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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.

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.

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.

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.

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.

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.

Women aged 18-26 characterized according to R. M. Baevskiĭ'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.

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.

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.

The action of cordiamine and pentylene tetrazole upon the tonicity of the thoracic and jugular lymph trunks and the arterial pressure was studied in acute experiments on dogs by employing perfusion with Lock's solution under constant pressure. It is shown that pentylene tetrazole forces down, as a rule, the lymph vessels tone, while cordiamine primarily brings it up.

The level of y-aminobutyric acid (GABA) was determined in the brain of rats 1 hr. after i.p. injection of chlorpromazine, prochlorperazine, diazepam, trimipramine, methamphetamine and nikethamide. Diazepam increased, and, trimipramine and amphetamine decreased the brain GABA level over wide dose ranges. Low doses of chlorpromazine and prochlorperazine increased but high doses of the drugs reduced the GABA level. Low doses of nikethamide reduced whereas high doses increased the level of GABA. The effects of the drugs have been discussed in relation to the brain GABA level.

The convulsant, 3-mercaptopropionic acid (100-1000 microM) enhanced potassium-evoked release of exogenous D-aspartate from slices of rat cerebral cortex and cerebellum, but not that from slices of hippocampus. Elevation of excitant amino acid release may contribute to the convulsant action of 3-mercaptopropionic acid. Unlike the convulsant barbiturate CHEB, 3-mercaptopropionic acid did not influence protoveratrine-stimulated release of D-aspartate and its action on potassium-evoked release appeared to be not dependent on calcium ion fluxes. Several other convulsants, including bemegride (200 microM), benzodiazepine Ro-5-3663 (100 M), nikethamide (500 microM), pentylenetetrazole (500 microM), and 4,6,6-trimethylcaprolactam (100 and 500 microM), and the glutamate decarboxylase inhibitor isoniazid (500 microM) failed to influence potassium-evoked release of D-aspartate.

A method was worked out to assess in a quantitative and dose-dependent way the development of catalepsy of mice after low doses of haloperidol. This method was also capable of detecting the anticataleptic effect of phenytoin and the catalepsy-enhancing effect of nikethamide. After 4 weeks' isolation, the mice became aggressive and revealed increased susceptibility to the cataleptic effect of haloperidol. The analysis of the data indicates that in these experiments altered central mechanisms were more important than changes of the peripheral pharmacokinetics of haloperidol.

High serum gamma-glutamyl transpeptidase activity was found in cord blood of newborn boys. This activity decreased to lower values on the 4th and 7th days. In newborns treated for 3 days following the birth with a combination of phenobarbital and nicethamide an increase of gamma-glutamyl transpeptidase activity occurred from the 4th to the 7th days. The 7th day levels were significantly higher when compared with the controls. Simultaneous determination of urinary glucaric acid excretion confirmed the induction of hepatic microsomal enzymes in glucuronic acid pathway. This could also be demonstrated by a pronounced decrease of serum bilirubin levels in groups receiving the enzyme inducers whether phenobarbital was administered intramuscularly or orally as sodium salt solution.

A study was made of the nature and specificity of the increase in biphenyl 2-hydroxylase activity after preincubation of liver microsomal preparations with various carcinogens in vitro. This enhancement of enzyme activity in vitro was investigated in mouse, hamster and rat, and although the rat appears to be atypical in the variation of the pattern of 2- and 4-hydroxylation with age, similar enhancements were detectable in each species examined. An increase in biphenyl 2-hydroxylase activity was apparent 2h after intraperitoneal administration of safrole or benzopyrene to mature Wistar albino rats and appeared to be similar in nature to that observed after preincubation of liver microsomal preparations with the same chemical in vitro. Investigation of other drug-metabolizing enzyme systems suggests that the enhancing effects of carcinogens in vitro are specific for biphenyl 2-hydroxylase. No correlation between the enhancement of biphenyl 2-hydroxylase and inhibtion of biphenyl 4-hydroxylase was apparent.

In order to understand the relationship between the cough and respiratory centers in the brain stem, we investigated the effects of respiratory stimulants, pentylenetetrazol (PTZ) and nikethamide (NK), and a respiratory depressant, pentobarbital (PB)on the cough reflex. Coughs were induced in lightly anesthetized dogs by intraarterially into the vertebral artery. The rate (RR), amplitude (RA), and volume (RV) of the respiration and the number (NC) and amplitude (AC) of the cough reflex induced were used as indices. PTZ and NK, even at subthreshold doses for respiratory stimulation, enhanced the cough reflex (NC; not AC). On the other hand, PB at subthreshold doses for a respiratory depression decreased both NC and AC. The above findings suggest that respiratory stimulants generally enhance the cough reflex, and respiratory depressants reduce the cough reflex. Additionally, the thresholds for the cough responses to respiratory drugs are lower than those for the respiratory responses.

It has been shown in experiments on male rats that administration of cordiamine per os in a dose of 73 mg/kg for 45 days provokes hepatomegaly, proliferation of smooth endoplasmic reticulum in hepatocytes, an increase in the microsomal fraction release, rise in the content of cytochrome P450 and in the rate of N-demethylation of ethylmorphine and p-hydroxylation of aniline in liver microsomes. The spectral magnitude of cytochrome P450 binding with aniline and cordiamine does not change under the effect of the latter drug, while interaction of the enzyme with ethylmorphine decreases. The rate of the recovery of the cytochrome P450-ethylmorphine complex increases 3-fold. It is assumed that an increase in the content of cytochrome and in the rate of xenobiotic hydroxylation in microsomes after prolonged administration of cordiamine might be regarded as substrate induction in nature.

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.

Injection of cordiamine (diethylamide of nicotinic acid) into rats subcutaneously in doses of 40 and 120 mg/kg for 4 days led to an increase in the activity of NADPH-oxidase, NADPH-cytochrome-c- and nitrotetrasolium reductases, as well as to an elevation of cytochrome P450 content in the liver cytoplasmic network. As regards the pattern of enzyme induction, cordiamine is classified with inductors of the phenobarbital type. However, as to the activation potency, it is noticeably inferior to phenobarbital. Electron-transport function of the enzymes of the NADH-dependent redox-chain of the organella does not show essential changes after cordiamine injection.

The paper concerns the situation in which, for a considerable time, the onset of each respiratory cycle coincides with one and the same section of a cardiac cycle. A standardized procedure is described with which, in anesthetized rabbits, the potentiality of the biological mechanisms responsible for the phenomenon may be quantified. The procedure consists of progressively prolonging the cardiac cycles by selectively cooling the sinus node. Care is taken that during such procedure a situation is passed in which the respiratory cycles are a multiple of the cardiac cycles. The synchronizing kybernetic system, if any, must click in, then. As the prolonging of the cardiac cycles continues, the synchrony will get lost the sooner the weaker the potentialities of the kybernetic system and vice versa. Four drugs are tested as to their potential action on the kybernetic system. Nikethamide and methylphenidate tend to decrease its efficacy, allobarbital and benzoctamine tend to increase it, none of them, however, being conclusively effective.

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.

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.

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.

Although clinicall undesirable, the fortuitous pharmacologic interactions between local anesthetic agents and analeptic drugs may be protective when large doses of both agents are used. Mice pretreated with procaine, lidocaine, and tetracaine had a lower incidence of seizures when convulsive doses of either nikethamide or doxapram hydrochloride were given intraperitoneally. Mortality was also decreased in the groups given nikethamide and was zero in the animals treated with doxapram. All animals treated with pentylenetetrazol convulsed and only lidocaine (also used as an anticonvulsant) was able to reduce mortality in this group. Of the local anesthetic agents, tetracaine afforded the least protection from death, whereas lidocaine seemed to be most effective.

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%.

Investigation concerning the respiratory-analeptical effect of partially cyclic and ring methylated nicethamide analogues are reported. The respiration of the rabbit determined by the mask method, served as pharmacological model.