolérance. Nitroglycerin induces a vasodilation dependent concentration of the coronary arteries. The concentration-response curve for nitroglycerin is shifted to the right for coronary arteries pre-incubated with nitroglycerin ("tolerant"). Indeed, to have the same vasodilator effect of nitroglycerin, higher concentrations will be required for the pre-incubated segments. This phenomenon is characteristic of tolerance.
Une co-incubation avec la mélatonine ou les ligands mélatoninergiques, agonistes ou antagonistes de l'invention permet de maintenir une réponse normale des coronaires à la nitroglycérine. Co-incubation with melatonin or the melatoninergic ligands, agonists or antagonists of the invention makes it possible to maintain a normal response of the coronaries to nitroglycerin.
Les résultats montrent que les composés mélatoninergiques de l'invention s'opposent au développement de la tolérance aux composés nitrés.The results show that the melatoninergic compounds of the invention oppose the development of tolerance to nitro compounds.
Claims (12)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0002952A FR2805993B1 (en) | 2000-03-08 | 2000-03-08 | USE OF MELATONINERGIC LIGANDS FOR OBTAINING PHARMACEUTICAL COMPOSITIONS FOR THE PREVENTION OR TREATMENT OF THE DEVELOPMENT OF NITER COMPOUND TOLERANCE |
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| FR0002952A FR2805993B1 (en) | 2000-03-08 | 2000-03-08 | USE OF MELATONINERGIC LIGANDS FOR OBTAINING PHARMACEUTICAL COMPOSITIONS FOR THE PREVENTION OR TREATMENT OF THE DEVELOPMENT OF NITER COMPOUND TOLERANCE |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0873993A1 (en) * | 1997-04-25 | 1998-10-28 | Adir Et Compagnie | Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them |
| US5843986A (en) * | 1994-10-21 | 1998-12-01 | Adir Et Compagnie | Tricyclic amide compounds |
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| US5843986A (en) * | 1994-10-21 | 1998-12-01 | Adir Et Compagnie | Tricyclic amide compounds |
| EP0873993A1 (en) * | 1997-04-25 | 1998-10-28 | Adir Et Compagnie | Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them |
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| "martindale", 1995, COUNCIL OF ROYAL PHARMACEUTICAL SOCIETY, XP002140911 * |
| DAVE R.H. ET AL: "The effect of melatonin on hemodynamics, blood flow, and myocardial infarct size in a rabbit model of ischemia-reperfusion.", JOURNAL OF CARDIOVASCULAR PHARMACOLOGY AND THERAPEUTICS, (1998) 3/2 (153-160)., XP000914017 * |
| MAROT, CHRISTOPHE ET AL: "Pharmacophoric search and 3D-QSAR comparative molecular field analysis studies on agonists of melatonin sheep receptors", J. MED. CHEM. (1998), 41(23), 4453-4465, XP002916345 * |
| MARTINET L ET AL: "Entrainment of circadian rhythms by S-20098, a melatonin agonist, is dose and plasma concentration dependent.", PHARMACOLOGY, BIOCHEMISTRY AND BEHAVIOR, (1996 AUG) 54 (4) 713-8., XP000913939 * |
| TING K N ET AL: "Effects of melatonin and trolox on ischaemia-reperfusion injury in the Langendorff rat isolated heart.", BRITISH JOURNAL OF PHARMACOLOGY, vol. 128, no. PROC. SUPPL., October 1999 (1999-10-01), British Pharmacological Society Joint Meeting with the German Society for Experimental and Clinical Pharmacology and Toxicology;Nottingham, England, UK; July 14-16, 1999, pages 67P, XP000913924, ISSN: 0007-1188 * |
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