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Carbon-13 nuclear magnetic resonance techniques were employed to examine the effects of solvent environment on rotational barriers in a series of molecules structurally-related to the analeptic, nikethamide: N,N-dimethylnicotinamide, N,N-di-n-propylnicotinamide, and 1-nicotinoyl piperidine. Total bandshape analysis was performed for the exchanging alkyl carbon resonances of these compounds as a function of temperature in four solvent systems: D2O, CH3OD, CH3CH2OD and CDCl3. The rate constants for rotation about the amide bond obtained in this way were used to calculate free energy (delta G), enthalpy (delta H) and entropy (delta S) of activation parameters for this process. Our results indicate that rotational barriers are less affected by the nature of the alkyl chain attached to the amide nitrogen than by the size and polarity of the solvent molecules. Interpretation of the thermodynamic parameters in light of both nikethamide analogue structure and solvent type has further clarified the manner in which hydrogen bonding interactions between solvent molecules and the carbonyl oxygen of these analogues stabilize transition state conformers.
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.
1. In the neuronally isolated cortex of the cat, local application of bemegride, picrotoxin, nikethamide, caffeine and strychnine facilitated the surface positive response of the isolated cortex and lowered the stimulus threshold for this response. Excepting nikethamide, they all produced convulsive discharge in the isolated cortex unrelated to the applied stimulus.2. Local application of glutamate to the cortex produced spreading depression, which was sometimes preceded by spontaneous positive bursting.3. In contrast to the "general depressants" which produce a relatively consistent pattern of effects on the electrical responses of isolated cortex, the "general stimulants", although they all have excitatory effects on isolated cortex, each produced a greatly different type of electrical response in the isolated cortex, suggesting that several different mechanisms of action are responsible for their effects.
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.
Sixty-seven babies were utilized to (a) document the serum bilirubin lowering effect and safety of a phenobarbitone and nikethamide combination in neonatal hyperbilirubinaemia of non-hemolytic origin; (b) determine whether birthweight and/or SGOT, SGPT or SGGT activity on day one of life correlated with the maximum serum bilirubin level achieved; and (c) investigate the pattern of hepatic enzyme levels in serum under normal conditions anf following drug induction. Results indicate a significantly lower serum bilirubin level in the treated group of babies. Birthweight and day one SGGT levels, and SGGT/birthweight ratio correlated well with the maximum serum bilirubin reached, the latter ratio being particularly useful in predicting the degree of hyperbilirubinaemia.
Rats treated with phenobarbitone, phenaglycodol, glutethimide, nikethamide, meprobamate, chlorbutol and chlorpromazine showed an increased metabolism of pentobarbitone and, at the same time, a diminished sleeping-time after pentobarbitone. This effect developed 24 hr after treatment, the maximum increase in metabolism occurring after about 48 hr. The increased pentobarbitone metabolism was inhibited by ethionine injected shortly before treatment. Using a liver slice preparation, increased pentobarbitone metabolism was also observed in vitro. These results are in accord with the view that the capacity of compounds to increase pentobarbitone metabolism may be related to their ability to act directly on microsomal enzyme systems.
1. The effects of central stimulant drugs injected intraperitoneally were examined on the release of acetylcholine (ACh) from the cerebral cortex of the anaesthetized rat. The effects of the drugs in increasing ACh release were approximately parallel to the increases produced in the electrical activity of the brain.2. Leptazol in a dose of 150 mg/kg increased the release of ACh by 2.9 times the resting release and in a dose of 300 mg/kg by 7.5 times; on the e.e.g. the injection produced a large increase in the electrical activity.3. Picrotoxin in a dose of 12 mg/kg increased the release of ACh by 7.5 times and on the e.e.g. caused a large increase in activity.4. Strychnine in doses of 8 mg/kg and 12 mg/kg increased the release of ACh by 2.0 and 2.4 times and produced a small increase in the activity of the e.e.g.5. Dexamphetamine in a dose of 100 mg/kg increased the release of ACh by 1.9 times and had no appreciable effect on the e.e.g.6. Nikethamide in a dose of 2 g/kg increased the release of ACh by 2.3 times and produced no appreciable change in the e.e.g.7. Caffeine in a dose of 100 mg/kg produced no significant effect on the release of ACh.