Evaluation of the Content of Aquaporin-5 and Epithelial Sodium Channel in the Lungs of Rats during the Development of Toxic Pulmonary Edema Caused by Intoxication with Acylating Pulmonotoxicants.

We studied the content of aquaporin-5 (AQP5) and epithelial sodium channel (ENaC) in rat lungs during the development of toxic pulmonary edema (TPE) caused by intoxication with phosgene and perfluoroisobutylene (1.5 LC50). The lung body weight index (LBI) was calculated and histological examination of the lung tissues was performed. Localization and expression of AQP5 and ENaC were determined by immunohistochemistry. Intoxication led to a significant (p<0.05) increase in LBI and histological changes typical of TPE 1 and 3 h after the exposure. In 1 and 3 h after phosgene intoxication, the AQP5 and ENaC content significantly (p<0.05) increased in comparison with the control. Similar changes in the AQP5 and ENaC content were observed 1 and 3 h after exposure to perfluoroisobutylene. It was hypothesized that AQP5 plays an important role in the formation of TPE caused by intoxication with acylating pulmonotoxicants. An increase in the content of ENaC can be considered as a compensatory reaction of the body aimed at clearance of the alveolar fluid.

Polymorphism of Oprm1 Gene and Its Association with Manifestations of N-(1-Phenethyl-4-Piperidyl)Propionanilide Intoxication in Rats.

We studied association of Oprm1 gene polymorphisms with signs of N-(1-phenethyl-4-piperidyl)propionanilide intoxication in rats. It was found that the rate of intoxication in laboratory animals depends on genetic features. A polymorphic variant rs105312806 of Oprm1 gene can be a possible marker of animal sensitivity to opioid receptor agonists. This hypothesis was supported by differences in the rats of intoxication signs such as time to lateral posture and sleep duration in homozygous rats carrying different alleles. In rats with AA genotype, the time to lateral posture was shorter by 1.3 times and sleep duration was longer by 3.5 times than in carriers of GG genotype.

Study of the Efficiency of the Hydroporation for Delivery of Plasmid DNA to the Cells on the Model of Toxic Neuropathy.

We compared the efficiency of delivery of plasmid DNA (active ingredient concentration 1 mg/kg) that provides production of nerve growth factor (NGF) after intravenous administration to rats and after administration by hydroporation. The method of hydroporation ensured plasmid penetration into the liver tissue and lengthened the time of its detection in the organ. DNA concentration in 1 h after its introduction by hydroporation or intravenous route was 0.7 and 0.05 ng/mg tissue, respectively. The use of this transfection method ensured preservation of NGF DNA in the liver tissue at a level of 0.24 ng/mg of tissue 1 day after administration of the plasmid construct, while after intravenous administration, expression of the analyzed DNA was not detected in blood and liver samples. After hydroporation, the maximum of relative normalized expression of cDNA (270 rel. units) was observed after 4 h, and after 1 day, this parameter decreased to 35 rel. units. Introduction of plasmid DNA of NGF by hydroporation prevented the development of disorders of neuromuscular conduction in a rats model of toxic neuropathy induced by subacute administration of malathion in a dose of 0.5 LD50.

Study of the Oxime-induced Reactivation of Acetyl- and Butyrylcholinesterase of Human with Inhibition of Organophosphorus Insecticide In Vitro.

The efficiency of different reactivators of cholinesterase (toxogonin, dipiroxime, pralidoxime, carboxim, HI-6, and methoxime) at inhibition of butyrylcholinesterase and human acetylcholinesterase by organophosphate insecticide malathion was evaluated in in vitro experiments. Most reactivators increased inhibition of butyrylcholinesterase in comparison with the control, but HI-6 in a concentration of 10-3 mol/liter partially (10%) restored activity of the enzyme. Oxime-induced reactivation of acetylcholinesterase was most pronounced in dipyroxime and toxogonin: parameters of the kinetics of reduction of the phosphorylated enzyme differed by more than 2 times from the values received with the use of other reactivators.

Analysis of the Efficiency of Microencapsulated Sustained-Release Form of Naloxone on the Experimental Model of Fentanyl Poisoning.

We compared samples of microencapsulated naloxone prepared by using spray drying technique. 2-Hydroxypropyl-ß-cyclodextrin, sodium alginate, polycaprolactone, and carboxymethyl cellulose were used as the carriers. It was found that the combination of naloxone with sodium alginate was characterized by the highest naloxone content in the matrix and the lowest release rate (100% release time was 60 min). Using the model of respiratory disturbances caused by 10 ED50 fentanyl (anesthetic effect), we studied the effects of naloxone-sodium alginate complex on the dynamics of CO2 concentration in the expired air. It was shown that treatment with the developed microencapsulated naloxone after fentanyl injection allowed reducing the therapeutic dose of the antagonist by more than 2 times and eliminated the necessity of repeated injections.

[Experimental comparative pharmacokinetics of levofloxacin, triazavirin, and related conjugate].

A comparative study of the pharmacokinetics of levofloxacin and triazavirine as well as 2-methylthio-6-nitro-1,2,4-triazolo[5,1-ñ]-1,2,4-triazine-7(4Í)-ide (3S)-(-)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-7H-pyrido[1,2,3-d,e]-1,4-benzoxazine-6-carboxylic acid (conjugate 2) obtained by conjugation of triazavirine and levofloxacin, representing a new class of pharmacological agents, was carried out in experiments on rats. It is established that conjugate 2 in comparison to individual levofloxacin and triazavirine has a higher relative bioavailability and lower rate of elimination, which can lead to improved effectiveness of therapy at reduced dose and frequency of drug administration.

[Features of bemithyl pharmacokinetics upon inhalation administration].

A comparative study of bemithyl pharmacokinetics was carried out upon its inhalation, intragastric and intravenous administration. The main drug metabolites were identified and the pharmacokinetic parameters were calculated. The obtained results suggest that the inhalation administration of bemithyl is a promising replacement for oral administration, which is related to high bioavailability of the drug and the absence of the effect of "first pass" through the liver.

Use of inclusion complex of cyclodextrin with ambenonium to improve the treatment of anticholinesterase poisoning.

The complex of ambenonium with methyl-ß-cyclodextrin injected intramuscularly to rats caused more pronounced inhibition of acetylcholinesterase in erythrocyte and brain than free drug. The use of this complex as part of combined therapy significantly reduces mortality in animals during experimental anticholinesterase poisoning in comparison with the controls.

Prospects of using benzodiazepines in complex therapy of poisonings with anticholinesterase agents.

The efficiency of benzodiazepines on mouse model of anticholinesterase poisoning was shown. The protective effects of clonazepam and midazolam were observed at high (1 TD50, incoordination) and medium (0.3 TD50) doses and the effects of phenazepam and diazepam were found only at high doses. Midazolam produced the most pronounced protective effect: administration of this drug significantly increased the protective index of atropine+HI-6 combination during poisoning.

[Specific features of the anticonvulsant effect of memantine in mice intoxicated with a model organic phosphate].

The effect of memantine administration has been studied on the model of mice poisoning with an anticholinesterase compound. It is established that the memantine action is due to its influence on the cholinesterase activity in the brain, blood plasma, and erythrocytes in addition to its NMDA-blocking action. Memantine promotes oxime-induced erythrocyte enzyme reactivation on the model of mice poisoning with anticholinesterase compound (0.8 LD50).

[Pharmacological activity of n-(1-phenethyl-4-piperidyl) propionanilide modified by encapsulation in PLGA nanoparticles].

Technological parameters for the effective encapsulation of n-(1-phenethyl-4-piperidyl)propionanilide in poly(lactid-co-glycolide) (PLG) nanoparticles have been determined. Depending on the ratio of drug fractions adsorbed on the particle surface and associated with the polymer matrix, n-(1-phenethyl-4-piperidyl)propionanilide (200 microg/kg, i/m) loaded PLG nanospheres accelerated time onset and increased duration of sleep in rats: by a factor of 1.6 - 2.0 for polymer associated drug fraction within 40 - 60% and by a factor of 2.2 - 2.6 for polymer associated drug fraction within 60 - 80%. A similar increase of sleep duration was observed when free n-(1-phenethyl-4-piperidyl)-propionanilide was administered at doses within 400 - 500 microg/kg.

[Study of tolerance of central muscarinic receptor blockers].

The tolerance of five central muscarinic receptor antagonists has been studied in experimental animals. According to the effect on orientation-exploratory reaction, drugs were arranged in the following order of increasing toxicity: procyclidine < trihexiphenidyl < benactizine < atropine < scopolamine. For the same therapeutic index, trihexiphenidyl and benactizine were characterized by the maximum tolerance (TD50/ED50 > 10) in mice. Scopolamine and atropine exhibited anticonvulsant activity at doses exceeding the threshold values by a factor of 6.3 and 3.9, respectively. For procyclidine, the average anticonvulsant dose was threefold lower than the threshold value. Benactizine and procyclidine had maximum tolerance levels in rats. The TD50/ED50 ratio for these drugs was greater than 3 (against 0.5 - 0.7 in groups treated with trihexiphenidyl, atropine and scopolamine).

[Effect of losartan on acute renal failure induced by severe ethylene glycol poisoning in rats].

The effect of an angiotensin receptor II antagonist (losartan) on the model acute renal failure (ARF) induced by severe ethylene glycol poisoning at 2/3 LD50 has been studied in rats. It is established that losartan administration (20 mg/kg for 72 h) produces a significant (4-fold) increase in the animal death rate, which is associated with ARF transition to a decompensation stage. Pronounced changes in the qualitative and quantitative composition of diurnal diuresis, more than 8-fold increase in the creatinine level, and 18-fold increase in the blood urea have been observed. Thus, the administration of losartan to ethylene glycol poisoned rats causes more pronounced degeneration of proximal tubule epithelium and destruction of glomeruli. It is concluded that the use of losartan for the treatment of ARF is inexpedient.

[Studying toxicity caused by interaction of caffeine and ketorolac].

Combined administration of caffeine and ketorolac (NSAID) is accompanied by all possible types of drug interaction. Side effects of the drug combination are mostly due to the action of ketorolac and manifested by decompensated renal failure and progressive endotoxemia within 3 - 7 days after single administration of drugs. Thus, the amplification of ketorolac effects by caffeine must be taken into consideration in prescribing NSAIDs.

[Antioxidant properties of some sulfur-containing substances].

The antioxidant properties of sulfur-containing substances have been experimentally studied in vitro. Unithiol exhibits a wide spectrum us radicals. For this reason, unithiol can be considered, along with ascorbic acid, as a universal drug for the reduction of free radical reactions.

Feasibility of myocardial pH-monitoring during heart surgery under conditions of cardioplegic ischemia.

The first results of the use of pH-monitoring of the myocardium with a Khuri monitor (Terumo Cardiovascular Systems Corporation) are presented. Before aorta clamping, the pH changes depended on the initial degree of damage to the examined myocardial segment. The cardioplegia protocol was urgently modified due to pH-monitoring, which helped to normalize pH and to prevent severe postoperative complications. The thermometric and pH-metric data were compared with the results of clinical and morphological studies. pH-monitoring made it possible to control myocardial vitality during the surgical intervention.