The way to assess individual sensitivity to nitrates

 

(57) Abstract:

The invention relates to medicine and can be used when assessing the sensitivity of the organism to retropreparation and the determination of nitrate tolerance. The method provides improved safety, reproducibility and reliability assessment of the effectiveness of nitrates and identify them tolerance, as well as expanding the possibilities for carrying out this assessment in persons with contraindications to performing the tests, with dosed physical load. Examine the blood vessels of the ocular fundus of the patient on remediations retinal camera before and after intake of nitrate at the time of maximum effect of the drug), then use the system for processing graphics produce simultaneous automatic measurement of the diameter of the branches of the Central retinal vein at identical locations. To increase the diameter of venules by more than 10% of the original judge on the effectiveness of the drug. The decrease in the degree of expansion venules when you study in the course of treatment micropreparative shows the development of tolerance to them.

The invention relates to medicine, namely to methods of diagnosing pathological conditions, and can Am. Nitrates are currently one of the main tools used in the treatment of various forms of angina, myocardial infarction and heart failure (fishchenko A. D., Vertkin A. L., A. Martynov, I. the Use of nitrates in the treatment of ischemic heart disease // Cardiology. - 1996. - N 2. C. 88-95.; Belenkov Y. N., Mareev Y. C., Ageev F. T. Medical ways to improve the prognosis of patients with chronic heart failure/ M: insight, 1997. - S. 92). However, in some cases their use is ineffective in the absence of them individual sensitivity or development of tolerance. Under tolerance micropredators understand the reduction effect of the drugs in this group during their continuous reception (Sumarokov, A. B., Blokhin A. B., Menshikov, M. Y., Kuzmin A. C., Chikvashvili D. I., Ruda M. J. Clinical-instrumental and biochemical study of nitrate tolerance in patients with coronary atherosclerosis // Cardiology. - 1995. - So 35. - N 2 - N-4-8). The development of nitrate tolerance in severely limits the effectiveness of drug therapy and is a serious threat to patients with ischemic heart disease (Stroganov, I., Sergeev, P. C., Shyla C. Y. , Dukhan A. C. Mechanisms vasodilate is. C. 4 - 10; Ismailov, E. Application of Akinola to prevent the development of nitrate tolerance in patients with ischemic heart disease: author. dis. Kida. - M., 1996. - S. 22). Additionally, this condition requires the use of higher doses of nitrates, which naturally has an impact on strengthening their toxic effects.

Studies on patent and scientific and medical literature identified a number of ways of assessing the effectiveness of micropreparative and determination of nitrate tolerance. Evaluation of the antianginal efficacy of nitrates can be made according to the frequency of angina attacks and the amount of nitroglycerin tablets. However, it is known that patients with marked improvement, as a rule, seek to increase physical activity, and those whose condition is deteriorating, on the contrary to reduce the physical load. As a result, the frequency of angina attacks and the amount of nitroglycerin tablets may not accurately reflect the degree of effectiveness of micropreparative (Blizzard Century. And., Davydov A. B. Drugs nitrates in cardiology. M. : Medicine, 1989. - S. 92).

There is a way to determine ernits, nitrosospira and products of their biotransformation, but cannot be used to assess the effectiveness of nitrates, because the system concentration of nitroglycerin does not correlate with the development of nitrate tolerance (Stroganov, I. et al. The vasodilating mechanisms of action of nitrates and the development of tolerance to them // Chem. Pharm. log. - 1992. - T. 26, No. 11-12. - c. 4-9, Panov A. A., Olista E. A. Tolerance to nitrates. Astrakhan. 1994. S. 22).

There is a method of determining the development of tolerance to nitrates reduction drugs nitroglycerin in heart rate and blood pressure (Abrams J. Tolerance to organic nitrates// Circulation. - 1986. - Vol. 74. - N-6. - P. 1181 - 1185). However, the development of tolerance to the effect of nitrate on blood vessels may not be accompanied by a weakening antianginalnogo effect (Blizzard Century. And., Davydov A. B. Drugs nitrates in cardiology. M.: Medicine, 1989. - S. 84). This is because the weakening of the arterial vascular effect of vascular effect is not always accompanied by a reduction venodilating effect (Jahnchen E. Relationship between pharmacokinetics and pharmacodynamics of organic nitrates // Z. Kardiol. - 1986. - Vol. 75. - Suppl. 3. - P. 13-15). It venodilation effect play the main role in the mechanism of antianginal action of nitrates (Blizzard Century. And. , Davydov A. B. Pre the cardia //Therapeutic archive 1989, N 8, 61 so. - S. 146-150).

There is a method of determining individual sensitivity to the antianginal drugs in patients with ischemic heart disease (ed. mon. N 1399679, MKI G 01 N 33/48, bull. N 20; 1988), which consists in the registration of the electrocardiogram on the background of the introduction of dipyridamole before and after the appointment of the study drug. The method allows for individual choice antianginal funds, including nitrates. However, it is based on provoking myocardial ischemia that is not safe for the patient. The test may develop tachycardia, headache, nausea, General weakness, increasing shortness of breath (in 40.5% of cases), abnormal heart rhythm (23.6%) (Furkalo N. K. Yanovsky, C., Sledzevska I. K. Clinical and instrumental diagnosis of lesions of the heart and coronary vessels. - K.: Health, 1990. - 192 S.).

Dipyridamole sample has a number of contra-indications: myocardial infarction transferred for less than 1 month ago, first developed and progressive angina, severe arrhythmias, circulatory failure IIB-III stage, cardiac aneurysm and aortic stenosis aortic (Aronov, D. M.. lupanova B. N. Functional tests in cardiology /Cardiology. -omicheskogo of coronary lesions (Furkalo N. K. Yanovsky, C., Sledzevska I. K. Clinical and instrumental diagnosis of lesions of the heart and coronary vessels . - K.: Health, 1990. - 192 S.).

Author's certificate N 1394130 protected method of determining individual sensitivity to nitrates in patients with ischemic heart disease (ed. mon. N 1394130, MKI G 01 N 33/48; bull. N 17; 1988). This method is based on a series of ad tests with subsequent measurement of the temperature of exhaled air on 2 - 14 minute after each reception of nitroglycerine. At the maximum temperature determine the optimal dose of the drug. The method allows to assess individual sensitivity to nitrates in patients with ischemic heart disease, however, has several disadvantages. First of all, this method is indirect because it is based on indicators that are only indirectly can indicate the presence of hemodynamic action of nitrates, causing their antianginal effect. This undoubtedly reduces the information content of the described method. In addition, it requires multiple (3-6 times) techniques micropreparative with an interval of 10 minutes in an ever-increasing dose. There is a high risk of overdose nitrates, uvelichenie method depends on the ambient temperature.

As the prototype was taken way to determine the effectiveness of long-acting nitrates on the results of the paired exercise of samples described by Blizzard C. I. and co-authors in "the Problem of nitrate tolerance and the ways of its solution in patients with angina" (Therapeutic archive. - 1993. - So 65. - N 9. - S. 34 - 39). This method consists in carrying out exercise of samples before treatment (without drug) and with the first dose of the drug. Evaluation of the effectiveness of the nitrates produced by the change in the length of the repeated load within 1 hour after ingestion of nitrate compared to the baseline (T) to achieve an identical criteria: reduction of ischemic ST segment type to 1 mm and more through 0,08 after point j and/or angina. The drug is considered effective if T2 min (Blizzard Century. And., debut C. Y., kokurina E. C., Kozyreva, M. P., E. Bochkareva Century the Problem of nitrate tolerance and the ways of its solution in patients with angina //Therapeutic archive. - 1993. - So 65. - N 9. - S. 34 - 39). To assess the development of tolerance to nitrates spend a third cycle ergometry at the end of the treatment micropreparative. Shortening T, against the backdrop of prolonged nitrate, less than 2 min, systems the VA M. P., E. Bochkareva Century the Problem of nitrate tolerance and the ways of its solution in patients with angina //Therapeutic archive. - 1993. - So 65. - N 9. S. 34 - 39).

This method allows to evaluate the effectiveness of long-acting nitrates and to determine the development of tolerance to them. However, it is not possible to assess the effectiveness of short-acting nitrates because the estimated duration less than the time required for holding the Bicycle ergometry. In addition, the conduct of Bicycle ergometry is not possible in the pathology of the musculoskeletal system. Obliterating atherosclerosis of lower extremities, changes the terminal portion of QRs complex on the electrocardiogram at rest, poor physical fitness of the patient. The tests with physical exercise is not safe and can cause pulmonary edema, ventricular fibrillation of the heart and severe coronary insufficiency in the form of sudden coronary death or myocardial infarction (Kaltenbachm M./ Forms of exercise testing// Detection of ischemic myocardium with exetcise/ Ed. F. Looden, L. Seipel. - Berlin: Springer Verlag; New York: Heidelberg, 1982. - P. 3-9; Diseases of the heart and blood vessels. A guide for physicians: 4 so-So 1. /Diamond I. I., Aronov, D. M., Atkov O. Y., Ed. Chazov E. I. - M.: Medicine, 1992. - S. 297). Xtry myocardial infarction (less than 4 weeks from the onset of the disease); unstable angina; circulatory failure IIB - III stage classification. Strazhesko-Vasilenko; severe respiratory failure; cerebrovascular circulation; myocarditis (first 3 months); acute thrombophlebitis; acute infectious diseases; dangerous arrhythmias and conduction (early and frequent ventricular extrasystoles, atrial-ventricular block II-III degree); dissecting aneurysm of the aorta.

Relative: arterial hypertension at values of blood pressure over 200/100 mm RT.article; atrial fibrillation; blockade of the branches of the bundle of his; heart failure, in which you want to apply glycosides; the defeat of the main trunk of the left coronary artery; aortic stenosis; metabolic disease (diabetes mellitus, myxedema and thyrotoxicosis).

In addition, in 10% of cases of possible false-positive, and 4 to 14% of cases of false negative test results (Furkalo N. K. Yanovsky, C., Sledzevska I. K. Clinical instrumentation diagnosis of lesions of the heart and coronary vessels. - K. : Health, 1990. - S. 28). All this greatly limits the range of persons who can use the above method and reduces the reproducibility and doscover is rnost method of evaluating the effectiveness of nitrates and identify them tolerance, as well as empowering the estimates are for persons with contraindications to performing the tests, with dosed physical load.

This goal is achieved by research vessels of the ocular fundus on remediations retinal camera (e.g. TRC-NW53/TRC-NW5SF Topcon [Japan]). The method is as follows. The patient on an empty stomach, before taking drugs, shoots vessels of the ocular fundus remediations retinal camera. Then someone introduced nitrate and produce re-schema of the fundus vessels at the time of maximum effect of the drug after 7 to 10 minutes for preparations of short action and after 1 hour for prolonged forms. Using the processing system graphical images included in the software bundle IMAGEnet for Windows, perform the mapping and processing of images before and after administration of the drug. This produces simultaneous automatic measurement of the diameter of the branches of the Central retinal vein (venules). To increase the diameter of the venules are judged on the effectiveness of the drug. The expansion of the branches of the Central retinal vein by more than 10% from the original is the criterion of the effectiveness of nitrate. The absence of R. the values of the dose of the drug. The presence of nitrate tolerance establish a consistent hold 3 research: prior to the treatment of micropreparative, after taking the first dose of nitrate and another, identical doses of the drug in the course of the treatment. To reduce the degree of expansion of the venous vessels of the ocular fundus in response to receiving micropreparative judged on the development of nitrate tolerance.

Example 1.

Patient F., 72 years old, diagnosis: ischemic heart disease, angina III F. CL , postinfarction cardiosclerosis, a rhythm on the type of atrial arrhythmia, H1.

To determine the effectiveness of micropreparative in the patient, outpatient performed the inspection and measurement of the venous vessels of the ocular fundus on nemidreatic retinal camera with a subsequent test with sublingual administration of 1 mg of nitroglycerin. When you re-inspection after 10 min revealed an increase in the diameter of the branches of the Central retinal vein at 25% of initial value, which indicates the effectiveness of nitroglycerin in this patient. This allowed the subsequent patient successfully apply sublingual 1 mg nitroglycerin for relief of angina Praia angina, postinfarct cardiosclerosis, H1.

Upon admission to the hospital to determine individual sensitivity to the drug From the Mac (the isosorbide dinitrate treatment) was conducted inspection and measurement of the venules of the fundus vessels before and after (within 1 hour) receiving nitrate at a dose of 20 mg of the test Results testified to the effectiveness of this dose From Poppy patient, because venules of the fundus vessels expanded it by 22% from the original. The drug was assigned to a patient for a continuous 4 times per day, which will significantly reduce the number of (5 times) and intensity of angina attacks.

Example 3.

Patient R. 77 years old, diagnosis: ischemic heart disease, angina IV F. CL., postinfarction cardiosclerosis, the rhythm type of paroxysmal ventricular tachycardia, HII B.

When admitted to hospital, the patient performed the test with nitrogranulong (5.2 mg) by the method described above. In the course of the samples revealed the expansion of the venules of the vessels of the ocular fundus by 15%. The drug was found to be effective and assigned dose of 5.2 mg 4 times a day. On the 18th day of a hospital stay, the patient became more frequent angina attacks. To confirm a preference for USA no venodilating effect of the drug. Dose nitrogranulonga was doubled (10,4 mg per dose), which led to the restoration of the antianginal effects of the drug, improve the patient's condition, and was confirmed by the presence of venodilatation (19% of baseline) during re-examination of the fundus vessels.

Compared with the prototype, the method has the following advantages:

the method is absolutely safe and does not cause complications from cardiovascular system;

the method has no contraindications;

the method is highly reproducible, and does not give false-positive and false-negative results;

expands the circle of persons who may evaluate the effectiveness of nitrates;

to evaluate the effectiveness of micropreparative both short and long actions.

The way to assess individual sensitivity to nitrates by enteral intake of micropreparative, wherein the patient on an empty stomach before medication shoots vessels of the ocular fundus remediations retinal camera (for example, TRC-NW53/TRC-NW5SF company Torso, Japan), then he is prescribed nitrate and produce a re-imaging of the fundus vessels at the moment of maximum action the system for processing graphics, the included software IMAGE net for Windows, generate the mapping and processing of images before and after administration of the drug and to increase the diameter of the branches of the Central retinal vein (venules) are judged on the effectiveness of the drug, the expansion of the branches of the Central retinal vein by more than 10% from the original, is a criterion of the effectiveness of nitrate, no expansion venules or increase their diameter is less than 10% after administration of nitrate indicates the inefficiency of the dose of the drug, and to determine the possible development during treatment nitrate tolerance in the patient, the patient carried out an additional study by giving the same dose of the drug with subsequent research on retinal cell and decreasing the degree of expansion of the venous vessels of the ocular fundus in response to receiving micropreparative ascertain the development of nitrate tolerance.

 

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