Method for treating patients at chronic glomerulonephritis

FIELD: medicine, nephrology.

SUBSTANCE: the present innovation deals with introducing mildronate per 0.25 g 4 times daily about 30 min before meals for 3 wk, and then - per 0.25 g thrice daily about 30 min before meals for 4 wk at the background of daily intake of dipiridamol at the dosage of 200 mg/d. If necessary, therapeutic course should be repeated in 6 mo. The innovation improves endothelial function that leads to suppressed inflammatory process in kidneys and their improved functional capacity.

EFFECT: higher efficiency of therapy.

1 ex, 1 tbl


The invention relates to medicine, namely to therapy related to the treatment of patients with chronic glomerulonephritis (CS).

Known methods of treatment pumps, which is to assign polyunsaturated fatty acids, tocopherol, vitamin E, alpha-arginine, angiotensin-converting enzyme inhibitors (ACEI), blockers of angiotensin II receptors, antioxidants, calcium antagonists (AK) dihydropyridine, gipolipidemicheskih drugs (statins), estrogen in women after the menopause(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11).

The use of these drugs has a regulating influence on one of the links of the pathogenesis of immunocomplex formation process in CS, the largest value which attach to endothelial dysfunction, underlying various pathological conditions, including determines the degree of activity of process pumps. Each of them has certain undesirable effects, for example, ACEI in 1/3 of the patients cause severe dry cough; estrogens exert proinflammatory and prothrombinase effects; AK dihydropyridine reduce blood pressure and tachycardia and is not effective in the presence of an inhibitor of NO synthase; preferred statins in individuals with hyperlipidemia.

Moreover, at present, no major randomisierte the NoMAS study was not proved the high efficacy of these drugs in relation to correct endothelial dysfunction, including at CS. And so the search for new drugs aimed at normalization of endothelial dysfunction, underlie many pathological conditions (atherosclerosis, hypertension, inflammatory diseases, and others), is very important.

The closest in technical essence to the present invention is a method of treating CS by assigning enalapril maleate (Enap, the company KRKA) in an individually adjusted dose, provides hypotensive effect, from 5 to 20 mg 1 time a day for 6 weeks (7). The course of treatment Enap improves vasomotor endothelial function in 64,7% of patients; to reduce the aggregation capacity of platelets on average, 42%; lower levels of von Willebrand factor by 23%; the decrease in blood pressure (BP). In 23,5% of patients reported an improvement of endothelium-dependent relaxation, and 11.8% of patients this indicator has deteriorated.

Thus, the known method is not effective enough, so as not leads to normalization of endothelial function in patients with arterial hypertension, also Enap, as well as other representatives of ACEI, often causes prolonged admission dry cough, endothelization action is possible only when the dose providing a hypotensive effect in patients with arterial hypertension, is it unacceptable for persons with normal numbers And/A.

Studies on the effect of ACEI in patients with CS on endothelial function have not been conducted, although work on the effect of ACEI on for CS and nefropatia there are (9, 10).

The problem solved by the invention is to increase the effectiveness of treatment due to correction of endothelial dysfunction in patients with CS while reducing side effects and getting more pronounced and persistent effect, and prevent progression of the disease.

This task is achieved by a new method of treatment of CS, which is to assign pharmacotherapy, and appoint Mildronate 0.25 g for 30 minutes before a meal 4 times a day for 3 weeks and 0.25 g for 30 minutes to reception 3 times a day for 4 weeks on the background daily intake of dipyridamole dose of 200 mg per day, if necessary, treatment in 6 months repeat.

The drug Mildronate (dihydrate 3/2,2,2-trimethyl, hydrazine-propionate), a structural analogue γ-butirobetaina inhibition β-oxidation of fatty acids by decreasing the synthesis of endogenous carnitine and slow migration of activated long chain fatty acids across the membrane of mitochondria (12). The manufacturer of the drug PJSC Grindeks, Latvia (instruction).

Mildronate improves metabolic processes, has cytoprotective, cardiovascular, hypolipidemics them, hypoglycemic and immunocorrective properties, eliminates functional disturbances of the nervous system (12-19), which is very important in patients with CS to prevent disease progression and improve the quality of life of patients.

There is clinical experience using mildronata with ischemic heart disease, physical stress in athletes, the abstinence syndrome in chronic alcoholism, dishormonal cardiopathy, the case and retinopathy, acute and chronic disorders of the blood supply to the brain (13-19).

Usage data mildronata to ensure pumps and for the correction of endothelial dysfunction in the medical-scientific and patent literature are absent, thus, the proposed method meets the criteria of the invention of "novelty."

The method is as follows: after being diagnosed every day, Mildronate 0.25 g 4 times a day 30 minutes before meals for 3 weeks, and then 0.25 g 3 times a day 30 minutes before meals for 4 weeks in patients receiving dipyridamole dose of 200 mg per day, if necessary, treatment in 6 months repeat.

After completing the course of therapy assess the dynamics of the state of endothelium - dependent vasodilatation (EDVD) of the brachial artery using ultrasound duplex functional is on A.Celermayery et al. (20), the number of circulating blood endothelial endothelial cells (CDA) and renal functional reserve (PFR), which represents the difference between the glomerular filtration rate, defined on an empty stomach and after stimulation of protein load.

CS is immune inflammatory diseases of the kidneys, mainly affecting the glomeruli and is steadily progressing, gradually leading to the development of nephrosclerosis and chronic renal failure. Chronicity and progression of the disease contributes to the persistence of antigens in the circulation with damage to the endothelium, activation of coagulation and deposition of fibrin in the microvasculature of the kidney(1, 2, 3, 21, 22, 23, 24, 25).

The vascular endothelium is a hormonally active tissue, providing for the regulation of vascular tone and blood clotting, as well as the adhesion of leukocytes and platelets, permeability and vascular remodeling(4, 23, 24, 25).

Functional reorganization of the endothelium in inflammatory processes and various vascular diseases in increasing the production of free radicals leads primarily to breach the synthesis of endothelial relaxing factor - nitric oxide (NO), which causes vasodilatation, inhibits the proliferation of smooth muscle cells, has an anti-platelet agent is burnt and anticoagulant properties, thereby prevents vascular remodeling (11).

One of the principles of correction of endothelial dysfunction is the pharmacological stimulation of endothelium-dependent release of nitric monoxide(2, 11, 19).

The purpose mildronata with antioxidant, immunomodulatory, angio and cytoprotective properties, allows you to simultaneously act on immunopositive inflammation and the microcirculation of the kidney, lipid peroxidation and metabolism and thereby to neutralize the main causal factors in the development of endothelial dysfunction in CS.

Mode of administration and dose mildronata selected in the process of clinical observations of patients pumps with signs of endothelial dysfunction, as the use of lower doses and another mode had no significant positive treatment effect. The appointment of high doses mildronata did not increase therapeutic effect. Patients prescribed Mildronate on the traditional background for such options CS therapy dipyridamole at a dose of 200 mg per day, with desegregate property, based on the synergy of their interaction.


As an example, treatment pumps according to the proposed method provides a case history of the patient Smirnova AS, 35, who was in the Nephrology Department of the Regional clinically the coy hospital with a diagnosis of Chronic mesangiocapillary glomerulonephritis, isolated urinary syndrome.

Was admitted to the Department routinely with complaints about the presence of edema of the legs and face, dull pain in the lumbar region, periodically urine red color.

From the anamnesis revealed that he first changed the color of urine ("meat slops") after suffering a sore throat 12 years ago. When contacting the clinic revealed proteinuria and hematuria transient nature, and the state was regarded as "reactive kidney. However, during periodic medical examinations revealed minimal changes in the urine (daily proteinuria up to 0.2 g, erythrocyturia Nechiporenko to 2500). Because the patient felt well, I ignored the recommendations of the studies in stationary conditions. Two years ago, after hypothermia swelling and changes in the urine of nephritic character.

Was examined in the Nephrology Department and according to biopsy verified diagnosis of chronic mezangioproliferativnom glomerulonephritis with a minimal degree of inflammatory activity. Were assigned to the chimes 200 mg and Enap 5 mg per day.

Medications the patient has not taken regularly and the last 10 days before entering the marked deterioration.

At objective examination satisfactory. The position of an active, clear consciousness. Weight 76 kg, height - 178 with whom. The normal skin color and moisture. The subcutaneous layer is moderately developed. The thyroid gland is not enlarged. Swelling of legs, feet, paraorbital. A/D 130/85 mm Hg, heart rate of 78 beats per minute. The respiratory and digestive systems without significant deviations from the norm. Heart sounds are clear, regular rhythm. The apical impulse is displaced slightly to the left. Deep palpation of the kidneys moderately painful. The symptom of "tapping" positive on both sides.

Following studies were conducted.

1. Complete blood count: Hb - 135 g/l, erythrocytes - 4,4×1012/l, leucocytes - 6,3×109/l, eosinophils - 3%, stab - 5%, segmented - 56%, lymphocytes - 27%, monocytes 7%, and ESR - 14 mm/h

2. Urinalysis: Udis 1018 (fluctuations 1010-1018), protein - 1,11 g/l (daily proteinuria was 1.94 g), leukocytes to 6 in the field of view, erythrocytes 6-8 in the field of view, Nechiporenko erythrocytes 10.000.

3. Biochemical parameters blood glucose - 4.2 mmol/l, bilirubin to 18.6 µmol/l, urea - 6.6 mmol/l, creatinine - 110 µmol/l, fibrinogen - 4.0 g/l, protein 66 g/l, albumin is 54.5%, α1to-4.5%, α2-9,1%, β - 4,5% γ-globulins is 27.3%, Alt - 0,48, ASAT - 0,36.

4. Sample Rehberg: glomerular filtration - 80 ml/min, reabsorption - 98%.

5. Bacteriological examination of urine: no growth of microorganisms.

6. Ultrasound: P is at his left 12× 5 cm, right 11×6 cm, nephroptosis on the right of the I degree. The ratio of the layers is 1:1. Cup-pelvis system is somewhat condensed, the contours blurred.

7. The immunological: CD2-1,12, CD3-1,05, CD70-0,29, CD4-0,56, CD8-0,38, CD4/CD8-1,5 CD16-0,15, CEC - 180 ed, Ig A - 3.6 g/l, Ig M - 2.1 g/l, Ig G and 9.8 g/l, HCT test - spontaneous - 12,4%, stimulated and 15.3%.

8. Excretory urography: signs of pyelonephritis and anomalies of the kidneys was not detected.

9. Functional renal reserve (FPR) - 7%

10. Circulating dokumentalnye the endothelial cells (CDA) CL/100 μl.

11. Endothelium-dependent vasodilatation (EDVD) of the brachial artery with reactive hyperemia of 6.3%.

12. Morphological study neobiota - signs of chronic mezangioproliferativnom glomerulonephritis with symptoms of inflammatory activity and endothelial dysfunction.

On the basis of clinical, instrumental, laboratory and morphological data diagnosed chronic mezangioproliferativnom glomerulonephritis in the acute phase.

According to the proposed method, the patient is assigned Mildronate 0.25 g for 30 minutes before a meal 4 times a day for 3 weeks in hospital and 0.25 g for 30 minutes before a meal 3 times a day for 4 weeks on an outpatient basis after taking dipyridamole 200 mg daily.

Treatment with Mildronate patient peremeshalos, side effects are not identified.

During the examination in dynamics after 7 weeks of treatment with Mildronate positive effect on the following parameters:

clinical - improved health and swelling disappeared;

urinary syndrome - proteinuria decreased to 0.5 g/day, erythrocyturia 4.000;

glomerular filtration increased to 90 ml/min;

CD4/CD8 (immunoregulatory index) - 1,8;

functional renal reserve (FPR) increased to 15%;

the endothelial cells (CDA) - 4 cells/100 μl;

endothelium-dependent vasodilatation (EDVD) to 10.7%.

We have analyzed the results of treatment with Mildronate on taking dipyridamole 22 CS patients with signs of acute inflammatory process and phenomena of endothelial dysfunction in age from 23 to 35 years, mostly with mezangioproliferativnom option. The comparison group consisted of 15 patients with CS who received only dipyridamole.

Treatment of patients was well tolerated, adverse reactions to receiving mildronata not marked.

The results of studies of urine, renal function, endothelium-dependent vasodilatation and circulating endothelial cells are presented in table 1.

As can be seen from the data in the study group treated for 7 weeks Mildronate on the proposed method, showed a significant improvement of endothelial function, reduction of the prot is Nuria and erythrocyturia, the increase in functional renal reserve and immunoregulating index. In cases of negative clinical dynamics after 6 months patients re-treatment was conducted according to the proposed method.

The application of the proposed method allows to achieve a positive effect on endothelial function and immunoregulatory index, which undoubtedly contributed to the suppression of the inflammatory process in the kidneys and improve the functional capacity of the kidneys in patients with CS in contrast to patients in the comparison group, where significant positive dynamics of the studied parameters have not been set.

Thus, the proposed method of treatment to achieve the desired positive effect, namely to increase the efficiency of treatment of patients with CS with the phenomena of endothelial dysfunction by reducing side effects get more pronounced and persistent therapeutic effect and to prevent progression of the disease.

Table 1

The dynamics of the studied parameters in the application of the method of treatment of patients with CS
IndicatorsThe studied patients CS n=22Healthy individuals (n=15
Before the treatmentAfter the treatment
Proteinuria (g/day)1,24±0,230,84±0,17*≤ mg/day
Erythrocyturia Nechiporenko (cells/ml)6.876,8±126,44.244,3±96,5756,8±25,4
Functional renal reserve (%)7,3±2,112,613,1*19,7±4,8
Endothelium-dependent vasodilatation (%)8,4±1,911,7±1,5*14,3±2,9
Circulating desquamated endothelial cells (cells/100 ál)9,8±1,76,3±1,9*4,1±0,4
Note: * - significance of differences in parameters before and after treatment (p<0,05)

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6. Sitnikova M., Maximov T.A., S.N. Kozlov. and others On the relationship of markers of endothelial dysfunction and renal hemodynamics in patients with heart failure and the impact of the long-term therapy with perindopril. // The wedge. pharmacology and therapeutics. - 2001, No. 10, 49-52.

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9. Katerina IM, Tareeva I.E., I. Gerasimenko, etc. the Use of angiotensin-converting enzyme inhibitors in chronic diffuse diseases of the kidneys. // Ter. archive, 1995, No. 5. - P.20-24.

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11. Mukhin I.V., Nikolenko V.Y., G.A. Ignatenko Role of nitric oxide in the pathogenesis of chronic glomerulonephritis (literature review) // Nephrology, 2003, No. 1. - P.41-45.

12. Calvinist IA Mildronate - mechanism of action and the prospects of it is applications. Riga: Publishing house of PJSC "Grindeks", 2001. - 39 S.

13. Nedosekin S.A., N. Petrova, Kutuzov SUPERVISION, Perene NB the Quality of life of patients with chronic heart failure. The effect of treatment with Mildronate. // Ter. archive, 1999, №8. - P.10-12.

14. Koselska O.A. Influence mildronata on exercise performance, hemodynamics and oxygen balance in the body of patients with angina: author. dis....Kida. the honey. Sciences. - Tomsk, 1990, 23 S.

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18. Teplyakov A.T., Senkevich T.V., Stepicheva T.A., Mamchur S.E. Myocardial cytoprotection inhibitor β-oxidation of fatty acids by Mildronate in monotherapy and in combination with β-blocker-atenolol in patients with myocardial dysfunction of the left ventricle // Cardiology, 2003, No. 12. - P.15-18.

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Method for the treatment of patients with chronic glomerulonephritis by pharmacotherapy, characterized in that the prescribed Mildronate 0.25 g 4 times a day 30 minutes before meals for 3 weeks and then at 0, 25 g 3 times a day 30 minutes before meals for 4 weeks on the background daily intake of dipyridamole dose of 200 mg per day, if necessary, treatment in 6 months repeat.


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The invention relates to new derivatives of 4-phenylpyrimidine and their pharmaceutically acceptable acid additive salts, which possess the properties of receptor antagonists neirokinina(NK-1), and can be used to treat diseases, oposredstvovanii NK-1 receptor, for example, headache, Alzheimer's disease, multiple sclerosis, cardiovascular changes, oedema, chronic inflammatory diseases and so on

The invention relates to new N-heterocyclic derivatives of the formula (I):

where: A means-OR1-C(O)N(R1R2or-N(R1R21; each X, Y and Z independently represents N or C(R19); each U represents N or C(R5), provided that U is N only when X represents N, and Z and Y denote CR19; each W represents N or CH; V denotes: (1) N(R4); (2) C(R4)H; or (3) the groupdirectly related to the group -(C(R14R20)n-A,denotes a 5-6-membered N-heterocyclyl, optionally containing 6-membered ring additional heteroatom selected from oxygen, sulfur and NR6where R6denotes hydrogen, optionally substituted phenyl, 6-membered heterocyclyl containing 1-2 nitrogen atom, optionally substituted 5-membered heterocyclyl containing 1-2 nitrogen atom, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl,1-6alkoxycarbonyl, acetyl, etc

The invention relates to new nitrogen-containing aromatic 6-membered cyclic compounds of the formula (I) or their pharmaceutically acceptable salts, demonstrating excellent selective PDE V inhibitory activity

FIELD: veterinary medicine.

SUBSTANCE: method involves administering aqueous solution containing 4.5% of diamidine, in combination with 2.5% of primacine and 20% of polyethylene glycol-6000.

EFFECT: increased reliability of treatment results.