На статиите на д-р Милка Милчева Милева, представени при кандидатстване за хабилитация I. Публикации, свързани с дисертационната



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Р Е З Ю М Е Т А
на статиите на д-р Милка Милчева Милева,

представени при кандидатстване за хабилитация
I. Публикации, свързани с дисертационната тема


  1. Effect of rimantadine on the processes of lipid peroxidation in some model systems (2000) Compt. Rend. Bulg. Acad. Sci. 9: 69 – 73



Mileva M., V. Hadjimitova, T. Traykov, A. S. Galabov, St. Ribarov
Summary: In the recent years in the extreme prophylactic and treatment of influenza virus infections the chimiotherapeutic rimantadine hydrochloride (Rim) is widely used. It has a manifested antiflue effect upon diseases caused by viruses type A (H3N2). In the course of the disease Rim interacts with M2 protein molecule of the influenza virus as it decreases both the ability of this molecule to form a hydrophobic channel and its affinity towards the lipid bilayer of the host-cell.

The influenza virus infections are accompanied by the so-called “oxidative stress”, which is expressed in an intensified generation of reactive oxygen species (ROS). This generation probably results in processes of LPO. The therapeutic effect of Rim is due indisputably to its specific action upon the virus replication. In our former paper it was demonstrated that Rim decreases the contents of the products of LPO in mice upon experimental influenza infection with virus A/Aichi/2/68(H3N2).



In order to elucidate the mechanism of this effect, the ability of Rim to interact with the O2-, to influence their generation and probably to change the level of LPO in model systems and tissue homogenate is investigated. The O2- is very important for the induction of LPO in biological system.


  1. Effect of vitamin E on lipid peroxidation and liver monooxygenase activity in experimental influenza virus infection (2000) Toxicol. Lett. 114: 39-45.


Mileva M., L. Tantcheva, R. Bakalova, A. S. Galabov, V. Savov, St. Ribarov
Abstract: Influenza virus infection was associated with development of oxidative stress in liver of mice, viz. increase in amount of lipid peroxidation products, decrease in cytochrome P-450 and NADP.H-cytochrome c-reductase activity, and inhibition of liver monooxygenases (aniline hydroxylase, ethylmorphine-N-demethylase, amidopyrine-Ndemethylase and analgin-N-demethylase). These effects were most pronounced on the 7th day after virus inoculation as compared to the 5th one. Supplementation of mice with vitamin E before virus inoculation leads to liver protection against oxidative stress and toxicosis. A marked decrease of lipid peroxidation products and an increase of cytochrome P-450 and activities of monooxygenases was established. The stabilizing effect of vitamin E was dose-dependent and was most pronounced on the 5th day after virus inoculation as compared to the 7th one.


  1. Antioxidant properties of rimantadine in influenza virus infected mice and in some model systems. (2000) Zeitschrift fuеr Naturforschung 55: 824 – 829


Mileva M., V Hadjimitova, L. Tantcheva, T. Traykov, A. S. Galabov, V. Savov, St. Ribarov
Abstract: Influenza virus infection is associated with development of oxidative stress in lung and blood plasma, viz. increase of primary and secondary lipid peroxidation products. It was established that rimantadine (rimantadine hydrochloride) treatment led to a decrease of the products of lipid peroxidation in tissues of mice experimentally infected with influenza virus A/Aichi/2/68 (H3N2). The effect is strongest in blood plasma (a decrease of about 50%) and weaker in the lung (about 20%). To elucidate the mechanism of this action of rimantadine, experiments were carried out with some model systems. The capability of rimantadine to scavenge superoxide radicals (scavenging properties) was studied in a system of xanthine-xanthine oxidase to generate superoxide. The amount of superoxide was measured spectrophotometrically by the NBT-test and by chemiluminesce. Rimantadine does not show scavenging properties and its antioxidant effect observed in vivo, is not a result of its direct action on the processes of lipid peroxidation and/or interaction with antioxidant enzymes. The antioxidant properties of rimantadine were investigated by measurement of induced lipid peroxidation in a Fe2+ and (Fe2+ - EDTA) system with an egg liposomal suspension. Our findings with model systems do not prove an antioxidant or prooxidant effect of the drug on the processes of lipid peroxidation. Apparently the observed antioxidant effect of rimantadine in vivo is not connected directly with free radical processes in the organism.


  1. Effect of vitamin E supplementation on lipid peroxidation in blood and lung of influenza virus infected mice (2002) Comp. Immunol. Microbiol. Inf. Dis. 25: 1 – 11.


Mileva M., R. Bakalova, L. Tantcheva, A.S. Galabov, St. Ribarov
Abstract: Influenza virus infection was associated with development of oxidative stress in liver of mice, viz. increase in amount of lipid peroxidation products, decrease in cytochrome P-450 and NADP.H-cytochrome c-reductase activity, and inhibition of liver monooxygenases (aniline hydroxylase, ethylmorphine-N-demethylase, amidopyrine-Ndemethylase and analgin-N-demethylase). These effects were most pronounced on the 7th day after virus inoculation as compared to the 5th one. Supplementation of mice with vitamin E before virus inoculation leads to liver protection against oxidative stress and toxicosis. A marked decrease of lipid peroxidation products and an increase of cytochrome P-450 and activities of monooxygenases was established. The stabilizing effect of vitamin E was dose-dependent and was most pronounced on the 5th day after virus inoculation as compared to the 7th one.

II. Публикации извън дисертационната тема
5. Acuta toxicity and effect on hepatic oxidative drug metabolism of mopiridone (1994) Arzneimittel-Forschung/Drug research 44: 354 – 357.
Tantcheva L., A.S. Galabov, M.Behar, D. Sidzhakova
Abstract: Mopyridone (CAS 82822-14-8) is a new chemotherapeutic with a strong antiviral effect (vs. influenza- and toga viruses) and certain advantages over the chemotherapeutics known so far. Toxicological studies reveal its low oral and intraperitoneal toxicity in mice and rats. The 5- and 14-day administration of mopyridone (37.5 mg/kg b.w., orally) to male rats established a growing tendency to the shortening of hexobarbital sleeping time, associated with moderate changes in the hepatic oxidase activity on the 15th day, most pronounced for amidopyrine N-demethylase (by 37%) and less for benzphetamine N-demethylase (by 17%). Aniline hydroxylase activity was slightly diminished (by 18% and 16%, resp.). No significant changes in the components of the electron-transport chain of cytochrome P-450 were established--the content of cytochrome P-450, cytochrome b-5 and cytochrome C reductase, both after 5- and 14-day mopyridone administration.


  1. Flavonoids in Tanacetun Vulgare (1995) Fitoterapia 4: 373 – 4

Ivancheva S., M.Behar


Abstract: Plant: Tancetum vulgare L. (Asteraceae), air-dried parts, collected in Bulgaria, August 1991. Voucher specimen at the Herbarium of the Botanical Institute, Voucher N. 2480.

Uses in traditional medicine. Anthelmintic, spasmolitic, emmenagoguge, home remedy for intestinal worms, insects flies and lice, anticancer and antimicrobi-activities.

Previously isolated contents. Flavonoids, sesquiterpene lactones, tannins.

New-isolated constituents. Orientin (0.003%) and luteolin 7-O-glycoside (0.01%).
Acknowledgements. Work supported by BNFS (Bulgaria). Thanks are also due to Prof. Dr. E. Wollenweber, Botanical Institute TH, Darmstadt, Germany, for providing authentically samples.

7. Свободно-радикални процеси при атерогенезата (1997) Актуална липидология (2): 21-30.
Бакалова Р., В. Хаджимитова, М. Милева, Ст. Рибаров
Abstract: The data during the last 10 years demonstrated the important role of free radical processes in atherogenesis.

The article summarizes the data on oxidative modification of low density lipoproteins (LDL) as a major risk factor of atherogenesis. It accent two basal group of factors affecting the oxidative modification of LDL.

1) Prooxidant status of plasma lipoproteins, including: increased synthesis of cathecholamines, conversion of xanthine-dehydrogenase to xanthyne-oxydase, activation of lipoxygenases and phospholipase A2, activation of lipid peroxidatoin and free radical oxidation of proteins and nucleic acids;

2) Decreased antioxidant capacity of oxidative LDL (oxLDL), and possibility of genetic determination of this factor;



It is presented a comparative analysis of prooxidant – antioxidant balance of native LDL and oxLDL, isolated from clinical healthy blood donors, and from patients with atherogenetic disorders, respectively. The fatty acid and lipid compositions of lipoproteins are demonstrated in oxLDL.

  • Increased content of free fatty acids (to 180% vs native LDL);

  • Decreased content of polyunsaturated fatty – the main substrate of lipid peroxidation;

  • Decreased content of phosphatidylcholine (to 50 – 60% vs native LDL);

  • Increased content of lysophospholipids and triglycerides;

  • Strongly increased content of the primary products of lipid peroxidation – fatty acid hydroperoxides and conjugated dienes;

  • Increased content of the end products of lipid peroxidation – TBA-reactive substances and fluorescent lipofuscine-like products;

  • Strongly decreased content of natural lipid soluble antioxidants – tocopherols, tocotrienols, ubiquinols, carotenoids etc. (complete consumption).

It is demonstrated also that the oxidation of LDL leads to disturbances of liver binding with exogenous lipid soluble antioxidants.
8. Flavonoids, phenolic and triterpenic acids in the Mentha spicata (L.) Hugs. group from Bulgaria (1997) Phytologica Balcanica (2): 89-93.
Stoeva T., S. Ivancheva, M. Behar
Abstract: The cultivated Bulgarian representatives of Mentha spicata group previously tested for essential oil content were subjected to the analysis of the quality and quantity of flavonoid fraction. The total content of flavonoids was determined by spectrophotomety (0.07 – 0.22%). The highest average content (0.15%) and the maximum content (0.22%) of flavonoids were registered in M. spicata ssp. Spicata. Five flavonoids, 1 phenolic acid and 2 triterprnic acid were established by TLS and UV-spectrometry. Three promising forms with favorable combinations of 3 important features (satisfactory quantity and quality of flavonoids and high content of essential oil) were selected.
9. Essential oils, flavonoids, phenolic and triterpenic acids in the Mentha spicata group (L.) Huds. from Bulgaria (1998) Lek. Sirov. 17: 63 – 77
Stoeva T., S. Ivancheva, M. Behar
Abstract: We are tested some cultivated Bulgarian representatives of Mentha spicata group for essential oil, phenolic and triterpenic acids content. The drugs were subjected to the analysis of the quality and quantity of flavonoid fraction. The total content of flavonoids was determined by spectrophotomety (0.07 – 0.22%). The highest average content (0.15%) and the maximum content (0.22%) of flavonoids were registered in M. spicata ssp. Spicata. Five flavonoids, 1 phenolic acid and 2 triterprnic acid were established by TLS and UV-spectrometry. Three promising forms with favorable combinations of 3 important features (satisfactory quantity and quality of flavonoids and high content of essential oil) were selected.

10. Флуориметричен анализ при изследване литолоитичното действие на българския препарат “Фармалит” при болни с уратна литиаза (1999) Балнеология 2: 7 – 11.
Иванова М., М. Милева, Г. Георгиев, Р. Янева, И. Георгиев

Резюме: Бъбречнокаменната болест (нефролитиаза) е заболяване със социално значение. Тя е обект на изследване от много различни специалисти. Препаратите за лечение на уратна литиаза са основани на корекция на рН на урината (рН – 7). Българският препарат Фармалит има свойството да образува водно-разтворим комплекс с пикочната киселина от конкрементите. В представената статия използваме емисионен спектрален анализ за доказване на получения комплекс между препарата и пикочната киселина.
11. Dissolution of cysteine calculi with a plants extract. Spectrophotometry analysis (1999) Kidney stones, Proceedings of the 8-th European Symposium on Urolithiasis, Parma, Italy, June 9-12, 1999, p 571-572
Atanassova S., M. Ivanova, M. Mileva, M. Tzvetkov, Tz. Tzvetkov, M. Jankulova
Summary: One of rare forms of urolitiasis is cysteine (i.e. amino acid), with frequency of dissemination between 0.5-20.0% in general population. It is a genetically determinant form of litiasis which affects children and young people. Normally, in urine of healthy human the concentration of amino acid cysteine is 40 – 50 mg per 24 hours. When any disturbances in its rearbsorbtion in renal tubular cells are present its concentration in urine increases to 100 mg per 24 hours. High concentration of cystine amino acid in urine with pH about 6,5 is an important factor precipitation of this amino acid and formation of concrement. The plant extract can to dissolve the concrement probably do to formation of water soluble complex compounds.
12. Effect of He-Ne laser treatment on the level of lipid peroxidation products in experimental cataract of rabbit eyes (2000) Methods Find. Exp. Clin. Pharmacol. 22: 679 – 681
Mileva M., G. Zlateva, S. Karabasheva, I. Antonov, V. Hadjimitova
Summary: The effects of low-intensity laser (LIL) irradiation on the grading of the level of lens opacity (i), and on the level of lipid peroxidation products and activities of antioxidant enzymes in lens (ii) during experimental Diquat-induced Cataract in rabbit eyes were studied. At the end of 10th week the lens of Diquat-treated animals opacitated to 4-5 grade. Subsequent treatment of the lens by low-intensity He-Ne laser does not alter significantly the level of opacity (4-5 grade). It was observed that experimental model of Cataract lead to significant increase of lipid peroxidation products (conjugated dienes, malondialdehyde, fluorescent lipofuscine-like products) as well as to significant changes in antioxidant enzyme activities (increase of SOD-activity and decrease of Catalase-activity). Treatment of Diquat-modified lens by low-intensity He-Ne laser resulted to a slight decrease of SOD-activity and does not affect additionally Catalase-activity.

Summarizing, the results demonstrated that LIL-irradiation has not a protective effect on the cataractogenesis and oxidative stress, induced by Diquat in rabbit eyes. It is supposed that the effect of LIL-irradiation on the experimental Catarct depends on the dose applied, prolongation of laser treatment and lens structure.



13. Preventive effect of vitamin E on the processes of free radical lipid peroxidation and monooxygenase enzyme activity in experimental influenza virus infection (2001) In: Advances in experimental medicine and biology. Eds. B. M. Dansette, S. Snyder, M. Dellacorge, J. J. Gibson, H. Gram, D. J. Jollow, T. J. Munks and I. J. Sipes, Cluwer Academic/ Plenum publishers, New York, Boston, Dortrecht, London, Moscow, Vol. 500, p. 257 – 260.
Stoeva, E., L. Tantcheva, M. Mileva, V. Savov, A.S. Galabov, A. Braykova
Resume: Influenza virus infection is associated with development of oxidative stress in the liver, lung and blood plasma, viz. increase of primary and secondary lipid peroxidation products. It was established that rimantadine (rimantadine hydrochloride) treatment led to a decrease of the products of lipid peroxidation in tissues of mice experimentally infected with influenza virus A/Aichi/2/68 (H3N2).
14. Free radical lipid peroxidation and monooxygenase activity in experimental influenza virus infection after treatment with Rimantadine. (2001) In: Advaces in experimental medicine and biology. Eds. B. M. Dansette, S. Snyder, M. Dellacorge, J. J. Gibson, H. Gram, D. J. Jollow, T. J. Munks and I. J. Sipes, Cluwer Academic/ Plenum publishers, New York, Boston, Dortrecht, London, Moscow, Vol. 500, p. 217 – 220
Tantcheva L., E. Pavlova, V. Savov, A. S. Galabov, M. Mileva, A. Braykova
Resume: The processes of lipid peroxidation (LPO) in cell membranes modify effectively the lipid structure of biomembranes and the activity of drug metaboilizing enzyme systems (DMES) and especially cytochtome P-450 – dependent microsomal monooxyhenaze. Reactive oxygen species (ROS) are generating in this system leading to chain development of LPO processes. Influenza virus infection activated the LPO processes in the liver, lung and blood plasma.Vitamin E is not an agent with specific antiviral action, its antioxidant properties is moderate the course of the infection in dose-dependent manner do to its role as membrane-protector.
15. Pharmacodynamic of the antioxidant action of alpha-tocopherol and its derivatives in animal tissues (2000) Acta Physiol. Pharmacol. Bulg. 25: 19 – 26.
Bakalova, R., M. Mileva, G. Zlateva, St. Ribarov
Abstract: The aim of the present work was to determine the pharmacodynamic of antioxidant effect of alpha-tocopherol and its derivatives (alpha-tocopheryl esters and chromanols with different chain-length) in the animal tissues, as well as the role of cytochrome P-450 in biotransformation of these compounds. Alpha-tocopherol and its derivatives were injected intraperitoneally in rats or mice in a single dose 100 mmol per kg b.w. The animals were sacrified at different time-intervals (0, 1, 2, 4, 8, 12, 24, 36 hours) and the liver, heart, brain and sceletal muscles were removed, homogenized and incubated with lipid peroxidation (LPO) inducers - (Fe2+ + ascorbate). LPO was evidenced by the generated malone dialdehyde (MDA). Data were expressed as percent of LPO inhibition by alpha-tocopherol or its derivatives as compared to control group. We were o bserved that the kinetic curves of the inhibitory action of alpha-tocopherol and its derivatives on LPO were characterized with three phases: a phase of increasing antioxidant activity, a phase of maximal antioxidant activity (about 60-95% LPO inhibition), and a phase of decreasing antioxidant activity. Alpha-tocopheryl esters possessed dynamics of antioxidant action the same as alpha-tocopherol. Therefore the hydrolysis of alpha-tocopheryl esters in animal organism is not a limiting factor for their antioxidant effect. The alpha-tocopherol derivatives with short chain-length (C1, C6) had a shorter times of half-life in animal tissues in comparison of alpha-tocopherol or its esters. We were established in in vitro experiments that C1 and C6 are substrates of cytochrome P-450. In contrast, alpha-tocopherol and its esters did not bind to cytochrome P-450 even at concentrations as high as 10 mmol/l. Apparently, C1 and C6 were undergone to biotransformation by liver monooxigenase system and were excreeted more quickly from organism.
16. Determination of malondialdehyde in biological samples by solid-phase extraction and high-performance liquid chromatography (2000) Methods Find. Exp. Clin. Pharmacol. 22: 267 – 269
Bakalova R., M. Mileva, Ch. Kotsev, V. Bardarov, St. Ribarov
Abstract: An analytical procedure for determination of malondialdehyde in tissue homogenates and blood serum was developed. A reaction with 2,4-dinitrophenylhydrazine is used followed by cleaning up of the derivative by solid-phase extraction. The samples were analyzed by isocratic high-performance liquid chromatography (HPLC) using a narrow-bore HPLC-column. A good separation of the 1-pyrazole peak from that of 2,4-dinitrophenylhydrazine was observed. A high linear dependence was established by the concentration of 1-pyrazole in the range of 10-5000 ng/ml. The detection limit of the method applied for tissue homogenates and blood serum was approximately 10 ng/ml or lower, and RSD of the method was 9% (n = 8). The peak of 1-pyrazole for these samples was well separated from the other matrix peaks. Experiments carried out evaluated that the solid-phase extraction might be an effective step of the sample preparation, significantly increasing the selectivity of the analysis and the life-time of the column. The method seems to be applicable for determination of malondialdehyde in different biological samples.



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