[Venotropic (phlebotropic) agents]. / Venotropnye (flebotropnye) sredstva.

Data on pharmacodynamics and clinical use of venodilators, venoconstrictors and venoprotectors are discussed.

[Drug delivery to the brain with nanoparticles]. / Dostavka lekarstvennykh preparatov v mozg s pomoshch'iu nanochastits.

Drugs can be delivered to brain with the aid of poly(butylcyanoacrylate) (PBCA) nanoparticles coated with polysorbate 80. These carriers can penetrate BBB and deliver drugs of various structures, including peptides, hydrophilic compounds, and lipophilic compounds eliminated from brain with P-glycoprotein. When a suspension of polysorbate-coated PBCA nanoparticles is introduced into blood, apolipoproteins of the blood plasma adsorb on the particle surface and then interact with receptors of low-density lipoproteins situated in endothelial cells of cerebral vessels, thus stimulating endocytosis.

Pharmacological regulation of descending cortical control of the nociceptive processing.

Clinical and experimental data indicate that the cerebral cortex plays an important role in pain perception and endogenous antinociceptive system function. Moreover, the enhancement of descending inhibitory cortical control may be involved in the mechanisms of analgetic effect of some agents. The present study was designed to investigate the effect of cortical electrical stimulation (as a model of descending inhibitory control) on the behavioral and electrophysiological signs of nociceptive response, decipher the mechanisms involved therein and evaluate the action of central analgesics (both opioid and non-opioid) on descending cortical control. In acute experiments in cats the inhibitory cortical influence on neuronal activity produced by nociceptive stimuli (electrical stimulation of tooth pulp, C-fibers of afferent somatic nerves, afferent cardiac structures) was most marked after stimulation of the first and second sensory and fronto-orbital areas. In chronic experiments on rats cortical stimulation reduced behavioral signs of visceral pain (writhing test) and also delayed the development of neuropathic pain syndrome along with lowering its intensity. Mu-opioid receptor agonists (morphine, fentanyl) potentiated the inhibitory cortical effect on the evoked neuronal activity. Pentazocine, which has pronounced kappa-receptor agonistic activity, was less effective. Naloxone eliminated the effects of both cortical stimulation and opioid analgesics. Serotonin receptor antagonist methysergide as well as p-chlorophenylalanine significantly decreased inhibitory cortical control and opioids effect. Monoamine re-uptake inhibitors with analgetic properties (imipramine, fluoxetine) potentiated the inhibitory effect of cortical stimulation. Adrenoceptor, dopamine, acetylcholine, GABA-receptor agents and antagonists of NMDA receptors had minor or no effect. Among non-narcotic analgesics, inhibitors of cyclooxygenase, metamysole and ketorolak increased only moderately the descending cortical control of nociception. Thus, the cerebral cortex is able to control the nociceptive processing in different pain syndromes (somatic, visceral or neuropathic pain). Opioidergic and serotonergic systems play the key role in this control. The effect over the cortical descending control is likely to be one of the components of the analgetic effect exerted by opioids and some other central analgesics.

[The delivery of loperamide to the brain by using polybutyl cyanoacrylate nanoparticles]. / Dostavka loperamida v mozg s pomoshch'iu polibutiltsianoarilatnykh nanochastits.

The possibility of using polysorbate 80-coated nanoparticles for the delivery of the water insoluble opioid (lyonist loperamide across the blood-brain barrier was investigated. The analgesic effect after i.v. injection of the preparations was used as the indication of drug transport through this barrier. Intravenous injection of the particulate formulation resulted in a long and significant analgesic effect. A polysorbate 80 loperamide solution induced a much less pronounced and very short analgesia. Uncoated nanoparticles loaded with loperamide were unable to produce analgesia. Polysorbate 80-coated PBCA nanoparticles loaded with loperamide led to the transport of loperamide to the brain.

Significant entry of tubocurarine into the brain of rats by adsorption to polysorbate 80-coated polybutylcyanoacrylate nanoparticles: an in situ brain perfusion study.

The possibility of using polysorbate 80-coated polybutylcyanoacrylate nanoparticles to deliver low molecular polar hydrophilic drugs to the CNS has been studied. Tubocurarine (a quaternary ammonium salt) does not penetrate the normal intact blood-brain barrier. However, the injection of this drug directly into the cerebral ventricles of the brain provokes the development of epileptiform seizures as assessed by electroencephalogram (EEG). An in situ perfused rat brain technique was used as an experimental technique together with a simultaneous recording of the EEG. Nanoparticles were prepared by butylcyanoacrylate polymerization in an acidic medium. Fifteen minutes after the introduction of tubocurarine-loaded polysorbate 80-coated nanoparticles into the perfusate, epileptiform spikes in the EEG appeared. Intraventricular injection of tubocurarine caused the appearance of the EEG seizures 5 min after administration. Neither tubocurarine solution nor tubocurarine-loaded nanoparticles without polysorbate 80 or a mixture of polysorbate 80 and tubocurarine were able to influence the EEG. Thus only the loading of tubocurarine onto the polysorbate 80-coated nanoparticles appears to enable the transport of this quaternary ammonium compound through the blood-brain barrier.

[The descending cortical control of nociceptive signals: the neurochemical mechanisms and pharmacological control]. / Niskhodiashchii kortikal'nyi kontrol' notsitseptivnykh signalov: neirokhimicheskie mekhanizmy, farmakologicheskaia reguliatsiia.

The purpose of the present study was to determine whether electrical cortical stimulation (as a model of descending inhibitory control) could alter the electrophysiological and behavioral signs of a nociceptive response. The inhibitory cortical influence on the neuronal activity produced by nociceptive stimuli (the tooth pulp, C-fibers of afferent somatic nerves, cardiac afferents) was most marked during electrical stimulation the somatosensory (Sn and St) and fronto-orbital cortices. In chronic experiments, somatosensory cortical stimulation delayed the development of the deafferentation pain syndrome and reduced its intensity. The opioid mu-receptor agonists morphine and fentanyl potentiated the inhibitory action of the cortex on evoked neuronal activity. Pentazocine, a kappa-receptor agonist, was less effective. The opioid receptor blocker naloxone eliminated the effect of both cortical stimulation and opioid analgesics. The serotonin receptor blocker methisergide significantly decreased cortical action. Monoamine reuptake inhibitors (amitriptyline, imipramine, fluoxetine) potentiated the effect of cortical stimulation. Adrenergic, dopaminergic cholinergic, and GABA-ergic substances had a little effect. Among nonopioid analgesics, metamyzol and ketorolak only increased moderately descending cortical control.

Delivery of loperamide across the blood-brain barrier with polysorbate 80-coated polybutylcyanoacrylate nanoparticles.

PURPOSE: The possibility of using polysorbate 80-coated nanoparticles for the delivery of the water insoluble opioid agonist loperamide across the blood-brain barrier was investigated. The analgesic effect after i.v. injection of the preparations was used to indicate drug transport through this barrier. METHODS: Loperamide was incorporated into PBCA nanoparticles. Drug-containing nanoparticles were coated with polysorbate 80 and injected intravenously into mice. Analgesia was then measured by the tail-flick test. RESULTS: Intravenous injection of the particulate formulation resulted in a long and significant analgesic effect. A polysorbate 80 loperamide solution induced a much less pronounced and very short analgesia. Uncoated nanoparticles loaded with loperamide were unable to produce analgesia. CONCLUSIONS: Polysorbate 80-coated PBCA nanoparticles loaded with loperamide enabled the transport of loperamide to the brain.

[Transport of the hexapeptide dalargin across the hemato-encephalic barrier into the brain using polymer nanoparticles]. / Transport geksapeptida dalargina cherez gematoéntsefalicheskii bar'er v mozg s pomoshch'iu polimernykh nanochastits.

The drug targeting to the brain by polysorbate 80-coated nanoparticles was studied. The leu-enkephalin analog dalargin was used as a model drug for investigating the drug penetration through the blood-brain barrier. The nociceptive threshold was measured by the tail flick test. The intravenous injection of dalargin bound by sorption to poly(butylcyanoacrylate) nanoparticles subsequently coated with polysorbate 80 induced the analgesic effect in 5.0 and 7.5 mg/kg doses. The pretreatment with naloxone prevented this effect No other controls exhibited the analgesic activity, including the dalargin solution (10 mg/kg, i.v.), dalargin bound to nanoparticles not coated with polysorbate 80; and a simple mixture of dalargin, nanoparticles, and polysorbate 80 mixed directly before the intravenous injection. The luminescent and electron microscopy demonstrated the presence of separate nanoparticles in the capillary endothelium and cerebral neurons, as well as luminescent-labeled polymer in Purkinje's cells of the cerebellum.

Passage of peptides through the blood-brain barrier with colloidal polymer particles (nanoparticles).

Transport of the hexapeptide dalargin across the blood-brain barrier was accomplished using a nanoparticle formulation. The formulation consisted of dalargin bound to poly(butyl cyanoacrylate) nanoparticles by sorption, coated with polysorbate 80. Intravenous injection of this formulation to mice resulted in an analgesic effect. All controls, including a simple mixture of the three components (drugs, nanoparticles, and surfactant) mixed directly before i.v. injection, exhibited no effect. Analgesia was also prevented by pretreatment with naloxone. Fluorescent and electron microscopic studies indicated that the passage of the particle-bound drug occurred by phagocytic uptake of the polysorbate 80-coated nanoparticles by the brain blood vessel endothelial cells.

Opioid ligands with extraordinarily high mu-selectivity: dermorphin tetrapeptides containing thymine-modified alanine residues.

Four new [D-MetO2]dermorphin tetrapeptides with substituted N- and C-terminal groups and a thymine-modified alanine residue at position 4 were prepared and tested for their activity. All analogues were found to be mu-opioid receptor ligands. Two of them, H-Tyr-D-MetO-Phe-TalNHR (R = H, Ad) displayed an extremely high mu-opioid receptor selectivity comparable with that of the most mu-selective agonists among opioid peptides.

Stimulant effect of thyrotropin-releasing hormone and its analog, RGH 2202, on the diaphragm respiratory activity, and their antagonism with morphine: possible involvement of the N-methyl-D-aspartate receptors.

Thyrotropin-releasing hormone (TRH) was reported to stimulate respiration and abolish the respiratory depressant effect of morphine-like analgesics. Some TRH analogs which have a diminished hormonal activity may be of interest as potential non-specific opioid antagonists. The mechanism of this effect of TRH and its analogs is still unclear. Thus, in the present work the respiratory stimulant effect of TRH and its analog RGH 2202 was studied in the urethane-anesthetized vagotomized artificially-ventilated rats. The integrated diaphragmatic electromyogram was used to evaluate the effects of the drugs. TRH and RGH 2202 administered either i.v. or directly onto the dorsal medullary surface significantly increased the respiratory activity of the diaphragm. TRH and RGH 2202 also effectively antagonized the diaphragm activity depression caused by morphine. The latency, time course and activity of RGH 2202 turned out to be close to those of TRH. The possible involvement of N-methyl-D-aspartate (NMDA) receptors in the mechanism of action of TRH and RGH 2202 was also investigated. It was shown that the non-competitive NMDA antagonists ketamine and MK-801 and the competitive antagonist D-amino-5-phosphonovalerate after local or i.v. administration prevented or discontinued the diaphragm activity stimulation by TRH and RGH 2202. Moreover, they blocked the antagonistic action of TRH and RGH 2202 on the morphine-induced diaphragm activity depression. Thus, we conclude, that TRH and RGH 2202 cause similar stimulant effects on the respiratory activity of the diaphragm and effectively antagonize its depression by morphine. These effects are likely to be mediated by the NMDA receptors located in the central respiratory structures.

Antinociceptive activity of muscarinomimetic agents.

The effect of the agents with muscarinomimetic activity on the nociceptive transmission in the spinal cord was studied in spinal rats. Oxotremorine (5-20 micrograms/kg, i.v.), arecoline (0.25-1.0 mg/kg, i.v.), pilocarpine (5-20 mg/kg, i.v.) and aceclidine (0.25-1.0 mg/kg, i.v.) inhibited the nociceptive flexor reflex induced by intraarterial injection of bradykinin. Muscarinomimetics in the same doses and anticholinesterase agents physostigmine (1-4 micrograms, intrathecally) and galanthamine (25-100 micrograms, intrathecally) inhibited bradykinin-induced bioelectric activity in the spinal ventrolateral tracts. Atropine (1 mg/kg, i.v.) abolished the inhibitory effect of the agents tested on the nociceptive flexor reflex and bioelectric activity.

Employment of magnet-susceptible microparticles for the targeting of drugs.

It has been demonstrated in cats that magnet-susceptible microspheres and liposomes containing neuromuscular blocking agents (dipyronium, pyrocurinum and diadonium) caused a deeper inhibition of the neuromuscular transmission in the limb placed in the magnetic field than in the control limb located beyond the field. The microparticles containing a short-acting neuromuscular blocking agent diadonium appeared to have the highest selectivity of action. The present method allows a pronounced neuromuscular block in a target area to be achieved without noticeable effect on PCO2 of the exhaled air.

[Relation of the structure, rate of hydrolysis and activity of dicarboxylic acid esters]. / O zavisimosti mezhdu stroeniem, skorost'iu gidroliza i aktivnost'iu éfirov dikarbonovykh kislot.

The kinetics of enzymatic cholinesterase hydrolysis of dicarboxylic acid esters with neuromuscular blocking activity was studied in vitro. The maximum hydrolysis rate was shown to increase on elongation of the distance between ester groups both in the compounds containing a hydrophobic adamantyl radical attached to quaternary nitrogen and in bis-esters not containing adamantyl radicals. The comparison of neuromuscular blocking activity in vivo, enzymatic hydrolysis rates and activity on isolated skeletal muscle of some compounds demonstrated that in vivo activity is in a higher correlation with the maximum hydrolysis rate of the compounds that with activity in isolated skeletal muscle before or after cholinesterase inhibition.

[Study of magnet-controlled transport of curare-like preparations of diadonium and dipyronium in animal experiments]. / Izuchenie magnitoupravliaemogo transporta kurarepodobnykh preparatov diadoniia i dipironiia v éksperimentakh na zhivotnykh.

The experiments on cats have shown that liposomes containing ferrocolloid and neuromuscular blocking agents (diadonium or dipyronium) cause selective muscle relaxation in the animal limb placed into the magnetic field, compared to the control limb kept outside the field. This effect was not related to the action of the magnetic field per se on neuromuscular transmission or the potency of neuromuscular blocking agents not contained in liposomes, but was induced by the accumulation of magnet-controlled liposomes in the target limb. The use of magnet-controlled liposomes for diadonium and dipyronium transport to one of the animal limbs decreases their unfavourable effect on respiratory muscle function.