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According to scientific literature data the effect of estrogen administration depends on the way of intake. Oral intake of estradiol has effect on the lipoproteid level as it is linked with its entrance to liver, further biotransformation, alteration under the influence of steroid exchange of lipids and proteins in liver. Under the influence of hormonal therapy with tablet agents due to the effect of primary passage through liver there are alterations in hepatic metabolism. Tablet estrogens (or metabolits) increase the pool of free cholesterol of liver and increase saturation of bile with the latter. Moreover, estrogens can potentially affect the composition of bile acids pool: during the therapy percent ration ofxenodesoxycholic acid amount decreases. That acid prevents formation of gall-stones more than other bile salts. It is supposed that unfavorable hepatobilliary effects can be linked with
the increase of estrone concentration in administration of oral forms of the therapy. If taken for a long term estrogen containing agents cause isolated cholestasis syndrome, which is rarely diagnosed clinically. The data we achieved testify the probability of the development of cholestasis syndrome in patients of the I group, who administered 17-beta estradiol. While the patients of the II group, who administered tefestrol, had no clinical laboratory deviations in hepatic-billiary system.
Conclusions. The results of the performed research confirm the possibility of administration of both 17-beta estradiol and tefestrol in the complex of hormonal therapy for teenager girls with hypo gonadism. Patients with diseases of hepatic-billiary system and its chronic forms in history should prefer tefestrol in combination with didrogesterone.
References:
1. Jukovski M. A., Golubeva P. V., Chkhenze L. V. On the problem of diagnostics and therapy of disorders of sexual differentiation in children. Pediatrics. 1998, 1; 11: 43-49. (in Russian).
2. Irgasheva S. U. Clinical-hormonal characteristics and the choice of therapeutic tactics in retardation of sexual development of girls. Obstetric and gynecological diseases journal. 2008; LVII (4): 85-88. (in Russian).
3. Kobozeva N. V., Kuznetsova M. N., Gurkin U. A. Gynecology of children and teenagers. St. Petersburg: 1999. (in Russian).
4. Fuad I. K. Some forms ofhyper gonadotropic amenorrhea (clinical progress, diagnostics); thesis... Cand. Med. Scien. Moscow; 1988. (in Russian).
5. Schoultz B. HRT and Body compartments: breast and liver. Menopause review. 1997; II (2): 1997.
Shirinova Inobat Anvarovna, Candidate of biological sciences, National University of Gulistan, senior researcher E-mail: [email protected]
Influence of catacyn and benzonalum on Ca 2+ - accumulation capacity of mitochondrion of a liver of the rats poisoning with toxic of a cobra naja naja pxina Echwald
Abstract: It is fixed, that after injection in an organism of animals of Benzonalum or catacyn Ca2+ accumulation capacity of mitochondria of liver is decreased. Injecting of cobra's toxic in an organism of animals bring to increasing of entering of Ca2+ in mitochondria. At injecting in an organism of Benzonalum or catacyn on phone of poisoning of an animal with cobra's toxic it takes place suppression of Ca2+ — accumulation capacity of mitochondria.
Keywords: catacyn, bensonalum, cobra, naja, oxina, snake, poison, toxic.
Background. It is known, that benzonalum and catacyn have effect of antihypoxants and immediately influence on gas oxygenous metabolism and power metabolism Mx at hypoxia [1; 2]. It is known, that antihypoxants — gutimin and a natrium hydroxybu-turate are effective both as prophylactic using and after a poisoning of snakes [3; 4]. The problem on possibility of direct acting of antihypoxants of catacyn and benzonalum on calcium accumulation capacity of mitochondrion of different elements of animals on background of action of toxins of snakes is remained openly [5; 6; 7].
Well-known, that ions of Ca 2+ regulates many intracellular processes, including the formation of energy. Regulation is realized or direct allosterical action of Ca 2+ in ferments — targets, or indirect, by activation/retardation of various protein kinases and protein phophotases, considered customary, that ions Ca 2+ can modulate activity of ATF in mitochondrion for the bill of activation of several degydrogenase of Kreb's cycle [8; 9]. It is known, that Ca 2+can modulate the activity of translokaz of adenia nucleotides [10]. The top speed of synthesis and hydrolysis of ATF in mitochondria of a liver of a rat is watched after adding to breathing mitochondria of
5.10-7M Ca 2+. Lowering of Ca 2+ to 10-8 or its increasing to 10-6 M is resulted to a braking of oxidized phosphorilisation and hydrolysis of ATF [11].
The purpose of the produced job is the research of action of benzonalum and catacyn on transport Ca2+ mitochondria of cells of a liver of healthy animal and poisoned of cobra.
Material and methods
In experimental researches there were used white rats in mass of the average 200-230r. Animals were maintained on a blended ration in good aerated, light premises, in wood cage (50x30 cm) till 8-10 rats in each. Forage and water to rats were given without limitation.
Animals have been separated on 4 groups on 10 animals in each. Animals of first, second and third groups were injected intramuscular with toxic of Central Asia cobra naja naja oxina Echwald in a dose of 160 mkg/kg of weight. Through two minutes animals of the second and third groups were injected catacyn or benzonalum on 50 mg/kg ofweight in edition. The fourth group of rats received a physiologic solution. Through 15 mines after injecting of toxic of
Influence of catacyn and benzonalum on Ca 2+ - accumulation capacity of mitochondrion of a liver.
a cobra the animals were decapitated. Toxic of the Central Asian cobra received from institute of Zoology ofAcademy of Sciences of Uzbekistan. Samples of toxic of a collection of 2002, exsiccated in desiccators over calcium chloride have been used.
Mitochondria from cells of a liver of rats got on special method [12]. Transfer of Ca 2+ through mitochondria membrane was registered by the metrical method pH, grounded on fluctuation of 2H +/Ca 2+ of metabolism ofmitochondria [13]. At consecutive adding of several portions of chloride calcium to suspension of mitochondria, the absorbing of Ca 2+ in exchange for protons is replaced by a spontaneous going out of accumulated Ca 2+. It is connected with damage of membranes of the mitochondrion, called basically the activation of phospholipase A2 and phospholipase D with larger concentration of Ca 2+, separate of oxidative phosphorylation, fluctuation of membrane penetrating, and also opening of cyclo-sporine A — a sensitive pore [14; 15; 16]. Than it is more Ca 2+ mitochondrion can accumulate till its self arbitrary free throw out, there are more stable membrane structures to damage action of these ions. Depending on a number of conditions of stoichiometry, the change of Ca 2+ on protons can vary [17]. As in the presence of phosphate in the quality of penetrate anion the stoichiometry of 2H +/Ca 2+ of metabolism is constant and is approximately equally 1, in experiments the medium of an incubation maintained 120 mmol tris-KCl, 10 mmol tris- HC1, 5 mmol a succinate, pH 7.4, potenone (lmkg/ml) and 1 mmol phosphate. The system was supported with solution of HC1 of known concentration. Protein is determined on method of Lowry O. H. et al. [18].
Results and discussion It is fixed, that after injecting in an organism of animals of Benzonalum and catacyn Ca 2 the accumulating capacity of mitochondria of a liver is decreased (tab. 1). So, injecting in an organism of Benzonalum of 50 mg on kg of mass of body of Ca 2 the accumulating capacity of mitochondria of a liver is decreased on 32,4% from monitoring level, and catacyn — on
26,8%. Decrease of Ca 2+ accumulating capacity of mitochondria with higher indicated antihypoxants is connected with inhibition of absorption fUnction of mitochondria of ion Ca 2+, or catacyn and benzonalum which are increased the content of glycoprotein specifically connected with Ca 2+ or they are activated rianodine receptor [19]. Adding of rianodine to insolate mitochondria has been resulted to suppression of transport of Ca 2+ and inhibited higher amplitude swelling of mitochondria.
The results, received in the present series of researches, are allowed to know, that catacyn and Benzonalum are inhibited the influx of Ca 2+ in a mitochondria.
Table 1. - Influence of Benzonalum and catacyn on Ca 2+ accumulating capacity of Mitochondria of a liver of rats (M±m; n=8-10) (M±m; n = 8-10)
Preparations Ca 2+ — accumulating capacity, nmol/mg of protein
Control 82,8 ±3,7
Benzonalum 56,0 ±3,2
Control 84,3 ± 4,4
Catacyn 61,7±3,9
Remarks: here and in tabl.2 the medium of an incubation is maintained: 120 mM KC1, 1 mM KH2PO4, 5mM a succinate, 10 mM tris-Hcl (pH 7,4), 1 mkg/ml rotenone.
In a following series of experiments, influence of Benzonalum and catacyn on Ca 2+ accumulation capacity of mitochondria of a liver of animals on phone of toxic of a cobra (tab.2) has been learnt. It is fixed, that under the influence of toxics the absorption of ions of calcium in mitochondria of a liver of rats raises on 68,6% from norm's level. In the presence of Benzonalum it has been compounded only — 17,4%, catacyn — 20,4%. It means, that Benzonalum and catacyn decreases.
Table 2. - Influence of toxic effect of cobra on Ca 2+ accumulation capacity of mitochondria of a liver of rats on phone of Benzonalum and catacyn (M±m; n = 8-10)
Indexes Ca 2+ — accumulation capacity, nmol/mg of protein
Healthy animals The animals who have received toxin of cobra
Control Benzonalum Catacyn
Liver 91,4 ±5,9 154,1 ± 12,6**** 107,3 ±8,2 110,1±6,7
% 100 168,6 117,4
Ca 2+ accumulation capacity of mitochondria, that is almost completely remove a negative effect of toxic of a cobra. In our opinion, toxic of a cobra calls the progressive increase of Ca 2+, gives a signal to implementation of Ca 2+ cycle on a mitochondrial membrane. This increase is prolonged until then while job of systems of an entrance and going out of Ca 2+ will be not lead to critical increasing of Ca 2+m till l-3^M. In these conditions there is take place the induction of Ca 2+ of dependent unspecific penetration of the inside membrane (so-called «membrane's time»). It is escorted by higher amplitude of swelling of mitochondria, damaging of the outward membrane
and releasing in a cytosol and is dissolved by proapoptical agents. To them it is concerned the cytochrome ^ become localize in inter-membranous area, apoptozinducycal factor, a number of caspaz, which one immediately participate in stage of starting up apoptical reactions, and also factor of Smas/DIABLO which are promoted an apoptosis and inactivates inhibitors apoptical proteins. Thus, at injecting in an organism of Benzonalum and catacyn on the phone of poisoning of an animals with toxic of a cobra there is a suppression of Ca 2+ transport and inhibition of higher amplitude swellings of mitochondria.
References:
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2. Juldashev N.M., Zijaeva A. V. Information letter, Tashkent, the certificate - № 0003. P. 3 (1994).
3. Kurmukov A. G., Nazrullaev A., Ahmerov R. N. Med. J. Uzb. - № l. P. 1, 7-9 (1990).
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6. Valtseva I. A., Strelkov V. M., Trudy R. P. 1 MMI. P. 84, 56-57. (1975).
7. Bogrova T. A. Actual questions of Neuropathology and Neurosurgery. P. 9, 5-10 (1976).
8. Chichkanov G. G., Bogomolov A. K. Bull. Exper. Biol. P. 3, 44-47 (1982).
9. Mashkovsky M. D. Pharmacology, (1987).
10. Novikov V. E. Pharm. Toxicol., P. 6, 9-11 (1991).
11. EvtodienkoJ. V., Azarashvili T. S. Biol. Chem., P. 65, 9, 1210-1214 (2000).
12. Scheider W. C., Hogeboom G. H. Cancer Res., P. 19, 1-22, (1951).
13. Almatov K. T., Ahmerov R. N. Human Physiol. Animals, P. 1, 50, (1993).
14. Gegelgans A. I. Dissert., P. 177, (1970).
15. Brockemeier K. M. Biochemistry, P. 16440-16449, (1995).
16. Madesh M., Balasubramanian K. A. Biophys., P 346, 2, 187-192, (1997).
17. Ganitkevich V. Y. Exp. Physiol. - V. 88. - N 1. P. 91-97. (2003).
18. Lowry O. H., Rosenbrough N. J.J. Biol. Chem. - V.193. - N3. P. 265-275. (1951).
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Shomuradova Shakhnoza Shavkatovna, Tashkent Pediatric Medical Institute, Senior scientific applicant-researcher at the Department of neonatology, E-mail: [email protected]
The state of hepatobiliary system in juvenile rheumatoid arthritis
Abstract: The Article is dedicated to the results of the clinical-biochemical, biophysical and pathomorphological study of liver in the patients with juvenile rheumatoid arthritis. Liver injury was found in 64.8% of patients with JRA., showing the signs of mesenchymal inflammation, hypoalbuminemia, hyperbilirubinemia, hyperenzymemia. The importance of elastography in the early diagnosis of liver fibrosis in patients with JRA was determined. The results of morphological studies of liver of the deceased JRA patients treated with methotrexate showed that, in contrast to patients who did not receive methotrexate, the development of more severe disorganized, dystrophic and immunopathological processes with transition to the sclerotic and fibromatous changes was noted.
Keywords: biochemistry of liver, hepatotoxicity, juvenile rheumatoid arthritis, methotrexate, pathomorphology, fibrosis, elastography of liver, juvenile rheumatoid arthritis.
Relevancy. Diffuse disease of connective tissue, which includes juvenile rheumatoid arthritis (JRA), is one of the most severe and socially important forms of chronic pathology in children. The tendency to early disablement and possibility of system manifestations with involvement of internal organs in the pathological process necessitate timely diagnostics of complications and choice of adequate therapy. Hepatobiliary system is vulnerable in JRA patients. Its reasons include autoimmune processes on the one hand, and effect of drugs on the other hand.
Hepatotoxic reactions appearing during the application of background therapy ofJRA depend on the duration of use and dose of drugs [4]. It is known that the possibility of adverse reactions increases with the increase of the amount of simultaneously used drugs. It is established that if a patient takes five or six drugs simultaneously, the possibility of an adverse effect reaches 80% [1, 12].
The analysis of published information in respect of most often used non-steroidal anti-inflammatory drugs (NAID) in JRA and golden standard of treatment — methotrexate (MTX), certifies about high possibility of liver injury. Hepatotoxicity of drugs used in rheumatology leads to the slow-down of the processes of bio-transformation of exo- and endobiotics, their accumulation in circulating blood and development of endogenous intoxication, worsening of pathological process and toxicity of used drugs [2; 3; 6]. Methotrexate suppresses the activity of methylenetetrahydro-folate reductase, which leads to the increase of the level of homocysteine and, in the future, to the enhancement of fatty infiltration of hepatocytes, development of inflammation, Ito-cells activity and liver fibrosis [7, 14]. Methotrexate can cause the increase of liver ferments activity, development of fibrosis and cirrhosis of
liver during long-term treatment [11]. However, the data about the frequency and severity of fibrosis and cirrhosis of liver during the use of methotrexate in doses used in rheumatic diseases is ambiguous [10].
As a result of the progress of pathological process, consecutive stages offibrosis develop in the liver, for the diagnostics ofwhich the elastography of liver, a non-invasive method, has recently become the safest and most informative [5; 9; 13]. With regard to the above stated, the problem of early diagnostics ofliver injury, enhancement of the efficiency ofJRA therapy with the simultaneous ensuring of the minimum of adverse effects of drugs is very relevant both, from the point of science and practical pediatrics.
Aim of research: to study clinical-biochemical, biophysical and pathomorphological characteristics of injury of hepatobiliary system in juvenile rheumatoid arthritis.
Material and methods of research. 91 patients with JRA aged from 1,5 to 17 were examined, out of which, there were 18 patients oligo- and 73 patients with poly-arthritic variants of disease.
Out of 91 patients, there were 50 (54,9%) boys and 41 (45,0%) girls. The duration of disease was from 1 to 10 years.
59 children showed clinical signs of liver injury (main group), and 32 children with JRA. without liver injury were included in the experimental group. The criteria of inclusion were the absence of earlier diseases of hepatobiliary system, absence of anti-bodies to the viruses of hepatitis B, C and D, which were determined by immune-ferment method. Ultra-sound (US) examinations of hepatobiliary system was conducted on the device SSD-630 «Alo-ka» (Japan). Elastography of liver was conducted with the help of the device «FibroScan 502 TOUCH» («EchoSens», France).
