Pharmacokinetics of a New Neuroprotector - Indenoquinoxalinone Derivative after Intravenous Administration in Rabbits and Rats.

The specific JNK inhibitor and NO donor 11H-indeno[1,2-b]quinoxalin-11-one oxime (IQ-1) demonstrated pronounced neuroprotective properties in an in vivo model of ischemic stroke in rats. The pharmacokinetic behavior of IQ-1 was studied in two animal species (rats, rabbits) after intravenous administration in a dose of 1 mg/kg. IQ-1 concentrations in venous blood plasma were measured by the liquid chromatography-tandem mass spectrometry method. The pharmacokinetics of IQ-1 was adequately described by the two-compartmental model. The calculated C0 for IQ-1 in rabbit and rat plasma were 2239.83±1229.55 and 1552.50±182.23 ng/ml, respectively. Two animal species are characterized by extensive tissue distribution of IQ-1 (Vss exceeded the total body water in rabbits and rats by 3.6 and 5.6 times, respectively) and high clearance values (88-94% of hepatic blood flow).

Role of JNK in the Regulation of Xenobiotic Metabolizing Function of Hepatocytes.

We studied the role of JNK in the regulation of the metabolism of xenobiotic venlafaxine by liver cells under in vitro conditions. The inhibitory role of this protein kinase in the biotransformation of this psychotropic agent by hepatocytes was demonstrated. JNK inhibitor added to the liver homogenate containing antidepressant enhanced and accelerated the formation of the only pharmacologically active venlafaxine metabolite O-desmethylvenlafaxine in the cell suspension. The results show the promise of studying modifiers of activity of intracellular signaling molecules (in particular, mitogen-activated protein kinases) to develop a fundamentally new approach to control the transformation of xenobiotics and to create a new class of pharmaceutical, target regulators of drugs metabolism.

Pharmacokinetics of a New Analgesic on the Basis of Hexaazaisowurtzitane Derivative.

We studied pharmacokinetics of a new analgesic based on a hexaazaisowurtzitane derivative (thiowurtzine, TWZ). A method for measuring TWZ in organs and tissues by HPLC/MS/MS was developed and validated. The sensitivity of the method under conditions of intragastric administration of TWZ to rats in a dose of 100 mg/kg is 0.5 ng/ml (calibration curve 0.5-400 ng/ml). The concentrations of the substance (Cmax) in the plasma, organs, and tissues of animals were 20-100 ng/ml, the time to reach the maximum concentration after a single dose (Tmax) was 2 h. The mean retention time of the substance in the body ranged from 5.67 to 17.15 h after administration. The highest concentrations were found in excretory organs (liver and kidneys), the substance also actively penetrated into muscle tissue. The medium concentrations were found in the brain and adipose tissue. The tropism to the heart tissues was minimal.

[The effectiveness of risk stratification systems in diagnosis of nodular thyroid disorders].

BACKGROUND: Risk stratification systems, one of the optimal solutions for differential diagnosis of nodular pituitary disorders, are currently under development. The high prevalence of pituitary diseases makes it necessary to evaluate the effectiveness of risk stratification systems and to widely implement them into routine clinical practice. AIM: To evaluate the effectiveness of modern risk stratification systems used to diagnose nodular pituitary disorders. MATERIAL AND METHODS: A total of 1,606 medical records of patients operated on for nodular pituitary disorders in 20062014 were analyzed. The preoperative ultrasonography results and cytological findings were evaluated. The ultrasonography results were classified using the TI-RADS system, while the biopsy data were classified using the TBSRTC system. The surgery protocol and the pathomorphological data were the truth criterion. The effectiveness of the TI-RADS and TBSRTC systems, as well as their contribution to the performance of endocrinologists in outpatient clinics, was analyzed. RESULTS: Cluster analysis revealed a significant volatility of ultrasonography signs in the TI-RADS category, while there was no dominant sign that could be considered the diagnostic standard. Factor analysis proved the consistency of the imaging TI-RADS system based on individual signs. The signs being evaluated are characterized by high significance level but different priorities depending on the type of putative pathology. Discriminant analysis revealed that TI-RADS was a robust and versatile system to be used for various types of nodular pituitary disorders. The overall effectiveness of the TI-RADS system in diagnosis of pituitary tumors was low: it was characterized by 75.4% sensitivity, 84.7% specificity, and 80.1% accuracy. However, this system concretized the indications for fine-needle aspiration biopsy and drew the cytologists attention to the likelihood of pituitary tumor. The implementation of the TBSRTC system reduced the percentage of non-informative (by 9.8%) and controversial results (by 1.7%). Cytological examination was more effective in detection of pituitary cancer compared to ultrasonography (91.0% accuracy, 94.9% specificity, and 76.5% sensitivity). The impressions of ultrasound technicians and cytologists were concordant in 873 (54.4%) cases. A survey conducted among endocrinologists in outpatient clinics showed that implementation of the TI-RADS and TBSRTC risk stratification systems reduced the decision time (p0.001) and errors both in diagnostics (p0.001) and treatment approach selection (p0.001). CONCLUSION: The combined use of the TI-RADS and TBSRTC systems allows one to personalize the treatment approaches for patients with nodular pituitary disorders. The implementation of these systems has a positive effect on endocrinologists performance as it reduces the decision time and the likelihood of making errors in diagnosis and treatment strategy selection.

Bioavailability of the Phenolic Antioxidant 4-Methyl-2,6-Diisobornylphenol After Oral Administration.

We compared bioavailability of 4-methyl-2,6-diisobornylphenol after single intragastric administration to rats in a dose of 200 mg/kg in starch suspension and in almond oil. Absorption of 4-methyl-2,6-diisobornylphenol in the gastrointestinal tract after administration in almond oil was much more efficient than after administration in aqueous starch mucus.

Pharmacological correction of the negative effects of acetylsalicylic acid on the energy production system.

Experiments of outbred rats with modeled xenobiotic load with acetylsalicylic acid (250 mg/kg for 7 days) revealed inhibition of mitochondrial respiration rate in states of rest and active phosphorylation, inhibition of succinate-dependent oxidation pathway, and a decrease in energization of organelles in the heart. For correction of the observed changes in energy production, succinic acid was preventively administered in a dose of 50 mg/kg for 7 days, which abolished the negative metabolic shifts in myocardial mitochondria. Comparison of pharmacokinetics of acetylsalicylic acid and acetylsalicylic acid against the background of succinate treatment performed on rabbits revealed complete coincidence of the studied parameters, which attests to the possibility of prevention of mitochondrial dysregulations with this Krebs cycle intermediate.

Hepatic and cerebral energy production system in rats with acute and chronic ethanol intoxication.

We studied the effects of ethanol on the energy production system in the brain and liver in acute and chronic intoxications. Ethanol was found to inhibit mitochondrial respiratory chain in the liver. Acute ethanol intoxication results in uncoupling of oxidative phosphorylation. NAD-dependent respiration prevails in chronic intoxication. In the brain, ethanol exposure induces a compensated low-energy shift with activation of fast mitochondrial metabolic cluster and uncoupling of oxidative phosphorylation.