[ANTIOXIDANT ACTIVITY OF XYMEDONE IN RATS WITH CHRONIC AUTOIMMUNE INFLAMMATION].

Effects of drug xymedone (in comparison to ionol) in a group of 32 white rats with experimental model of chronic autoimmune inflammation of rat paws (induced by Freund's adjuvant) were studied by measuring the volume of paw edema and determining the levels of lipid peroxidation (LPO) products and the activity of antioxidant enzymes in various tissues. Chronic autoimmune inflammation induced by Freund's adjuvant was characterized by the LPO intensification and disturbances of the level of antioxidant enzymes. Intragastric administration of xymedone (2,2-dihydro-4,6-dimethyl,-N-(ß-oxy-ethyl)-2-pyrimidon) at a dose of 169 mg/kg and reference drug ionol (2,6-ditretbutyl-4-methylphenol) at a dose of 220 mg/kg increased the activity of serum antioxidant enzymes by 19% and 11%, respectively, decreased the serum level of nitrite ion by 62% and 50%, and reduced the levels of LPO products in rat blood and homogenates of liver, kidney, and spleen by up to 80% (p < 0.05).

Anti-inflammatory and anti-oxidant properties: Is there a link?

BACKGROUND: It is believed that the anti-inflammatory activity of medicines is closely related to their antioxidant activity. However, in clinical practice rigorous evidence-based medicine approach fails to reveal important effects of antioxidants on patient important outcomes in inflammatory disorders, as has been shown by a number of Cochrane reviews [1-3]. OBJECTIVE: To evaluate anti-inflammatory and antioxidant effects of newly developed pharmacological agents: dimephosphone and its structural analogues ephorane and mephoprane, and xymedon, in comparison with prednisolone and etidronate in experimental animal model of adjuvant arthritis. METHODS: Experiments were conducted in 64 white mongrel rats of both sexes weighing 180-200 g, which were divided into 8 groups 8 rats each (4 males and 4 females each), kept under standard vivarium conditions with certified feeding ration (kombikorm). The study was approved by the local ethics committee. We induced adjuvant arthritis by administration under the plantar aponeurosis of the left hind paw of 0.1 ml of Freund's adjuvant (Sigma) in rats of 7 study groups. The groups were as follows: 1st group - intact animals (control); 2nd group - animals to whom the solvent (distilled water) was administered with intra-gastric tube in corresponding volume (control of the model); 3rd - 8th study groups, in which animals were administered with study agents each at a dose of 1 mmol/kg body weight: dimephosphone, ephorane, mephoprane, xymedon, etindronate and prednisolone. The intensity of the modeled arthritis was determined by measurements of paw volumes with plethysmometer (UgoBasile). We calculated the difference in rat paw volume before the administration (baseline) and after administration of Freund's adjuvant at 3, 7, 11, 15, 20, 27, 31, 38, 41 days. The development of secondary arthritis was documented by the increase in volume of both hind and fore paws and tails. On the 41st day of the experiment the animals were sacrificed under light ether anesthesia and exsanguinated. The blood was used to determine the activity of catalase and peroxidase, the content of the total, reduced and oxidized glutathione, the level of ceruloplasmin, conjugated dienes of unsaturated fatty acids (DC), TBA-interacting products (MDA), and the total antioxidant activity of serum (AOA). The results were processed statistically using the Student's t-test. RESULTS: The primary reaction to the Freund's adjuvant in a form of swelling of the ankle joint of the left hind paw was observed at 24 hours after its injection. External clinical manifestations of the modeled disease were more pronounced on the third day: local inflammatory reaction (redness, swelling, ulceration) was seen in all the animals at the injection site with the increase of the paw volume. On the 11th day of the experiment 20% of the animals developed secondary arthritis. The study agents dimephosphone, ephorane, and prednisone exerted anti-inflammatory effect decreasing the volume of left hind paws by 45%, 46% и 27% respectively on the 40th day of experiment. Mephoprane did not affect the primary inflammatory response to the Freund's adjuvant (rats' left hind paws), however it reduced the volume of the contralateral right paw (secondary arthritis) by 90% on the 20th day of the experiement. This ant-inflammatory effect was accompanied by documented antioxidant activity in case of dimephosphone, ephorane, prednisolone, but not mephoprane. Dimephosphone reduced the levels of lipid peroxidation products in rats blood by 46% (DC) and by 25% (MDA). Ephorane also reduced the levels of lipid peroxidation products in the blood by 46% (DC) and by 25% (MDA), increasing the level of glutathione by nearly half, both the total and the reduced form. Prednisolone reduced the level of lipid peroxidation products in blood by 61% (DC), but not the TBA-interacting products. Mefopran did not affect the blood level of lipid peroxidation products. Xymedon and etidronate showed no anti-inflammatory effect. Xymedon demonstrated anti-oxidant properties, decreasing the blood levels of lipid peroxidation products, while etidronate seemed to behave in pro-oxidant mode, increasing the blood levels of lipid peroxidation products. CONCLUSIONS: The effects of studied agents on the intensity of inflammation and lipid peroxidation were inconsistent. The results of the study did not show a clear link between anti-inflammatory and anti-oxidant activity. Further research in potential anti-inflammatory activity of new drugs exhibiting antioxidant properties needs to be done before recommending their use in clinical practice.

[Dimephosphone shows anti-inflammatory and anti-oxidative activity on chronic autoimmune inflammation model].

The anti-inflammatory activity of dimephosphone, xydiphone (ethidronate), and ionol (dibunol) and their effects on lipid peroxidation (LPO) indices and the activity of antioxidant enzymes in blood were studied on the model of Freund adjuvant induced arthritis in white laboratory rats. The Freund adjuvant induced chronic arthritis and increased the concentrations of PLO products and nitrite ions in the blood plasma. Only dimephosphone showed an anti-inflammatory action. Dimephosphone and ionol inhibited the LPO, whereas xydiphone did not influence the LPO indices in the blood.

[Mechanisms of genome instability in children with periventricular leucomalacia that resulted in cerebral palsy].

The activity of free-radical oxidation and the level of genome instability in children with periventricular leucomalacia that resulted in cerebral palsy have been studied. Genome destabilization, i.e., the elevation of erythrocyte micronuclei in the peripheral blood, has been reported. There was a correlation of a number of cells with cytogenetic rearrangements with the activity of antioxidant defense enzymes and the malonaldehyde level. It has been shown that genome instability occurs during the activation of endogenous mutagenesis and reduction of antiradical and antimutagenic defense. Having, along with the neurotrophic effect, antiradical and antimutagenic effects, cortexin is capable to inhibit the pronounced processes of free-radical oxidation and endogenous mutagenesis in patients with periventricular leucomalacia that resulted in spastic dyplegia exerting.

[Anti-inflammatory effects of amitriptyline, diazepam and mebicar using model of acute carrageenan-induced paw edema in rats].

The anti-inflammatory activity of amitriptyline, diazepam and a new, Russian tranquilizer mebicar was studied in a wide range of therapeutic doses on carrageenan-induced paw edema in rats. Mebicar at low doses showed greater and longer (up to 24 h) lasting anti-inflammatory activity as compared to that of amitriptyline and diazepam.

[Comparative analysis of dimephosphon, ionol, and xydiphone effects on indomethacin-induced gastric lesions in rats].

Gastroprotective activity of dimephosphon, xydiphone, and ionol and their effects on the lipid peroxidation (LPO) indices and the activity of antioxidant enzymes in blood and organ tissues were studied on the model of indomethacin-induced gastric lesions in white rats. The indomethacin-induced gastropathy leads to increased concentration of LPO products in blood plasma and tissues. Dimephosphon and ionol reduced the number of gastric lesions and prevented LPO activation. In contrast, xydiphone administration had no effect on indometacin-induced gastric lesions and was accompanied by increased concentration of LPO products in the blood, liver, kidneys, spleen and stomachs of rats.

[Clinical value of the local parameters of lipid peroxidation and antioxidative defense in patients after cataract extraction].

The postoperative period of cataract extraction and the parameters of lipid peroxidation (LPO) (dienic conjugates, TBA-active compounds) and the antioxidative activity (AOA) of tear were studied in 77 patients in relation to the type of a surgical intervention--extracapsular cataract extraction (ECCE) and phacoemulsification (PE). The incidence of severe postoperative uveitis was more than 3 times higher on days both 1 and 5 after surgery. Tear studies revealed a significant increase in the concentration of LPO products just on day 1, with its further slight increase by day 5 along with a further significant reduction in AOA, which indicates the significant consumption of antioxidative defense components and the expediency of using antioxidants. Comparison of tear biochemical parameters revealed no difference in patients after ECCE and PE. Thus, peroxidation processes reflect the severity of an inflammatory reaction in the early postoperative period, the study of the processes in tear is a noninvasive, high-informative method for recording the balance of LPO and antioxidative defense processes, which will assist in determining the direction of therapeutic measures to improve the outcome of a surgical intervention.

[Types of biochemical response to acute pharmacological indomethacin probe in healthy volunteers]. / Tipy biokhimicheskogo reagirovaniia zdorovykh dobrovol'tsev na ostruiu farmakologicheskuiu probu s indometatsinom.

By the type of biochemical response to acute pharmacological indomethacin probe, a group of both male and female healthy volunteers can be subdivided into two parts. The first part includes volunteers with a stability index reduced as a result of accumulation of the oxidized products and a decrease in the content of reduced glutathione (GSH). The second part includes volunteers with the stability index increased as a result of decrease in the amount of lipid peroxidation products and an increase in the GSH content. A difference between males and females with respect to the response type consisted in that females features changes in the gutathione buffer components, and males, in the activity of antioxidant enzymes (catalase and peroxidase).

Therapeutic efficiency of dimephosphone and xydiphone in experimental pulse therapy with prednisolone.

Experiments on rats showed that pulse therapy with prednisolone (100 mg/kg intraperitoneally for 3 days) stimulated urinary excretion of hydroxyproline, increased the content of inorganic phosphorus, promoted the increase in the content of dienic conjugates and catalase activity, and decreased serum levels of MDA and ceruloplasmin. Ten-day treatment with dimephosphone (208 mg/kg) or xydiphone (45 mg/kg) after pulse therapy with prednisolone normalized urinary excretion of hydroxyproline and reduced the levels of dienic conjugates. Dimephosphone did not change, while xydiphone normalized the level of MDA decreased by prednisolone.

[C-cells of the thyroid gland in experimental osteoporosis]. / C-kletki shchitovidnoi zhelezy pri éksperimental'nom osteoporoze.

The population of thyroid C-cells of female rabbits with ovariectomy-induced osteoporosis was studied using immunohistochemical method with antibodies against calcitonin (CT) and morphometrically. The development of osteoporosis was confirmed using radiology and densitometry. 8 weeks after the operation, after the detection of hypercalcemia and hypercalciuria, some of the animals were given a correcting treatment with calcium-containing drug and vitamin D3 or with a combination of calcium drug with hormonal estrogen-containing drug. 4 weeks after the treatment was started, thyroid C-cells in animals that received the drugs, were significantly larger than in the cells of control and ovariectomized rabbits that received no treatment. Following 12 and 22 weeks, in the animals treated with hormonal drug, both calcium concentrations in blood and urine and C-cell dimensions were normalized. Large C-cells with an intensive reaction to CT were observed at weeks 12 and 22 (weeks 20 and 30 after the operation) in the thyroid gland of the animals that received no treatment and of the animals that received calcium with food. In the last case, the morphological changes of C-cells were more pronounced, despite the insignificant differences in blood calcium concentrations in both groups. These results permit to suggest that the intensity of CT synthesis by C-cells may be influenced by calcium concentrations not only in the blood, but also in the intestinal lumen.

[Effect of dimephosphon and xydiphone on mineral metabolism and lipid peroxidation in rats subjected to "pulse-therapy" with prednisolone]. / Vliianie dimefosfona i ksidifona na mineral'nyi obmen i perekisnoe okislenie lipidov krys na modeli "pul's-terapii" prednizolonom.

The parameters of mineral metabolism, a lipid peroxidation (LPO) process, and the efficacy of antioxidant enzyme preparations were studied in rats with an osteoporosis model induced by the administration of prednisolone in a daily dose of 100 mg/kg (i.p.) over 3 days, which is analogous to a pulsed therapy schedule in clinics. The treatment with glucocorticosteroid enhanced the excretion of hydroxyproline and inorganic phosphates with urine, increased the LPO rate and antioxidant activity of the blood serum, and decreases the level of ceruloplasmin and the catalase activity in the blood. A prophylactic treatment with dimephosphon (208 mg/kg, p.o.) and xydiphone (45 mg/kg, p.o.) prevents from the prednisolone-induced LPO activation. Dimephosphon, in contrast to xydiphone, also prevents from a prednisolone-induced increase in the excretion of hydroxyproline and inorganic phosphates with urine.

[Effect of dimephosphon and xidifon on parameters of lipid peroxidation and the antioxidant system in rats subjected to the long-term administration of prednisolone]. / Vliianie dimefosfona i ksidifona na pokazateli perekisnogo okisleniia lipidov i antioksidantnoi sistemy krys, dlitel'no poluchavshikh prednizolon.

Experiments in rats with an osteoporosis model induced by the chronic administration of prednisolone (50 mg/kg, p.o., over 14 days) showed that the drug differently affects the lipid peroxidation (LPO) rate and the antioxidant system activity. Xydiphone (45 mg/kg, p.o.) administered over 14 days exhibited a perooxidant action. Dimephosphon (208 mg/kg, p.o.) administered over the same period of time produced an antioxidant effect as manifested by a growth in the catalase activity, an increase in the content of ceruloplasmin and glutathione, and a decrease in the content of LPO products in the blood serum and liver tissues. The results of combined administration of prednisolone and phosphonates indicate good prospects of the dimephosphon treatment as a means of normalization of the LPO and antioxidant system functioning disturbed by prolonged use of glucocorticoids.

[New approaches to prognosis of risk of development of gastropathies induced by nonsteroid anti-inflammatory agents]. / Novye podkhody k prognozirovaniiu riska razvitiia gastropatii, indutsirovannykh nesteroidnymi protivovospalitel'nymi sredstvami.

A pharmacological test with indomethacin is suggested for predicting the risk of NSAID-induced gastropathy. It is shown that patients with diagnoses of rheumatoid arthritis and osteoarthrosis can be divided into two groups with respect to the indomethacin test--"vulnerable" and "resistant", characterized by a high and low risk of NAIDS-induced gastropathy development, respectively. The proposed index of resistance to this disorder, together with the glutathione redox buffer test index, can be used as reliable criteria for predicting the NSAID-induced gastropathy.

[Comparative study of the effect of dimephosphon monophosphonate and xydiphone biphosphonate on the histomorphometric indices of rat vertebra in a model of glucocorticosteroid osteoporosis]. / Sravnitel'noe izuchenie vliianiia monofosfonata dimefosfona i bifosfonata ksidifona na gistomorfometricheskie pokazateli stroeniia pozvonkov krys pri modelirovanii gliukokortikosteroidnogo osteoporoza.

The efficacy of monophosphonate dimephosphon and diphosphonate xydiphon was compared by experiments in rats with an osteoporosis model induced by the chronic administration of prednisolone. The glucocorticosteroid decreased the total density of trabecules (in both bone and cartilage tissues) in histological micropreparations of lumbar vertebrae and reduced the total bone cell count and the calcium content in the bone tissue. Dimephosphon, administered on the prednisolone background over the same period of time, normalized the total relative density of trabecules (by increasing the cartilage content), the total bone cell count, and the calcium content. Under the same conditions, xydiphone normalized the total relative density of trabecules (by increasing the bone content), but did not influence the prednisolone-decreased content of cartilage, total cell count, and calcium content in the vertebrae. Thus, the test results reveal a significant advantage of dimephosphon over xydiphone.

[Comparative study of dimephosphon and xidiphone efficacy in steroid-induced osteoporosis in rats]. / Sravnitel'noe izuchenie éffektivnosti dimefosfona i ksidifona pri steroidnom osteoporoze u krys.

The efficacy of dimephosphon in comparison with xydiphone was studied in rats with an osteoporosis model induced by prednisolone administration at a daily dose of 50 mg/kg over a period of 14 days. The prednisolone treatment led to an increase in the content of oxyproline (a marker of bone resorption), calcium, and inorganic phosphates in the urine. Dimephosphon (monophosphate) decreased the levels of oxyproline, calcium, and inorganic phosphate in the urine. Xydiphone (biphosphonate) equally reduced the oxyproline excretion and the calcium level in urine, while rather insignificantly affecting the phosphaturia. Dimephosphon normalized the blood calcium level, while xydiphone decreased this parameter. An additional advantage of dimephosphon over xydiphone was manifested by normalization of the body weight of test rats and the total blood protein level.

[The "direct mitogen" lead nitrate causes an intensification in lipid peroxidation and Ito cell activation in the rat liver]. / "Priamoi mitogen" nitrat svintsa vyzyvaet usilenie perekisnogo okisleniia lipidov i aktivatsiiu kletok Ito v pecheni krys.

We have used biochemical and immunohistochemical methods to study lipid peroxidation and activation of Ito cells in rat liver after a single administration of lead nitrate, a "direct mitogen". Lead nitrate was shown to injure hepatocytes through an increased lipid peroxidation. Response to the injury included increase in the proliferative activity of parenchymal and sinusoidal liver cells. In addition, activation of Ito cells has been noted, which manifested as increased expression of desmin and increased proliferation. However, no transformation of Ito cells into myofibroblasts has been observed. We discuss the possible role of Ito cell activation in creating conditions for the proliferation of liver parenchymal cells after the injury by lead nitrate.

[The effect of ximedon on cholesterol metabolism and experimental atherosclerosis in rabbits]. / Vliianie ksimedona na metabolizm kholesterina i éksperimental'nyi ateroskleroz u krolikov.

The effects produced by the two pyrimidine derivatives pyridinol carbamate (parmidine) and xymedon on cholesterol metabolism and experimental atherosclerosis were comparatively studied in rabbits. The rabbits were fed either a chow containing cholesterol (200 mg/kg body weight) or the same diet also containing xymedon (30 mg/kg body weight) or pyridinol carbamate (30 mg/kg body weight). Total plasma cholesterol showed 5.5- and 4.7-fold increases in the rabbits receiving only cholesterol or cholesterol + pyridinol carbamate, respectively, as compared with that in the animals on a standard laboratory chow. In the rabbits given cholesterol+xymedon, cholesterol levels were 24% less than that in the animals taking cholesterol alone. In these animals, the aortic atherosclerotic damage index (ADI) was equal to 24.1%, which was 1.8-fold less than that in the cholesterol-fed rabbits. In the rabbits given cholesterol+pyridinol carbamate, ADI was decreased by 1.7 times, but it did not differ from that in the hypocholesterolemic rabbits. At the same time xymidone and pyridinol carbamate reduced the hepatic levels of total and esterified cholesterol. To elucidate the mechanism of action of xymedon, it was studied for effects on cholesterol metabolism in cultured rabbit hepatocytes and murine macrophage J774. Xymedon did not alter the esterification and other parameters of cholesterol metabolism in the cultured hepatocytes. It is suggested that the hypocholesterolemic effect was realized at the level of intestinal rather than hepatic cholesterol metabolic changes. The investigations made on the murine macrophage J744 showed that xymedone reduced cholesterol esterification in macrophages, evidently by inhibiting the activity of the enzyme acyl-CoA: cholesterol acyltransferase. The anti-atherosclerotic effect of xymedon seems to result from reductions in plasma cholesterol levels and cholesterol esterification in blood vascular cells.

[The comparative characteristics of the antiatherogenic effect of xymedon and parmidine]. / Sravnitel'naia kharakteristika antiaterogennogo éffekta ksimedona i parmidina.

We've studied xymedon (30 mg/kg, 12 m) and parmidin (pyridinolcarbamate 30 mg/kg, 12 m.) effects on the development of experimental cholesterol atherosclerosis on rabbits. It was demonstrated that after the use of xymedon aorta damage reduces twice. Xymedon also prevents accumulation of cholesterol and fatty degeneration of the liver. Antiatherogenic effect of xymedon resulted comparable with the effect of parmidin. As it was demonstrated in the present investigation and in the previous ones in contrast to parmidin, xymedon normalizes the lipoproteins balance owing to increase of HDL cholesterol. It also has regenerative activity on endotheliocytes and immunomodulator properties. That can be of great importance for the anti-atherosclerotic effects of the medicine.

[Effect of cimetidine on experimental atherogenesis in rabbits]. / Vliianie tsimetidina na éksperimental'nyi aterogenez u krolikov.

It was shown that cimetidine (10 mg/kg, 12 weeks) reduces the frequency and the degree of affection of rabbit's aortas during experimental cholesterol atherosclerosis. The protective effect of cimetidine on the liver where the contents of lipids, especially cholesterol esters reduced considerably, was noted. The nature of the fatty dystrophy changes from the large-drop to the small-drop one which should be considered as a favourable phenomenon. The anti-atherogenic and hepatoprotective effects of cimetidine can be explained by slowing-down of lipoperoxidation processes which is proved in respect of blood and aorta walls.

[The mechanism of action of dimephosphon]. / Mekhanizm deistviia dimefosfona.

It has been established in experiments on rats that the 7-day administration of dimephosphon per os increases blood levels of total mercapto groups and glutathione, changing the correlation of its forms in favour of the oxidized ones. This course of dimephosphon administration reduces blood concentration of lipid peroxidation products. The significance of these mechanisms in realization of the pharmacological effects of dimephosphon is under discussion.