Oxythiamine improves antifungal activity of ketoconazole evaluated in canine Malassezia pachydermatis strains.

BACKGROUND: Malassezia pachydermatis is an opportunistic yeast involved in skin and ear canal infections of dogs and cats. Reports suggest that strains of M. pachydermatis resistant to commonly used antifungal agents may be emerging. Therefore, new therapeutic strategies should be explored. OBJECTIVES: The synergistic effect of oxythiamine (OT) and ketoconazole (KTC) was analysed using a reference strain and field isolates (n = 66) of M. pachydermatis. Hydrogel formulations containing these components also were evaluated. METHODS AND MATERIALS: The minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) of OT, KTC and their mixtures were determined by a broth macrodilution method. The antifungal effects of hydrogel formulations were determined by a plate diffusion method. RESULTS: The MIC and MFC values of OT were in the range 0.08 × 103 to 10 × 103  mg/L. All M. pachydermatis strains showed higher susceptibility to KTC (MICs and MFCs in the range 0.04-0.32 mg/L). Formulations that combined OT and KTC showed a synergistic effect for all tested isolates (n = 66). Hydrogels that contained OT at a concentration of 10 × 103 or 20 × 103  mg/L and KTC at the concentration of 0.1 × 103  mg/L showed a stronger effect than a commercially available product with KTC alone (20 × 103  mg/L). CONCLUSIONS AND CLINICAL IMPORTANCE: Synergy of these drugs may allow for successful topical treatment which utilizes lower doses of KTC without changing its therapeutic effectiveness. Hydrogel formulations proved to be attractive drug carriers for potential topical use.

Anticancer efficacy of hydroxyethylthiamine diphosphate in vivo.

AIM: The aim of the presented article was investigation of anticancer efficacy of hydroxyethylthiamine diphosphate (HTD) in vivo. MATERIALS AND METHODS: The study was carried out on 30 C57BL/6J mice subcutaneously transplanted with Ehrlich carcinoma. Animals were treated with intraperitoneal injections of the solution composed from pyruvic acid and thiamine bromide every other day during 10 days and thereafter, every day during 2 weeks. Treatment efficacy was evaluated by tumor growth inhibition. RESULTS: In experimental animals treated with HTD, significant tumor growth inhibition has been registered: 73% at day 45(th) compared to the control group (p < 0.001). CONCLUSION: Treatment with HTD demonstrated high anticancer efficacy in vivo.

Pentose phosphate cycle oxidative and nonoxidative balance: A new vulnerable target for overcoming drug resistance in cancer.

The metabolic network of cancer cells confers adaptive mechanisms against many chemotherapeutic agents, but also presents critical constraints that make the cells vulnerable to perturbation of the network due to drug therapy. To identify these fragilities, combination therapies based on targeting the nucleic acid synthesis metabolic network at multiple points were tested. Results showed that cancer cells overcome single hit strategies through different metabolic network adaptations, demonstrating the robustness of cancer cell metabolism. Analysis of these adaptations also identified the maintenance of pentose phosphate cycle oxidative and nonoxidative balance to be critical for cancer cell survival and vulnerable to chemotherapeutic intervention. The vulnerability of cancer cells to the imbalance on pentose phosphate cycle was demonstrated by phenotypic phase plane analysis.

Antitumor activity of hydroxythiamine and methotrexate immobilized on monocarboxycellulose.

The aim of the present study was to examine the antitumor and antivitamin activities of some new combinations of methotrexate (MT) and hydroxythiamine (HT), antagonists of folic acid and thiamine, respectively, immobilized on monocarboxycellulose (MCC). Ehrlich ascites carcinoma and sarcoma 180 were used as test malignant tumors in mice. It has been shown, that the compounds studied decreased significantly the amount of mitotically dividing tumor cells and increased the percentage of dead cells, inhibited the tumor growth (up to 10-30 fold at the early stage of neoplasm development) and elongated the life-span of tumor-bearing animals (by 1.6-3.3-fold) as compared to the control. All MCC-immobilized HT and MT complexes studied demonstrated higher antitumor efficacy compared to the mixture of these drugs or each of the agents applied individually. The specific feature of the newly synthesized substances was strong and prolonged antitumor effect following single administration. The severity of thiamine and folic acid deficiencies essentially depended on the amount of HT and MT in the preparations. A close correlation was found between the inhibition of transketolase in the tumors and the antiblastoma properties of the preparations. It enables us to suggest, that the antithiamine action of these preparations is one of the important factors in the mechanism of their antitumor effect.

Changes in brain lipid composition in thiamine deficient rats.

Brain lipid composition was studied in thiamine deficient rats treated with thiamine antimetabolites (oxythiamine: OT, and pyrithiamine: PT) and thiamine deficient diet (TDD). After intraperitoneal injection of OT (40 mg/kg/day) or TDD feeding for 6 days, body weight gain decreased. However, the PT (500 micrograms/kg/day) treated rats or the pair fed control (PFC: TDD + thiamine of 5 mg/kg, i.p.) showed no decrease in body weight gain compared with the regular diet control (C). Brain lipid levels (total lipid, total cholesterol, triglyceride, phospholipid, sphingomyelin and cerebroside) were examined in four brain regions (cerebral cortex, subcortical structure, brain stem and cerebellum). Total lipid level increased in four regions in OT or TDD treated rats, but total lipid level in the cerebellum in PT treated rats decreased. Total cholesterol level increased in all treated rats, while the triglyceride level in the brain stem decreased dramatically in OT or TDD treated rats. Cerebroside levels of four regions in the PT, OT or TDD group remarkably decreased, and PFC rats showed a significant improvement of the decrease in cerebroside level. It is conceivable that these changes in brain lipid composition provided some clues for the histological and morphological changes of the brain as manifested by the myelin degradation in acute thiamine deficiency.

[Optimization of hydroxythiamine administration regimen in vitaminological research]. / Optimizatsiia rezhima ispol'zovaniia oksitiamina v vitaminologicheskikh issledovaniiakh.

A correlation between the different doses and inhibitory effect of hydroxythiamine relative to the activity of main thiamine pyrophosphate-dependent enzymes is studied in experiments on animals. It is established that the maximal inhibitory effect on the transketolase and oxoglutarate dehydrogenase activities is at a dose of antivitamin of 0.35 mmol/kg and that of pyruvate dehydrogenase of 0.55 mmol/kg. At lower doses of hydroxythiamine the inhibition of enzyme activities occurred in a dose-dependent manner.

[Thiamine pyrophosphate-dependent enzymes in the regenerating liver of albino rats under different regimens of oxythiamine administration]. / Aktivnost' tiaminpirofosfatsoderzhashchikh fermentov v regeneriruiushchei pecheni belykh krys pri razlichnykh rezhimakh vvedeniia oksitiamina.

Activities of the thiamine pyrophosphate-dependent enzymes (pyruvate dehydrogenase, oxoglutarate dehydrogenase, transketolase) were increased in regenerating rat liver tissue as compared with their activities in the intact tissue. After administration of oxythiamine (20 mg/kg, within 10 days, subcutaneously) into the animals the enzymatic activity studied was decreased.

[Effects of repeated administration of pyrithiamine and oxythiamine on timing behavior in rats (author's transl)].

Male Wistar rats were trained to hold down a lever for reinforcement with food pellets. No external stimulus signalled the end of the required duration. The minimum duration required was gradually raised to, and fixed at, 2 seconds. This was achieved in about 1-2 months. At the end of pre-drug training, the average response duration was 2.06 +/- 0.03 seconds in a daily 10-minute session. Daily injections of pyrithiamine, a thiamine analog which causes a rapid depletion of the brain vitamin, were given after the daily experimental session. The average response duration increased significantly by the 8th day of pyrithiamine treatment (2 mg/kg/day), without altering any other parameters examined. This pyrithiamine-induced change in duration, which was gradually diminished after the 14-day drug period, could be reversed with thiamine (2 doses of 5 mg/kg). On the other hand, oxythiamine did not cause an increase in duration over the 14 days of daily injections. The results obtained suggest that pyrithiamine exerted significant effects on discrimination of duration or internal timing mechanism in rats at the doses used, perhaps because of the depletion of the brain vitamin.

[Importance of insulin- and thiamine-dependent processes in regulating lipid metabolism in the rat liver]. / Znachenie insulin- i tiaminzavisimykh protsessov v reguliatsii lipidnogo obmena v pecheni krys.

Lipid metabolism in liver tissue, adipocyte sizes and dynamics of body mass alteration were studied after administration of insulin, hydroxythiamine both and their mixtures into rats. In presence of insulin content of triglycerides as well as the rate of 6-3H-glucose incorporation into total lipids, fatty acids, phospholipids and triglycerides was increased in liver tissue. Administration of hydroxythiamine both into intact animals and into the rats treated with insulin led to decrease in content of fatty acids in liver tissue, triglycerides in liver tissue and blood serum as well as to lowering in the rate of 6-3H-glucose incorporation into fatty acids and triglycerides of liver tissue. Insulin activated and hydroxythiamine inhibited the liver tissue acetyl-CoA-carboxylase. Among other factors inhibition of lipogenesis appears to be the most important for decrease in the size of adipocytes and in body mass of the animals treated with hydroxythiamine.

[Mechanism of the effect of varying saturation of the rat organism with thiamine on membrane-bound succinate dehydrogenase activity]. / K mekhanizmu vliianiia razlichnogo nasyshcheniia organizma krys tiaminom na aktivnost' membranno-sviazannogo fermenta suktsinatdegidrogenazy.

The properties of the membrane-bound succinate dehydrogenase (SDH) of rat liver mitochondria were studied in the presence of thiamine excess and deficiency in the body. In acute oxythiamine B1-avitaminosis, the content of phosphatidyl choline in the mitochondria fell and SDH activity was suppressed. After incubation of such mitochondria with a sonicated phospholipid emulsion from egg yolk the activity of the enzyme virtually returned to control values. Incubation of the mitochondria from control rats and animals given thiamine contained by phospholipid emulsion did not affect SDH activity.