Search

The aim of the study was to assess the probability of developing withdrawal syndrome caused by discontinuation of 5-day administration of thiowurtzine with naloxone challenge test in the experiment.Materials and methods. The test sample of the analgesic “Thiowurtzine, capsule 120 mg” served as the study object. The active pharmaceutical ingredient is an organic, low molecular weight compound 4-(3,4-dibromothiophene carbonyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo [5,5,0,03,11,05,9]dodecane that was first synthesized according to computer modeling results at the IPCET SB RAS (Biysk).The likelihood of developing physical dependence was explored by per os administration of thiowurtzine and the reference drug tramadol twice a day for 5 days as follows: 1) at 9 a.m. – thiowurtzine 50 mg / kg and tramadol 10 mg / kg, at 3 p.m. – thiowurtzine 50 mg / kg and tramadol 10 mg / kg; 2) at 9 a.m. – thiowurtzine 50 mg / kg and tramadol 10 mg / kg, at 3 p.m. – thiowurtzine 75 mg / kg and tramadol 15 mg / kg; 3) at 9 a.m. – thiowurtzine 75 mg / kg and tramadol 15 mg / kg, at 3 p.m. – thiowurtzine 75 mg / kg and tramadol 15 mg / kg; 4) at 9 a.m. – thiowurtzine 100 mg / kg and tramadol 20 mg / kg, at 3 p.m. – thiowurtzine 100 mg / kg and tramadol 20 mg / kg; 5) at 9 a.m. – thiowurtzine 100 mg / kg and tramadol 20 mg / kg, at 3 p.m. – naloxone 10 mg / kg subcutaneously.In all the groups, the intensity of the withdrawal syndrome was studied by specific features in outbred male CD1 mice. During one hour following the naloxone injection, health of mice was assessed according to dominant abstinence components and recessive traits of mild withdrawal syndrome. Two hours after the naloxone injection, the number of mice with negative body weight gain was determined. 24 hours after discontinuation of test compound administration, the open-field test was used to determine the impact on animal behavioral patterns (horizontal and vertical motor and exploratory activity, emotionality and its vegetative manifestations). The hot plate test was carried out to measure the analgesic activity (55˚). The criterion of the withdrawal syndrome severity was a decrease in the number of jumping reactions, changes in the general condition of the animals, stimulation of motor activity, manifestations of hyperalgesia, and a decrease in body weight.Results. No dominant abstinence components and recessive signs of withdrawal syndrome were detected in animals from the thiowurtzine groups. The data obtained in the study (orientation and exploratory behavior, motor activity, emotionality and its vegetative manifestations, grooming, etc.) allow to conclude that thiowurtzine causes no physical dependence in animals after discontinuation of its 5-day administration with naloxone challenge test, as opposed to the reference drug naloxone. A positive disinhibition effect of this analgesic was revealed due to the activated orientation and exploratory behavior (stress caused by the new environment) in the conditions of the open-field test. The animals showed no manifestations of hyperalgesia in the hot plate test. The animals treated with thiowurtzine did not demonstrate any changes in the body weight.Conclusion. The obtained results prove that thiowurtzine is a non-narcotic analgesic. It evokes no side effects typical of opioid analgesics (tramadol), including development of physical dependence and withdrawal syndrome following naloxone challenge test. Previous in vivo and in silico studies (docking, molecular modeling, molecular dynamics simulation) on the multi-target mechanism of thiowurtzine explain the absence of its morphine-like effect by the fact that the major targets of the analgesic are TRPA1 receptors and voltage-gated Ca 2+ channels. With a high degree of probability, the conclusions made herein predict no drug abuse development when thiowurtzine is used in the clinical setting. Absence of ulcerotoxicity found earlier will enable to administer thiowurtzine in long-term cycles for chronic pain syndrome.

Chronic pain syndrome (CPS) is a complex, hard to treat polyetiological condition. While there is a wide array of possible causes for CPS, it is most important in oncological context, since within oncological setting it may be induced both by the tumor itself and by the treatment modalities used against it. Analgesic therapy is, according to WHO, the primary method of managing CPS, and is effective in approximately 90% of cases. However, patients requiring strong opioids for pain management (III step of WHO’s “analgesic ladder”) face a number of complications associated with adverse events (AE), such as inhibition of respiratory control center, nausea, vomiting, and constipation. While constipation and vomiting are themselves amenable to therapeutic management, they can both significantly reduce quality of life and even require alteration of analgesic medication regime, thus potentially compromising the management of chronic pain. This has necessitated the creation of painkiller medication that would have a more favorable gastrointestinal AE profile while maintaining analgesic efficacy, such as fentanyl transdermal delivery systems (TDS) and oral formulations combining oxycodone and naloxone. The pharmacoeconomic comparison of these two medications in order to determine which of them is more economically rational within context of Russian healthcare is thus justified, and is the subject of this research effort. Aim. To perform evaluation of pharmacoeconomic (PHe) properties of combined naloxone/oxycodone formulation (Targin®) compared to fentanyl TDS (Fendivia®) in Russian oncological patients with CPS. Methodology. This PHe is conducted perspective of public health organizations of the RF at federal and national levels. The modelling horizon was 25 weeks. Comparator drugs were Targin® and Fendivia®. Randomized controlled clinical trials investigating safety and efficacy of these drugs were used as data source on safety and efficacy. A Markov model was constructed in order to estimate healthcare costs and patients outcomes. Each simulated patient group contained 100 patients. Retention of patients with adequate pain management in main treatment regime without dose increase was used as efficacy criterion, since this surrogate endpoint is most clinically relevant, reflecting ability of a given modelled treatment regimen to control chronic pain. These modelling results were used to perform the following types of pharmacoeconomic analysis: carrying out cost-effectiveness analysis (CEA), budget impact analysis (BIA), and evaluation of pharmacoeconomic expediency based on willingness-to-pay ratio (WTP). Result. Naloxone/oxycodone formulation dominates in CEA analysis (direct costs were 2,091 mln. rub. for naloxone/ oxycodone versus 3,747 mln. rub. for fentanyl TDS). The CER indicator for oxycodone/naloxone was 51 218 rub., while fentanyl TDS had CER of 317 409 rub. BIA revealed considerable budgetary burden reduction for oxycodone/naloxone, which was due to considerable reduction of GDP losses and expenses associated with disability and loss of working capacity. The resultant economy of government funds reached 44%. According to PHe analysis, both drugs are attractive for purposes of drug reimbursement system, but oxycodone/naloxone is dominant due to WTP/CER indicator of 32,1 (fentanyl TDS had WTP/CER of 5,1). Sensitivity analysis confirmed the robustness of these findings - CEA and BIA results remained stable even in case of 25% oxycodone/ naloxone price increase. Conclusion. Oxycodone/naloxone combination has been determined to be most pharmacoeconomically attractive due to higher efficiency of healthcare spending (due to domination in terms of CER) and reduction of GDP losses associated with complete disability which resulted in government budgetary savings of up to 44%.

Influence of intraperitoneal and intracerebroventricular DAGO (μ-opioid agonist) on the bile secretion and composition was studied in white rats having intact and denervated liver. DAGO was demostrated to alter bile composition significantly both intraperitoneally and intracerebroventricularly and these effects were opposite. Intact liver innervation is a necessary condition for intracerebroventricular DAGO to have its effect on bile secretion.

Ifluence of intraperitoneal and intracerebroventricular dalargin ( and  opioid agonist) on bile secretion and composition was studied in white rats with intact and denervated liver. Dalargin was demostrated to alter bile composition significantly both intraperitoneally and intracerebroventricularly and effects were opposite. Intact liver innervation is a must for intracerebroventricular dalargin to have its effect on bile secretion.

Influence of dalargin (non-selective mand d-аgonist), DADLE (selective) and DAGO (selective magonist) on the bile secretion frequency and cholates secretion was studied in acute experiments on isolated perfused liver of the white rats. Opioid peptides effects on isolated liver were revealed to mask by the higher levels of hierarchic regulation in intact liver.