Trapidil for use in the therapy of syndrome that may be influenc

Details Trapidil for use in the therapy of syndrome that may be influenc Trapidil for use in the therapy of syndrome that may be influenc

1997-10-09

2000-01-18

Page, Thurman K.

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

424465, A61K 920

Patent

active

060155787

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to the use of Trapidil (Trapymin) for preparing drugs suitable for the therapy of diseases which may be influenced favourably by the action of an immunomodulatory active ingredient. Chemically, the substance Trapidil is an N,N-diethyl-5-methyl-s-triazolo[1,5-a]-pyrimidine. Its clinical-pharmacological activity as known so far extends to the treatment of coronary cardiac diseases both in case of acute attacks as well as prophylaxis and long-term administration in case of this chronic disease. Trapidil, which acts as an anti-ischaemic agent, is not comparable with other coronary dilators and the remaining anti-angina coronary therapeutic agents of the prior art, for example the nitrates or nitro compounds such as nitroglycerine or isosorbide dinitrate, the .beta.-receptor blockers such as propranolol or calcium antagonists (Nifedipin), either with regard to its clinical spectrum of activity or its chemical structure.
In view of its triazolo[1,5-a)-pyrimidine structure, Trapidil holds a special position among coronary therapeutic agents, because it is the only active ingredient with this particular ring structure in this series of drugs. From the group of triazolo pyrimidines, only 1,4-dihydro-5-(2-propoxyphenyl)-7H-1,2,3-triazolo[4,5-d]-pyrimidine-7-one has been tested experimentally as an anti-asthmatic agent; the less common 5-amino-1,6-dihydro-7H-1,2,3-triazolo[4,5-d]-pyrimidine-7-one, also known as 8-azaguanine, is known as a cytostatic drug.
Experiments on the myocardium of animals (T. Betke, H. Mehl, W. Meier, W. Schmitz et al.: "Effects of the Triazolopyrimidine Trapidil on force of contraction, beating frequency and phosphodiesterase I-IV activity of guinea pig hearts", Arzneimittelforschung 41/5, p. 461-468, 1991) have shown that Trapidil inhibits the phospodiesterases I-IV, i.e. is an unspecified inhibitor of the isoenzymes PDE I-IV. This is in contrast to the specific PDE-inhibitors in the form of methyl xanthines, for example pentoxifylline, which is a specific inhibitor of the PDE III isoenzyme. This activity stands for an antagonistic effect with a view to the adenosine receptor. In other words, adenosine receptors are not influenced by Trapidil, which was shown by the experiments conducted by E. G. Krause "Hemmung der Isoenzyme der Phosphodiesterase aus Herzmuskel, glatter Muskulatur und Thrombozyten durch Trapidil" (Inhibition of isoenzymes of phosphodiesterase from the myocardium, non-striated muscles and thrombocytes by Trapidil) (cf. Trapidil Workshop, June 28/29, 1991 in Munich).
From Circulatory Shock, 44, pages 97-103 (1995), it is also known that pentoxifyllin may have advantages in case of bacterial infections or malaria of the mouse in connection with a TNF-.alpha.-inhibiting activity. It is also generally known that pentoxifyllin, a xanthine derivative having a completely different chemical structure from Trapidil, primarily activates circulation in the peripheral vessels. Thus, the circulatory activity of Trapidil with its effect on the coronaries is completely different from the action profile of pentoxifyllin.
In view of this specific action of Trapidil on the activity of the coronaries, it was surprising to find now that this triazolopyrimidine derivative has a favourable effect on a series of syndromes which respond to a substance with immunomodulatory activities. This includes a number of syndromes that occur in connection with infections, neoplasms and patho-immunogenic diseases. In particular, we have found unexpectedly that Trapidil has a tumour necrosis factor (TNF-.alpha.)-inhibiting activity.
In general, the TNF is a cytokine such as IFN-.gamma., IL and CSF which are formed by different types of cells such as monocytes or macrophages. This factor has a wide spectrum of biological activities which play a role in the response of the organism, for example, to infections, neoplasms and pathoimmunogenic diseases. These include, for example, an increased proagulating activity at the endothelium, extravasation, cytokine (IL-1, IL-8, CSF) synthesis

REFERENCES:
Bethke et al., "Effects of the Triazolopyrimidine Trapidil on Force of Contraction, Beating Frequency and Phosphodiesterase I-IV Activity in Guinea-pig Hearts.sup.1) ", Arzneim.-Forsch./Drug Res., 1991, pp. 461-468.
Espevik et al., "A highly sensitive cell line, WEHI 164 clone 13, for measuring cytotoxic factor/tumor necrosis factor from human monocytes", Journal of Immunological Methods, 95 (1986), pp. 99-105.
Hansen et al., "Re-examination and further development of a precise and rapid dye method for measuring cell growth/cell kill", Journal of Immunological Methods, 119 (1989) pp. 203-210.
Lee et al., "Low-Molecular-Weight TNF Biosynthesis Inhibitors: Strategies and Prospectives", Wiley-Liss, vol. 44, No. 3, Nov. 1994, pp. 97-103.

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