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.

Experimental Substantiation of Inhalation Administration of Pathogenic Therapy of Toxic Convulsive Disorder for Correction of External Respiration Disorders.

We studied the dynamics of respiratory function in rats during intratracheal poisoning with diisopropyl fluorophosphate and pentylenetetrazole in doses corresponding to the LD50 in humans. The maximum of external respiration impairment was recorded in 30 min after poisoning. Administration of diazepam and atropine both separately and in combination during the development of the first signs of poisoning did not significantly affect the respiration parameters, but reduced the incidence of seizures and contributed to a decrease in the rate of animal death. Intratracheal administration of cholinolytic, ß2-adrenomimetic, or glutamate receptors antagonist promoted correction of the respiratory function. It was found that the maximum therapeutic effect in case of diisopropyl fluorophosphates poisoning was achieved after intratracheal administration of ipratropium bromide (0.086 mg/kg), salbutamol (0.086 mg/kg), and MK-801 (0.1 mg/kg), while in case of pentylenetetrazole poisoning, intratracheal administration of ipratropium bromide (0.086 mg/kg) was most effective.

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.

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.

Use of nanotechnology in the creation of moden medicines-governmental funds and their targeting systems (literature review).

Properties of nanoscale carriers recommended by the European Pharmacopeia for use in the creation of drugs and their complexes with physiologically active substances are given. Ihe authors present general descriptions of the methods of creation and especially of carriers identified in the accumulation of experience in their use for creating drugs with desired properties of penetration of biological barriers and length of service of the therapeutic effect.

Changes in Respiratory Function during Treatment with Combination of Analgesic Substances Trimeperidine and Dexmedetomidine.

The effects of analgesic substances trimeperidine and dexmedetomidine and their combinations in different proportions (0.75:0.25, 0.5:0.5, 0.25:0.75 of the medium effective doses of each substance) on respiratory function was studied in experiments on rats. Administration of substances in 1 ED50 by analgesic effect (corresponded to medium therapeutic dose of trimeperidine in humans) was characterized by significantly longer suppression of respiration over 90 min in comparison with combined treatment with these substances. Administration of the substances in a dose of 8 ED50 by analgesic effect (corresponded to daily therapeutic dose) over 60 min was followed by more than 3-fold reduction in respiration frequency and respiratory minute volume, more pronounced in animals receiving trimeperidine. Combined administration of these drugs in the specifi ed dose induced less pronounced suppression of respiration and combined administration of trimeperidine and dexmedetomidine in proportion of 0.75:0.25 signifi cantly reduced the period of restoration of respiratory parameters in comparison with animals receiving single substances.

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.