RU2804734C1 - Application of dinitrosyl iron complex with glutathione-gs {(gs)2fe2(no)4} for the treatment of patients with pulmonary arterial hypertension - Google Patents

Abstract

FIELD: medicine; pharmaceuticals.

SUBSTANCE: treatment of pulmonary arterial hypertension. The use of dinitrosyl iron complex with glutathione-GS {(GS)₂Fe₂(NO)₄} as an hypotensive agent with NO-dependent vasodilation for the treatment of pulmonary arterial hypertension by intravenous administration (PAH) is disclosed.

EFFECT: effective treatment of patients with pulmonary arterial hypertension.

1 cl, 2 dwg

Description

The invention relates to the use of a dinitrosyl iron complex with glutathione-GS {(GS)2 Fe2(NO)4} as an antihypertensive agent with NO-dependent vasodilation for the treatment of pulmonary arterial hypertension (PAH). The invention provides an expansion of the arsenal of antihypertensive drugs with an improved spectrum of activity based on the specified iron complex, which is a water-soluble NO donor with a high safety profile.

Pulmonary arterial hypertension (PAH) is a rare life-threatening disease of the cardiovascular system with a median survival of patients until the advent of specific therapy of 2.8 years. In the pathogenesis of PAH, the main role belongs to the remodeling of the arteries of the pulmonary circulation as a result of changes in the production of a number of vasoactive mediators, which leads to an increase in pulmonary vascular resistance and pressure in the pulmonary artery, resulting in progressive right ventricular heart failure. In real clinical practice, patients with PAH often require long-term hospitalizations up to 4-6 times a year due to worsening right ventricular dysfunction, which, in turn, significantly increases treatment costs. In recent decades, specific drugs have been developed and introduced into clinical practice that affect three main pathogenesis of PAH: deficiency of nitric oxide and prostacyclin, as well as activation of the endothelin-1 system.

Endogenous nitric oxide (NO) is an important molecule involved in the regulation of vascular tone, the inflammatory and immune response, the blood coagulation system, and also affects the proliferation of fibroblasts and smooth muscle cells. One of the leading therapeutic targets in the treatment of pulmonary arterial hypertension is NO deficiency. An imbalance between the vasoactive and proliferative mediator (Endothelium-1) and NO, an antiproliferative vasodilator localized within the endothelium, underlies chronic pulmonary vasospasm, cell proliferation and in situ thrombosis in pulmonary arterial hypertension.

Pulmonary vascular remodeling in PAH occurs as a result of transformation of the pulmonary vascular bed as a result of changes in the formation, qualitative and quantitative characteristics of a series of vasoactive mediators produced by various types of endothelial cells, as well as changes in the nature of interactions between cells. In the 1980s, data on the fundamental role of the endothelium in acetylcholine-dependent vasodilation with the participation of endothelial vasodilating factor were first published, and the chemical properties of NO or endothelial vasorelaxing factor were described. Palmer R. et al. revealed a violation of the ability of pulmonary vessels to vasodilate due to a decrease in NO production and impaired NO synthase (NOS) activity in patients with chronic inflammatory process in the lungs.

NO donors (nitroglycerin, sodium nitroprusside, etc.) are widely used in modern cardiological practice, mainly to influence the coronary vessels. However, their application possibilities are limited. This is due to the short duration of its pharmacological action, a wide range of contraindications and the fairly frequent development of unwanted side effects.

(Degoute CS. Controlled hypotension: a guide to drug choice. Drugs. 2007; 67(7): 1053-1076).

The objective of the present invention is to expand the arsenal of medications for the treatment of pulmonary arterial hypertension.

The technical result consists in increasing the effectiveness of treatment of patients with pulmonary arterial hypertension.

This is achieved by using dinitrosyl iron complex with glutathione-GS {(GS)2 Fe2(NO)4} as an antihypertensive agent with NO-dependent vasodilation for the treatment of pulmonary arterial hypertension.

The binuclear dinitrosyl complex of iron with glutathione-GS {(GS)2 Fe2(NO)4}, which is a synthetic analogue of endogenous NO donors, is the basis of the drug Oksakom®. This drug was obtained as a result of the synthesis of dinitrosyl iron complex with glutathione tripeptide in the reaction of S-nitrosoglutathione with a mixture of glutathione and ferrous iron. Oxakom® is part of the pharmacological group of antihypertensive drugs that are direct NO donors. Its pharmacological effect is due to vasodilation, hypotensive, antiaggregation, antioxidant and immunomodulatory effects due to the fact that Oxakom® is a direct donor of NO.

After successful completion of preclinical trials, the highest priority indication, which has the most reliable evidence base of efficacy and safety, is subsequently selected for clinical trials. In this case, an analysis of the population of patients in whom the study is possible is carried out. Patients with arterial hypertension are the most numerous cohort of patients. And hypertensive crises are one of the most common reasons for calling emergency medical care, as well as disability of the population. Therefore, the main purpose of the drug dinitrosyl iron complex with glutathione-GS {(GS)2 Fe2(NO)4} (Oxakom®) is the antihypertensive effect and restoration of the coronary, contractile and pumping function of the left ventricle.

It should be noted that the pathogenesis of pulmonary arterial hypertension (PAH) and systemic arterial hypertension (AH) involves different mechanisms, but some pathogenetic links are similar. The therapeutic points of application of antihypertensive drugs for these diseases are mostly different. Therefore, antihypertensive drugs with the indication “arterial hypertension” are mostly not effective for pulmonary arterial hypertension.

Considering the preclinical and clinical trials of the drug Oxakom® as an effective and safe means for emergency reduction of systemic arterial pressure, it is possible to conclude that similar effectiveness of the drug Oxakom® will be achieved in patients with PAH to reduce pressure in the pulmonary artery (PAP).

According to the results of preclinical tests of the drug Oxakom® on Wistar rats with a monocrotaline model of PAH, it was shown that when the drug was administered intravenously at a dose of 40 mg/kg, blood pressure in the systemic circulation decreased by 20-25% from the initial level in both control and animals with PAH, maintaining this level during 1 hour of observation, and the sensitivity of the vessels of the pulmonary circulation to Oksacom® in PAH increased. This effect was absent in control rats. At the same time, pressure in the pulmonary circulation (systolic pressure in the right ventricle of the heart) in control animals decreased by a maximum of 10% with complete recovery within half an hour, and in animals with PAH - by 15-17% from the initial level and even after an hour it remained reduced by 13-14%. In FIG. Figure 1 shows the change in mean aortic pressure (MAP) and systolic pressure in the right ventricle (SPRV) with intravenous administration of Oxakom® to control rats and animals with pulmonary hypertension.

In FIG. Figure 2 shows the mechanism of action of the dinitrosyl iron complex with glutathione-GS {(GS)2 Fe2(NO)4} (Oxakom® drug) in pulmonary arterial hypertension, where GTP is guanosine triphosphate; GC - guanylate cyclase; cGMP-cyclic gaunosine monophosphate; PDE-5 inhibitor - phosphodiesterase type 5 inhibitor; PDE-5 - phosphodiesterase type 5. The effect of the drug is realized by restoring the level of endogenous NO, which, through activation of soluble guanylate cyclase, leads to an increase in intracellular cyclic gaunosine monophosphate, leading to the development of vasodilation of the vascular wall and a subsequent decrease in intravascular pressure.

These data suggest the possibility of intravenous use of Oxakom® in patients with pulmonary arterial hypertension in order to reduce pressure in the pulmonary artery and reduce right ventricular afterload.

The use of intravenous infusions of Oxakoma® can be considered as a drug strategy for the treatment of patients with clinical worsening of pulmonary arterial hypertension in order to reduce pressure in the pulmonary artery and stabilize hemodynamics, which in turn will lead to a reduction in hospital stay.

Thus, the features of the pathophysiology of pulmonary arterial hypertension justify the use of dinitrosyl iron complex with glutathione-GS {(GS)2 Fe2(NO)4} (Oxakom® drug) for a new purpose - pulmonary arterial hypertension. The use of Oxakom® in patients with pulmonary arterial hypertension with clinical deterioration, regardless of basic therapy, may be a potentially effective treatment by increasing the level of endogenous NO, reducing pulmonary artery pressure and stabilizing the condition of this category of patients. In addition, the use of Oksacom® can lead to overcoming refractoriness when taking phosphodiesterase-5 inhibitors, which can improve the pharmacoeconomic aspects of the treatment of patients with PAH.

Claims (1)

Use of dinitrosyl iron complex with glutathione-GS {(GS) ₂ Fe ₂ (NO) ₄ } as an antihypertensive agent with NO-dependent vasodilation for the treatment of pulmonary arterial hypertension by intravenous administration.