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Pharmacokinetics and Pharmacodynamics

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No 1 (2022)
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MODE OF ACTION

3-8 322
Abstract

   The effect of memantine (1 and 10 mg/kg/day), ladasten (50 mg/kg/day) and cyclantane (10 mg/kg/day) on the behavior of CD-1 mice differing in the phenotype of attention stability in the "closed enriched cross maze" test after three days of intraperitoneal administration was studied. It was found that in a subpopulation of mice with an initial attention deficit, these aminoadamantane derivatives partially restored the level of attention. The drugs equally worsened attention in a subpopulation with an initially high attention index by 40–47 % relative to the control, which indicates the absence of selectivity of the effect of these drugs with respect to attention deficit. However, this effect was not accompanied by a change in exploratory and locomotor activity, which makes it possible to make an assumption about the prospects for further study of the pharmacological effects of adamantane derivatives and optimization of their dose and duration of administration.

9-13 451
Abstract

   Background. The dipeptide drug Noopept, created at the Zakusov Institute of Pharmacology, has a wide range of pharmacological actions, including cytoprotective one. In connection with the increasing pollution of the environment, it is urgent to identify the protective properties of drugs with a negative effect of heavy metal compounds on the live system.

   The aim of the present study was to investigate the cytoprotective effects of Noopept under toxicity induced by heavy metal compounds using ciliates Paramecium caudatum as a test object.

   Methods. The ciliates Paramecium caudatum were exposed to 4 salts of heavy metals: cadmium chloride, lead acetate, copper sulfate, zinc sulfate, as well as nanoparticles of copper oxide and zinc oxide. Noopept was added to the medium with the experimental cells 30 min before the introduction of damaging agents, at concentrations of 0.01–10 μM. Results. It was found that the presence of metal salts in the medium significantly reduced the number Paramecium сaudatum cells, depending on the time of exposure. Noopept at all studied concentrations reduced cell death, while the maximum intensity of the effect was observed at a concentration of 1 μM.

   Conclusions. The results obtained make it possible to supplement data on the wide spectrum of Noopept's action.

PRECLINICAL PHARMACODYNAMICS STUDIES

14-19 3052
Abstract

   In rats with carrageenan-induced paw edema, diclofenac sodium significantly reduces exudation after ten-day preventive oral administration at a dose of 10 mg/kg but not 5 mg/kg. Mexidol at a dose of 100 mg/kg in combination with diclofenac sodium at a dose of 5 mg/kg (preventively orally, during 10 days, once a day) reduces paw edema during the first two out of four hours of its recording compared with the control group. However, ten-day preventive oral administration of mexidol at a dose of 100 mg/kg (once a day) increases the severity of carrageenan-induced paw edema in rats at four hours after the injection of the phlogogen.

20-29 358
Abstract

   Сomorbidity of malignant tumors and affective disorders is an urgent problem. It is known that some psychotropic drugs may adversely influence the growth of malignant tumors and metastasis; in the experiment, a connection between neurotransmitters and tumors was established. Earlier, in experiments on mice, the ability of diazepam to stimulate the growth of Ehrlich's ascites carcinoma was demonstrated.

   The aim of this study was to assess the role of central and peripheral benzodiazepine receptor sites in the stimulating effect of diazepam on Ehrlich's carcinoma. The effects of diazepam (0.03 and 3.0 mg / kg, intragastric) on the development of Ehrlich's ascites carcinoma and an orientation-exploratory response in the "open field" test on male SHK mice were studied. It was found that diazepam at a dose of 0.03 mg / kg, but not at a dose of 3 mg / kg, increases the cellularity of the malignant ascites. At the same time, diazepam in both doses studied causes an increase in the peripheral motor activity of mice, which indicates an increase in anxiety reactions. It was found that flumazenil, but not PK11195, attenuates the stimulating effect of diazepam on Ehrlich's ascites carcinoma and inhibits the pro-anxiogenic effect of a small dose of diazepam. The results obtained allow us to conclude that there is no associative relationship between the pro-tumor effect of diazepam and its effect on anxiety responses, but at the same time, the participation of central mechanisms in the stimulating effect of benzodiazepine on the tumor cannot be ruled out.

30-35 859
Abstract

   Background. The endogenous opioid system is involved in neuroadaptation produced by exogenous opioids. Synthesized on the basis of the regulatory peptide tuftsin, the anxiolytic selank inhibits the activity of enkephalin-degrading enzymes, increasing the level of leu-enkephalins in blood plasma.
   The aim of the work was to evaluate the effect of selank (0,3 and 0,9 mg/kg, i. p.) on morphine-induced analgesia in animal models. Methods. The experiments were performed in inbred male mice C57Bl/6 (n = 77). The “hot plate” test was used to evaluate the analgesic effect during thermal stimulation of nociceptors when mice were placed on a metal plate heated to 55 ± 0,5 °C, followed by registration of the latent period of the reaction 30, 60, 90, and 120 minutes after the administration of morphine.

   Results. Morphine at a dose of 3,0 mg/kg, i. p., caused antinociception with the maximum possible effect (MBE) of 9 %, selank at a dose of 0,9 mg/kg, without antinociception per se, when pretreated with the morphine, increased the latent reaction time, causing antinociception of 29,9 % MBE.

   Conclusion. For the first time the data obtained on the synergistic effect of selank and morphine in attenuation of acute somatic pain.

36-43 551
Abstract

   Background. A dimeric dipeptide mimetic of the brain-derived neurotrophic factor loop 4, bis(N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide (GSB-106), which activates TrkB, PI3K/AKT, MAPK/ERK and PLC-γ1 was created at the V. V. Zakusov Research Institute of Pharmacology. GSB-106 showed neuroprotective activity in vitro and in vivo at systemic administration.

   Objective. In the present study, we studied the effect of GSB-106 on the brain infarct volume, as well as on neurogenesis and synaptogenesis under conditions of experimental ischemic stroke induced by transient occlusion of the middle cerebral artery in rats, when it was first administered 24 h after ischemia onset.

   Methods. Dipeptide GSB-106 was administered i.p. in a dose of 0.1 mg/kg 24 h after surgery and then once a day, with the end of administration on theday 6 after surgery. On the day 7 brain samples were collected for morphometric and biochemical (Western-blot) analysis.

   Results. It was established that GSB-106 reduced the brain damage volume by 24%, restores impaired neurogenesis and/or gliogenesis (by Ki-67) in the hippocampus and in the striatum and completely restored the reduced immunoreactivity to synaptic markers synaptophysin and PSD-95 in the striatum.

   Conclusions. Thus, the dimeric dipeptide BDNF mimetic GSB-106 exhibits neuroregenerative properties at clinically relevant time window (24 h) in a model of ischemic stroke presumably due to stimulation of neurogenesis (and / or gliogenesis) and synaptogenesis.

PHARMACOKINETIC RESEARCHES

44-54 445
Abstract

   Drug development requires high-tech, simple, and sensitive methods. AlphaLISA method was announced as a universal method that would fit the listed criteria. However, research of other works on the pharmacokinetics of drugs related to this method showed a small number of pharmacokinetic studies in clinical trials. In this review, we focused on not only the positive aspects of the Alpha method, but also its disadvantages.

55-60 436
Abstract

  Review. Further development of the methodological level of the decision support system proposed for the organization of primary selection and experimental preclinical study of new drugs. Methods for describing and interpreting the main pharmacokinetic experiment (single intravenous administration of drugs) data are systematized. A scheme for choosing pharmacokinetic models based on visual pattern recognition is proposed. Visual data patterns allow prediction of pharmacokinetic behavior and properties of new drugs.

BIOEQUIVALENCE STUDIES

61-74 1982
Abstract

   Introduction. The advantages of fixed-dose combination losartan + amlodipine + rosuvastatin compared to mono-drugs and two-component combinations are to increase the therapeutic efficacy, to reduce the cost of the product and to make the drug easier to take which helps to improve patient adherence to therapy. A bioequivalence study of the three-component fixed-dose combinations Losartan + amlodipine + rosuvastatin Sanofi with coadministered Lozap® AM (Losartan+Amlodipine) and Crestor® (Rosuvastatin) was conducted.

   Aim. The purpose of the bioequivalence trial was a comparative study of the pharmacokinetics and evidence of the bioequivalence of two strengths of fixed-dose combination: 1) Losartan + amlodipine + rosuvastatin Sanofi (tablets, 50 mg + 5 mg + 10 mg) in comparison with coadministrated drugs Lozap® AM (losartan + amlodipine, tablets, 50 mg + 5 mg,) and Crestor® (rosuvastatin, tablets, 10 mg) in fasting healthy volunteers after a single administration; 2) Losartan + amlodipine + rosuvastatin Sanofi (tablets, 100 mg + 5 mg + 20 mg) in comparison with coadministrated drugs Lozap® AM (losartan + amlodipine, tablets, 100 mg + 5 mg) and Crestor® (rosuvastatin, tablets, 20 mg) in fasting healthy volunteers 18–45 years old after a single dose.

   Materials and methods. To prove bioequivalence, an open label, comparative, randomized, crossover four-period clinical trial was conducted for each strengths of fixed-dose combination. The concentrations of losartan, amlodipine and rosuvastatin in blood plasma samples obtained from volunteers were determined by a validated HPLC-MS/MS method. A pharmacokinetic and statistical analysis was performed and confidence intervals (CI) for the pharmacokinetic parameters Сmax, AUC0-72 (for amlodipine) and AUC0-t (for losartan and rosuvastatin) were calculated.   
   Results and discussion. Based on the results of statistical and pharmacokinetic analysis, it was shown that the studied formulations are bioequivalent in terms of pharmacokinetic parameters of losartan, amlodipine and rosuvastatin. 90 % CI were in the acceptable range for Сmax (of amlodipine), AUC0-72 (of amlodipine) and AUC0-t (of losartan and rosuvastatin). 90 % CI for Сmax of losartan and rosuvastatin were in the acceptable extended calculated range according to the protocol.

   Conclusion. Thus, according to the criteria used in the studies, the three-component fixed-dose combinations Losartan + amlodipine + rosuvastatin Sanofi are proved to be bioequivalent in comparison with coadministered Lozap® AM and Crestor®.



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ISSN 2587-7836 (Print)
ISSN 2686-8830 (Online)