Method for prophylaxis and treatment of systemic amyloidosis and nephropathic form thereof in experimental animals

FIELD: medicine, in particular experimental biology.

SUBSTANCE: invention relates to method for prophylaxis and treatment of systemic amyloidosis and nephropathic form thereof, induced in experimental animal. In this purpose 10 % mildronate solution is hypodermically administrated to animals every second day in dose of 50 mg/kg during last 14 days of experiment.

EFFECT: effective method for disease treatment due to simultaneous action on different component of pathogenesis, namely amyloid mass formation in kidney.

 

The invention relates to medicine, experimental biology and can be used for the prevention and treatment of amyloidosis and its nefroticescoy form.

Amyloidosis - stromal-vascular deproteinize characterized by the deposition in tissues and organs of abnormal fibrillar proteins, precursors of amyloid - glycoprotein complex. Pronounced amyloidosis leads to atrophy and sclerosis of the authorities, accompanied by the development of their functional failure (Dammacco F. Amyloidosis: clinical picture, immunological and biomolecular features, treatment prospects. // Ann Ital Med Int. 1991 Jan-Mar; 6(1 Pt2):107-16.).

One of the manifestations of generalized amyloidosis is renal amyloidosis with a bright clinico-morphological and nosological specificity. Microscopically kidney amyloid is usually found along the straight vessels and the collecting tubes. In intermediary zone and the pyramids stroma impregnated plasma proteins. Amyloid is deposited not only in the pyramids, but in the glomeruli. (Tinaztepe K. Renal amyloidosis in childhood. An overview of the topic with 25 years experience. // Turk J Pediatr. 1995 Oct-Dec; 37(4):357-73.).

Clinical expression of morphological changes in amyloid nephropathy consider urinary syndrome characterized by proteinuria, cylindruria, microhematuria, leukocyturia (Tareev E.M., 1958; Koval', 1970). In addition to urinary syndrome detected changes in filtration-realtor the operating processes in the kidney, disturbed electrolyte balance, there is hyponatremia and hypokalemia (Koval', 1970), accompanied by fluid retention. Death of patients with renal amyloidosis is usually due to chronic renal failure and uremia in the final stage of the disease.

In this regard, there is an urgent need to create and develop methods of prevention and treatment of amyloidosis and its nefroticescoy form.

Specific treatment of amyloidosis has not been developed, because there was no final view on the etiology and pathogenesis of this disease.

There is a method of treatment of secondary renal amyloidosis dimethylsulfoxide, taken us for similar (Loffler HJ, Brass H, Thoenes W, Linke RP. Familial Mediterranean fever with amyloidosis. Recent pathogenetic and therapeutic aspects // Dtsch Med Wochenschr. 1983 Feb 11; 108(6):210-5.; Murav'ev IuV The efficacy of dimethyl sulfoxide in secondary amyloidosis in patients with rheumatic diseases // Revmatologia (Mosk). 1990 Jan-Mar; (1):4-8.).

Disadvantages counterpart is that in some cases the sulfoxide can cause fatal heart arrhythmia (Zenhausern R, Tobler A, Leoncini L, Hess OM, Ferrari P. Fatal cardiac arrhythmia after infusion of dimethyl sulfoxide-cryopreserved hematopoietic stem cells in a patient with severe primary cardiac amyloidosis and end-stage renal failure. // Ann Hematol. 2000 Sep; 79(9):523-6.). Some authors consider questionable therapeutic effect of dimethyl sulfoxide in amyloidosis (Gruys E, Sijens RJ, Biewenga WJ. Dubious effect of dimethylsulphoxide (DMSO) therapy on amyloid deposits and amyloidosis. // Vet Res Commun. 1981Sep; 5(1):21-32.).

There is a method of prevention and treatment of ameridata kidney (Sobh M, Moustafa F, Hamed S, Ghoneim M. Effect of colchicine on schistosoma-induced renal amyloidosis in Syrian golden hamsters. // Nephron. 1995; 70(4):478-85.), involving the use of colchicine prescribed long-term (up to 5 years or more) to 1 mg per day, which was taken as a prototype as the most intimate way.

The disadvantage of the prototype is that colchicine and antimitoticescoy activity has hariolations action, depressing effect on leuko - and lymphopoiesis, may have nausea and vomiting. In case of overdose of possibly severe oppression. It is also possible diarrhea and temporary alopecia, the appearance of impurities of the blood in vomitus and tarry stools. In the treatment of colchicine should be carried out periodically a study of fecal occult blood. The drug is contraindicated in renal and hepatic insufficiency, chronic diseases, pregnancy (Mashkovsky PPM Medicines: in 2 volumes. Vol.2. - Kharkov "Torching", 1998. S). In some cases it develops the vacuolar randomity and necrotizing myopathy (Fernandez C, Figarella-Branger D, Alla P, Harle JR, Pellissier JF. Colchicine myopathy: a vacuolar myopathy with selective type I muscle fiber involvement. An immunohistochemical and electron microscopic study of two cases. // Acta Neuropathol (Berl). 2002 Feb; 103(2):100-6. Epub 2001 Dec 01.; Himmelmann F, Schroder JM. Colchicine myopathy in a case of familial Mediterranean fever: immunohistochemical and ultrastructural study of accumulated tubulinimmunoreactive material. // Acta Neuropathol (Berl). 1992; 83(4):440-4; Stefanidis I, Bohm R, Hagel J, Maurin N. Toxic myopathy with kidney failure as a colchicine side effect ifn familial Mediterranean fever // Dtsch Med Wochenschr. 1992 Aug 14; 117(33):1237-40.). Also described cases of myoneuropathy in children during treatment with colchicine (Harel L, Mukamel M, Amir J, Straussberg R, Cohen AH, Varsano I. Colchicine-induced myoneuropathy in childhood. // Eur J Pediatr. 1998 Oct; 157(10):853-5.). Colchicine is ineffective in patients with severe renal amyloidosis (Mery JP. The curative effect of colchicine in renal amyloidosis cannot currently be held to have been proven. // Presse Med. 1984 Nov 3; 13(39):2393; Lagrue G, Koeger AC, Benaym JC, Sobel A. Colchicine treatment of renal amylosis in familial paroxysmal polyserositis. // Ann Med Interne (Paris). 1981; 132(7):496-500.).

Prolonged use of these synthetic drugs can cause various side effects: gastrointestinal disorders, allergic reactions, leukopenia, thrombocytopenia, myoneuropathy, rhabdomyolysis, cause disruption of metabolic processes, which makes them long and prophylactic use.

In this regard, the aim of our work was to develop an efficient method for the prevention and treatment of amyloidosis and its nefroticescoy form on the basis of experimental research.

Our preference was given a unique pharmacological properties and latitude using the Mildronate, representing Atanasov γ-butirobetaina predecessor carnitine. Mildronate inhibits γ-butyrolactones (the enzyme responsible for the synthesis of carnitine) ka is nationallottery - the enzyme that determines the formation of the complex carnitine - activated fatty acids, which leads to reduction of the synthesis of carnitine, off β-oxidation of fatty acids, stimulation of glycolysis and increased production and accumulation of endogenous γ-butirobetaina in all cells. Switching from aerobic type of power supply for anaerobic prevents the accumulation of detergent products unfinished β-oxidation of fatty acids. Under the influence of mildronata in the Central nervous system increases the content of GABA and decreases the synthesis of norepinephrine, normalized concentration of epinephrine, cortisol, testosterone, ACTH, T3and T4and stimulates the functional activity of the neuroendocrine regulation. The drug is well established as a means for prevention, treatment and improve adaptation with exorbitant physical and mental stresses, and intoxication (Meyerson FS, pshennikov M.G.,1988; Sutulov UL, Logunova, L.V., 1999 and others). According to some researchers (Calvinist IA, 1991; simkhovitch B.Z., Marina D.V., Hagi HB, 1984), Mildronate, boosting microcirculation, reduces plasma wetting of the walls of blood vessels, reducing the release of plasma proteins in the tissue space.

The claimed invention is directed to solving the task of establishing with the person in the prevention and treatment of systemic amyloidosis and its nefroticescoy forms in experimental animals.

The solution to this problem provides a significant reduction in the severity of amyloidosis by reducing its accumulation and improve the functional status of the affected organs.

To achieve this, the technical result of the claimed invention, a method for the prevention and treatment of systemic amyloidosis and its nefroticescoy forms in experimental animals has the following essential features: animals are subcutaneous injection of 10% solution mildronata at the rate of 50 mg/kg for 14 days.

The proposed method differs from the prototype in that first applies pharmacological drug Mildronate for the prevention and treatment of amyloidosis and its nefroticescoy form. Mildronate has no toxic effects on humans and animals, has no unwanted side effects. Mildronate prevents the accumulation deterrent unfinished products β-oxidation of fatty acids, has immunomodulatory and cytomembranes action, increases the resistance of the tissues and organs in toxic effects and hypoxia. Under the influence of mildronata stimulates the functional activity of the neuroendocrine regulation. Mildronate, contributing to the expansion and stabilization of blood vessels of microcirculation, reduces the pathological process output is razmennyh proteins (direct component of amyloid in tissue space, that violates one of the mechanisms of pathogenesis of education amyloid masses.

The introduction of a 10% solution mildronata through the day at the rate of 50 mg/kg in the last 14 days of the experiment leads to reduced accumulation of amyloid masses in organs and tissues, as well as improving functional status affected pathological process of the organs, particularly the kidneys of experimental animals. The claimed method is efficient, cost effective and easily reproducible.

According to the author the information set of essential features that characterize the essence of the claimed invention, is not known, which allows to make a conclusion about conformity of the invention, the criterion of "novelty".

According to the author, the essence of the claimed invention should not be for experts explicitly known level of medicine, since it is not detected above the possibility of obtaining way of prevention and treatment of systemic amyloidosis and its nefroticescoy forms in experimental animals, which allows to conclude that the criterion of "inventive step".

The set of essential features that characterize the invention, in principle, can be repeatedly used in medicine with the result, consisting in an effective and easily reproducible methods for the E. prevention and treatment of systemic amyloidosis and its nefroticescoy forms in experimental animals, that allows to make a conclusion about conformity of the invention, the criterion of "industrial applicability".

This method is as follows.

To obtain a system of experimental amyloidosis and its nefroticescoy forms of conduct subcutaneous injection of albumin and 1 ml every other day based on the average mass of white mice males at the age of 5-6 months, 23.3 g (0.05 ml/g of body weight) for 30 days, two groups of animals (No. 2 and No. 3) subject to asepsis. At the same time, from the 16th day of the introduction of albumin, group No. 3 introduces the Mildronate 10% solution by subcutaneous injection at the rate of 50 mg/kg every other day. Group of animals No. 2 as the injection control is introduced 0.9% solution of sodium chloride in the same amount and terms that Mildronate mice group No. 3. Group No. 1 are intact animals.

After the time of the experiment (1 month). for the study of kidney function in conditions of spontaneous diuresis animals are placed in metabolic cages for 6 hours, during which urine is collected. In the urine examined the contents of sodium, potassium, calcium, creatinine, urine protein. To study the plasma endogenous creatinine animals slaughtered under anesthesia at the time of 30-40 days. Morphological study on the subject of amyloidosis (painting with hematoxylin, eosin and Congo red) in addition to the kidneys are the spleen, liver, heart. Samples of t is Anya fixed in 10% neutral formalin, subsequent preparation of paraffin sections with a thickness of 5-6 microns. Sections are stained with hematoxylin and eosin, Congo red. The study sections were performed in transmitted light using a microscope Micmed-1 under magnification ×80, ×200, ×400.

The results pathophysiological and histological study in group # 3 was compared with the performance of the group No. 2 and the intact group No. 1.

Example. Conducted a series of experiments of 3 groups:

1st group - intact (20 white mice).

2nd group (10 mice) - (amyloid) - animals was performed by subcutaneous injection of albumin in 1 ml a day and 0.9% solution as injection control within 30 days.

3rd group (10 mice) - (amyloid-treated) was performed by subcutaneous injection of albumin and 1 ml every other day for 30 days and 10% solution mildronata, administered to the animals s/C at the rate of 50 mg/kg in the last 14 days of the experiment.

For the study of kidney function in conditions of spontaneous diuresis animals were placed in metabolic cages for 6 hours, during which time the urine was collected. In urine was studied in sodium, potassium, calcium, creatinine, protein. To study the plasma endogenous creatinine animals were killed under anesthesia at the time of 30-40 days. Morphological study on the subject of amyloidosis (the color of Congo red) in addition to the kidney will expose the s spleen, liver, heart.

As a result, it was obtained morphological and pathophysiological evidence for the effectiveness of mildronata for the prevention and treatment of amyloidosis.

Histologically, the 2nd group of mice kidney amyloid was detected in the course of direct vessels and the collecting tubes. In intermediary zone and the pyramids stroma were drenched with blood plasma. Amyloid was deposited not only in the pyramids, but in the glomeruli. Changes of glomeruli was thickening and the bypass ratio of the membranes and capillary openings which aneurismatic expanded with a pronounced plasma soaking the walls. Amyloid deposits were found in many of capillary loops of most glomeruli, arterioles and arteries, in the course of their own membrane tubules. The cytoplasm of the epithelium of the tubules, more proximal, and the Lumina of the tubules filled with protein granules. In the spleen amyloid was postponed perifollicular, marked hyperplasia of lymphoid tissue. In the liver amyloid was deposited mainly in the centers of the slices around the vessels. The myocardium at the time of the experiment was free from congophilic deposits.

Animals of the 3rd group were observed similar pathological changes, but they were expressed significantly less sootvetstvovali earlier stage of the disease.

In the study of the main indicators of kidney function (table 1) in the 2nd group of mice revealed the following significant (p<0,05) changes. The level of spontaneous diuresis significantly decreased by 52% compared with controllata filtering significantly decreased by 87%. The tubular reabsorption was significantly decreased by 6.7%. Excretion of Na+, K+and CA+also significantly decreased by 46.5%, 52% and 68%, respectively. Dramatically increased the level of proteinuria more than 15 times compared to control.

Animals of the 3rd group of mice revealed the following significant (p<0,05) changes. The level of urine output significantly decreased by 25% compared with control, as compared with the 2nd group significantly increased by 55%. Glomerular filtration significantly decreased by 60% relative to control, as compared with the 2nd group significantly increased in 2 times. The tubular reabsorption was significantly decreased by 2.3% relative to control, as compared with the 2nd group significantly increased by 4.7%. Excretion of Na+, K+and CA+also significantly decreased by 14%, 16% and 26% relative to control. Compared with the 2nd group of excretion of Na+K+significantly increased by 61% and 76%, respectively. It was noted unreliable (p=MX 0.317) reduced excretion of CA++by 17.3% compared to the experimental group is amiloidoza. Increased level of proteinuria more than 9-fold relative to control, as compared with the 2nd group was significantly decreased by 32.7%.

On the background of the application mildronata significant recovery morpho-functional state of the kidney affected by amyloidosis, in particular significantly improve impaired glomerular filtration, tubular reabsorption is impaired, excretion of Na+and+increased diuresis, because of the multifactorial positive pharmacological properties of this drug. Mildronate prevents the accumulation of detergent products unfinished β-oxidation of fatty acids, has immunomodulatory and cytomembranes action, increases the resistance of the tissues and organs in toxic effects and hypoxia. Under the influence of mildronata stimulates the functional activity of the neuroendocrine regulation. Mildronate, contributing to the expansion and stabilization of blood vessels of microcirculation, reduces the pathological process of release of plasma proteins (direct component of amyloid in tissue space, which violates the pathogenesis of education amyloid masses.

Based on these positive multivariate properties mildronata and results of the research justifies the use is their preparation for the correction of structural-functional abnormalities of the kidneys not only in experimental renal amyloidosis, but in clinical practice.

Table 1

Therapeutic effect mildronata on the functional state of the kidneys in experimental amyloidosis
Indicators, units of measurementData, M±m
Gr. No. 1 (control)Gr. No. 2 (albumin)Gr. No. 3 (ALB.+milk.)
Diuresis, ml/h·10 g of body weight0,02048±0,0006520,009914±0,0003710,01538±0,000492
Glomerular filtration, ml/h·10 g of body weight0,8366±0,0207740,112285±0,0069920,3348±0,020373
The tubular reabsorption, %97,527±0,04284591±0,28535795,296±0,417152
Excretion of Na+, mmol/h·10 g of body weight3,195±0,0848821,71±0,2058802,758±0,179677
Excretion To+, mmol/h·10 g of body weight0,7733±0,0391320,3678±0,0209000,6468±0,022186
Excretion of CA++mmol/hour·10 g of body weight0,0140±0,0006400,0045±0,0003020,00372±0,000645
Protein is Oia, mg/ml0,0705±0,0039731,092±0,0566920,735±0,066144

From the above it follows that therapeutic application of mildronata is an effective method of prevention and treatment of systemic amyloidosis and its nefroticescoy forms in experimental animals.

The method of treatment nefroticescoy form of systemic amyloidosis in experimental animals, including the introduction of drugs, characterized in that the quality of a medicinal product to animals injected subcutaneously with 10%solution mildronata through the day at the rate of 50 mg/kg in the last 14 days of the experiment.



 

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