[Role of 5-HT(2A) receptor in increase in respiratory-related rhythmic discharge activity by nikethamide in neonatal rat transverse medullary slices].

To investigate the effects of nikethamide on the generation and modulation of rhythmic respiration of neonatal rats and the role of 5-HT(2A) receptor in this course, experiments were performed on the transverse medullary slices of neonatal rats (both sexes, 1-3 d) in vitro. The slices containing the medial region of the nucleus retrofacialis (mNRF) with the hypoglossal nerve rootlets were prepared in which the respiratory-related rhythmic discharge activity (RRDA) was recorded from the hypoglossal nerve rootlets by suction electrode. The possible role of nikethamide on RRDA was investigated by administration of an agonist of 5-HT(2A) receptor, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), and an antagonist of 5-HT(2A) receptor, ketanserine, dissolved in modified Krebos solution (MKS). Thirty slices were randomly divided into five groups: Group 1: the slices were perfused with different concentrations of nikethamide (0.5, 1, 3, 5, 7, 10 µg/mL), and the most effective concentration was selected; Group 2: the slices were perfused with DOI (40 µmol/L); Group 3: the slices were perfused with ketanserine (40 µmol/L); Group 4: the slices were perfused with ketanserine + DOI; Group 5: the slices were perfused with nikethamide, then perfused with nikethamide + ketanserine after washout of nikethamide. Nikethamide increased RRDA in transverse medullary slices at 0.5-7 µg/mL, and 5 µg/mL was the most effective concentration. DOI increased RRDA with prolonged inspiratory time (TI), increased integral amplitude (IA), and shortened respiratory cycle (RC). Ketanserine decreased RRDA with shortened TI, decreased IA and prolonged RC. Ketanserine + DOI had no significant effects on RRDA. The effects of nikethamide on RC and IA were totally and partially reversed by additional application of ketanserine, but the effect of nikethamide on TI was not influenced by ketanserine. It is proposed that nikethamide increases RRDA partly via 5-HT(2A) receptors.

[GABA A receptor participates in respiratory enhancement induced by nikethamide in neonatal rats].

OBJECTIVE: To investigate the role of GABA A receptor in nikethamide-induced respiratory enhancement in the medullary slices of neonatal rats. METHODS: Ex vivo medullary slices of neonatal rats (1 to 3 days old) containing the medial region of the nucleus retrofacialis with the hypoglossal nerve rootlets were prepared and perfused with modified Kreb's solution to record respiration-related rhythmic discharge activity (RRDA) from the hypoglossal nerve rootlets using suction electrodes. Thirty RRDA-positive slices were randomized into 5 equal groups and perfused with nikethamide (at concentrations of 0.5, 1, 3, 5, 7, and 10 microg/ml with the optimal nikethamide concentration determined), GABA (at 10, 20, 40, and 60 micromol/ to determine the optimal concentration), 10 micromol/ bicuculline, 10 micromol/ bicuculline plus 40 micromol/L GABA, and 5 microg/ml nikethamide followed by 5 microg/ml nikethamide plus 10 micromol/ bicuculline after wash out, respectively. RESULTS: Nikethamide increased RRDA at the concentrations of 0.5-7 microg/ml, and 5 microg/ml nikethamide showed the most distinct effect on the inspiratory time (TI), integral amplitude (IA), and respiratory cycle (RC). GABA at 40 micromol/ showed the most effective inhibition of RRDA in terms of TI, IA, and RC. Bicuculline at 10 micromol/ could increase the IA, TI and RC, but the combination of 10 micromol/ bicuculline and 40 micromol/ GABA had no significant effects on RRDA. Compared with nikethamide used alone, nikethamide plus bicuculline significantly increased TI and IA without affecting RC. CONCLUSION: Nikethamide can enhance RRDA of the hypoglossal nerve rootlets in the medullary slices of neonatal rats, and the effect can be partially mediated by the GABA A receptor.

Aqueous N,N-diethylnicotinamide (DENA) solution as a medium for accelerated release study of paclitaxel.

N,N-Diethylnicotinamide (DENA) was identified as an excellent hydrotropic agent for paclitaxel (PTX) in our previous studies. The aqueous solubility of PTX was increased by several orders of magnitude in the presence of DENA. Because of such a high hydrotropic property, DENA was used as a release medium providing a sink condition for the release of PTX from poly(lactic-co-glycolic acid) (PLGA) matrices. The release profiles of PTX from PLGA matrices into DENA, serum and phosphate-buffered saline (PBS) were compared. The stability of PTX in DENA and the degradation of PLGA molecules in DENA were examined. The degradation rate constant of PTX in 2 M DENA was similar to those in other aqueous solutions. The use of 2 M DENA as a release medium allowed differentiation of the release profiles of PTX from PLGA matrices made of different PLGA compositions. The PTX release from PLGA matrices was much faster in DENA solution than in serum or PBS, and the concentration of DENA affected the PTX release rate. The presence of DENA in the release medium increased the hydrolysis rate of PLGA polymers. The faster release of PTX from PLGA matrices in DENA solution may be due to the high PTX solubility and faster degradation of PLGA polymers in the presence of DENA. Our study suggests that the aqueous DENA solution can be used for the accelerated release study of PTX from PLGA matrices.

EFFECT OF NIKETHAMIDE AND DIAZEPAM ON THE LEVELS OF BIOGENIC AMINES IN THE DIFFERENT PARTS OF THE POULTRY BRAIN AT THREE AGE GROUPS.

Fifty four female poultry birds of 3, 4 and 5 months age were given nikethamide and diazepam intramuscularly as stimulant and depresent, respectively. The effects of above two drugs on the levels of biogenic amines were measured Fluorometrically in the rostral, middle and caudal portions of poultry brain. Diazepam increased the levels of 5-HT and dopamine in the caudal and middle portion of the brain respectively. The levels of dopamine and non-epinephrine increased with the nikethamide administration and also with increasing age of the birds, but the effect of diazepam was inconsistant. Unlike the levels of dopamine and nor-epinephrine which were maximum in middle protion, the epinephrine concentration was highest in the caudal portion of brain. It was concluded that 5-HT acted as inhibitory particularly in the caudal portion, whereas, catecholamines as excitatory neurotransmitter of the poultry brain. The increased levels of catecholamines in the poultry brain with increasing age speaks of their positive role in sexual maturity and subsequently in reproduction of the birds.

[Pharmacokinetics and pharmacodynamics of nikethamide after endotracheal administration in dogs].

Five dogs were anaesthetized by using i.v. 30 mg.kg-1 Na-pentobarbiturate. For each dog, the tracheostomy was done and a sterized rubber tube was inserted into the tracheal tract. Through the rubber tube, 10 ml sterized nikethamide (Nik) solution was rapidly injected into the tract via 10 ml syringe and 5 forceful ventilations were performed immediately with the aid of a balloon in 30 s. Following tracheal administration (ET) of Nik 8.3 or 25 mg.kg-1 in dogs the pharmacokinetics and pharmacodynamics were studied. Blood Nik concentrations were determined by phosphorimetric method. It was shown that the absorption of Nik via tracheal tract was very quick. The blood Nik levels were 7.9 and 10.6 micrograms.ml-1 at 0.5 min and reached the maxima of 12.8 and 31.9 micrograms.ml-1, at 2.5 min, respectively, which was higher than that of i.v. Nik 8.3 mg.kg-1. Time course of Nik concentrations in plasma after ET 8.3 and 25 mg.kg-1 were fitted to a 2-compartment open model with T1/2Ka 0.48 and 0.85 min, T1/2 alpha 2.37 and 1.68 min, T 1/2 beta 114 and 130 min, AUC 1201 and 2790 micrograms.min.ml-1, bioavailability 84.7% and 65.5%, respectively. One minute after i.v. or ET Nik (8.3 or 25 mg.kg-1), respiration rate and tidal volume were increased and reached the maxima after 5 min. The recovery of respiration rate and tidal volume were proportional to the blood Nik concentration after 5-45 min with a linear regression coefficient of 0.9. The results indicated that ET Nik may be used instead of i.v. in resuscitation.

[Effect of long-term administration of undevit and its combination with cordiamine on hydroxylation, glucuronidation and glutathione conjugation systems and lipid peroxidation in rat liver]. / Vliianie dlitelnogo vvedeniia undevita i ego kombinatsii s kordiaminomna gidroksiliruiushchuiu, gliukuro-, glutationkoníugiruiushchuiu sistemy i perekisnoe okislenie lipidov pecheni intaktnykh krys.

Increase of N-demethylase and antioxidant activities and decrease of amount of hydroperoxides were observed in liver of rats after intragastric administration of Undevit (1/8 dragee/rats/day, 5 times a week during 2 months). Combination of Undevit with Cordiamin (5 mg/rat/day) resulted in augmentation of cytochromes P-450 and b5 content and activities of their reductases, velocity of amidopyrine and ethylmorphine N-demethylation and oxidation of HADPH. Activities of UDP-glucuronyltransferase, glutathionetransferase and hydrophobity of microsomal membranes were also increased. Antioxidant activity was increased and amount of hydroperoxides in liver microsomes and homogenates and in plasma was decreased in greater degree after administration of combination two compounds than after administration of Undevit alone.

[The perception of an odogen is proportional to the activity of the autonomous nervous system in man]. / Pertseptsiia odogena proportsional'na aktivnosti avtonomnoi nervnoi sistemy u cheloveka.

Women aged 18-26 characterized according to R. M. Baevskii's cardiointervalometric criteria by the balance between sympathetic and parasympathetic activities ("normotonicity") participated in the experiments. Sniffing subthreshold concentrations of cordiamin solution vapour during 7-9 s was revealed to increase activity of the sympathetic nervous system and heart rate frequency with a decrease of its variability. Normotonic subjects with predominance of the parasympathetic activity were found to have lower thresholds of the odogen detection and to be more cardioreactive to the subthreshold odogen than the "normotonics" with slight predominance of the sympathetic activity.

[A comparative study of the effects of nicotinamide and diethylnicotinamid on hepatic monooxygenase, glucuronyl and glutathione conjugating systems]. / Sravnitel'noe izuchenie vliianiia nikotinamida i diétilnikotinamida na monooksigenaznuiu, gliukuronil- i glutationkon"iugiruiushchuiu sistemy pecheni.

The nicotinamide administration to rats (50 mg/kg, subcutaneously, over 5 days) increased the concentration of liver cytochrome b5, the activities of cytosol and microsomal glutathione S-transferase, UDP-glucuronosyltransferase and urinary excretion of bound glucuronic acid by 26.7, 33.1, 33.3, 53.0 and 31.0%, respectively. The chloral hydrate-induced sleep time in mice was reduced by 65%. Under similar experimental conditions the administration of equimolar amounts of diethylamide of nicotinic acid (75 mg/kg) exerted a more pronounced enzyme-stimulating effect. The cytochrome P-450 concentration, the activities of cytosol and microsomal glutathione S-transferase, UDP-glucuronosyltransferase as well as the sulphobromophthalein elimination from blood plasma and urinary excretion of bound glucuronic acid were increased by 37.0, 33.1, 54.6, 80.5, 24.5 and 49.0%, whereas the chloral hydrate-induced sleep time decreased by 75%. The nicotinamide and diethylamide of nicotinic acid stimulating effects on xenobiotic biotransformation in rat liver are assumed to be due to enhanced NADPH, glutathione and UDP-glucuronic acid biosynthesis as well as their antioxidant properties.

[The effect of diethylnicotinamide (cordiamine) on the activity of the hydroxylating and glucuronyl-conjugating systems in humans]. / Vliianie diétilnikotinamida (kordiamina) na aktivnost' gidroksiliruiushchei i gliukuronilkon''iugiruiushchei sistem u liudei.

Administration of diethylnicotinamide (250 mg orally three times for 8 days) to healthy subjects increased antipyrine (AP) elimination from the saliva by 23% and decreased its half-life by 26%. The excretion in the urine of the products of AP hydroxylation 3-carboxymethylantipyrine and nor-antipyrine as well as glucuronides 3-hydroxymethylantipyrine increased. A positive correlation between the dynamics of the excretion of antipyrine metabolites and glucuronic acid was observed. The elimination from blood of bilirubin glucuronides increased. Diethylnicotinamide in therapeutic doses is supposed to stimulate the processes of hydroxylation and glucuronyl conjugation in humans.

[Effect of the diethylamide of nicotinic acid (cordiamine) on the hydroxylating function of the liver]. / K voprosu o vliianii diétilamida nikotinovoi kisloty (kordiamina) na gidroksiliruiushchuiu funktsiiu pecheni.

Diethylamide of nicotinic acid (subcutaneously, 40 and 120 mg/kg, once a day for 4 days) was shown to exert no influence on p-hydroxylation of aniline and to increase the rate of N-demethylation of amidopyrine and ethylmorphine in the rat liver microsomal fraction by 21 and 47% as compared with the control. At the same dose of 40 mg/kg and the same schedule of administration the drug was found to increase urine excretion of antipyrine metabolites: nor-antipyrine, 4-hydroxy-antipyrine and the sum of metabolites by 229, 89 and 80%, respectively, during the first 90 min of the experiment. Excretion of antipyrine, 3-hydroxymethyl-antipyrine and 3-carboxymethyl-antipyrine underwent no significant changes. The duration of hexobarbital-induced sleep of the rats was shown to be decreased by 26%.

Potentiation of cathinone by caffeine and nikethamide.

The drug discrimination paradigm was employed to evaluate the effect of coadministration of both caffeine and nikethamide upon the discrimination of a low dose of cathinone. In rats trained to discriminate between 0.8 mg/kg l-cathinone and its vehicle in a two-lever food-motivated operant task, 0.2 mg/kg cathinone produced 29.2% of responses on the cathinone-appropriate lever. This lever was chosen in 0 and 50% of trials with 25 mg/kg nikethamide and 20 mg/kg caffeine, respectively. Coadministration of caffeine, nikethamide, or caffeine plus nikethamide with low-dose cathinone produced strong cathinone-like discriminative performance. This potentiattion of cathinone by caffeine and nikethamide is reflective of noncontrolled drugs of abuse containing similar combinations especially for that of antiadipositum X-112, a drug containing all three agents and widely abused in Europe.

[Antisoporific and cardiotropic properties of new amino acid derivatives of nicotinic acid]. / Antisnotvornye o kardiotropnye svoistva nekotorykh novykh aminokislotnykh proizvodnykh nikotinovoi kisloty.

On the models of urethane, nembutal and ethyl alcohol sleep it was shown that nicotinoylcapronate, nicotinoylserine and nicotinoylvaline possess antihypnotic properties being superior to those of cordiamine and on some models phenamine. Nicotinoylvaline and nicotinoylalanine normalized the myocardial contraction in animals with experimental ischemia.

[Interaction in vitro of nicotinamide and diethylnicotinamid (cordiamine) with enzymes of the liver microsomal hydoxylating system in the rat]. / Vzaimodeistvie in vitro nikotinamida i diétilnikotinamida (kordiamina) s fermentami gidroksiliruiushchei sistemy mikrosom pecheni krys.

Addition of nicotinamide and diethylnicotinamide (cordiamine) to rat liver microsomes leads to the formation of an enzyme-substrate Type II complex with cytochrome P-450. Diethylnicotinamide exceeded nicotinamide approximately 2-fold as regards the degree of the affinity to the enzyme. The ability of nicotinamide and diethylnicotinamide to interact with cytochrome P-450 underlies their antagonism with respect to in-vitro metabolism of the substrates of both Type I (amidopyrine) and Type II (aniline) as well as with respect to the competition with CO for the common center of binding on the enzyme.

The effect of solvent polarity upon rotational barriers in nikethamide.

In summary, dynamic nuclear magnetic resonance techniques were used to study the hindered internal rotation of the amide bond of the analeptic nikethamide. The rotatory motion of this bond was studied in a series of solvents of increasing polarity: CDCl3, CH3(CH2)3OD, CH3CH2OD, CH3OD and D2O. Motion about the amide bond was increasingly hindered in direct proportion to solvent polarity, correlating with enhanced hydrogen bond formation between nikethamide and the more polar solvent molecules. Diethylamide group motion would be expected to affect binding of the carbonyl oxygen to cholinergic receptor sites. The degree to which association to a receptor site can be affected by this rotatory motion may vary from 0 to 4 kcal/mole, the variability being entirely dependent upon the polarity of the binding site. An increase in rotamer lifetime, corresponding to a more polar environment, would be expected to enhance the kinetics of nikethamide association to the receptor site.