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PubMed1977

Toxic interactions of stimulants, narcotics and narcotic antagonists.

This study examines the lethality of combinations of central nervous system stimulants, narcotics and narcotic antagonists in rodents housed individually. The lethality of mice and rats from d-amphetamine was potentiated by methadone, cyclazocine and morphine, in that order of potency. Naloxone did not enhance lethality from d-amphetamine in mice, whereas it did antagonize lethality from morphine-d-amphetamine interactions. Naloxone did slightly enhance lethality from d-amphetamine in rats, but at a higher dose than those found to antagonize the lethality from morphine-d-amphetamine combinations. Methadone also enhanced the lethality from cocaine. These results have important implications for drug abusers and for patients being treated for narcotic addiction with either a methadone maintenance program or a cyclazocine administration program.

Animals↗
PubMed1975

The narcotic cue: evidence for the specificity of the stimulus properties of narcotic drugs.

Various non-narcotic drugs with intrinsic stimulus properties were found not to be generalized with fentanyl treatment in rats trained to discriminate fentanyl (0.04 mg/kg, s.c., t-30') from its solvent (s.c., t-30'). In contrast, five typical narcotic analgesics yielded dose-dependent generalization with fentanyl treatment. The results evidence the specific character of the narcotic cue in rats.

Animals↗
PubMedDate not supplied

[The effect of narcotic analgetic fenaridine and narcotic antagonist FI on the level of cyclic nucleotides in the brain of albino rats].

Content of cAMP and cGMP was estimated in rat brain corpus striatum after treatment with narcotic analgetic fenaridin and antagonist of narcotic analgetics F1 which are similar chemically. Various concentrations of fenaridin increased the cAMP content, whereas that of cGMP was not altered. At the same time, administration of the antagonist of narcotic analgetics F1 led to an increase in content of cGMP and to a distinct elevation of cAMP content.

4-Aminopyridine↗
PubMed1979

Comparative study of cardiovascular, neurological and metabolic side effects of 8 narcotics in dogs. Pethidine, piritramide, morphine, phenoperidine, fentanyl, R 39 209, sufentanil, R 34 995. III. Comparative study of the acute metabolic toxicity of the narcotics used in high and massive doses in curarised and mechanically ventilated dogs.

The I.V. administration in dogs of high and massive doses of narcotics produced an acute rise in CO2 consumption, a rise of plasma catecholamines and other slight biochemical and metabolic perturbances. A general trend towards metabolic acidosis and hypermetabolism was noticed but important differences appeared according the drugs and doses chosen. The safety margin for metabolic toxicity (ratio between IV doses producing severe metabolic side-effects and doses necessary for deep surgical analgesia) were calculated for each narcotic and found as follows: 1 for pethidine, 3.3 for piritramide, 13 for morphine and phenoperidine, 12.5 for R 39 209, 60 for fentanyl, 800 for sufentanil and 4 000 for R 34 995. Drug associations may decrease or increase the metabolic safety margin of the narcotics. Beneficial associations with morphinomimetics are found with droperidol, etomidate and flunitrazepam.

Acidosis↗
PubMed1979

Comparative study of cardiovascular, neurological and metabolic side effects of 8 narcotics in dogs. Pethidine, piritramide, morphine, phenoperidine, fentanyl, R 39 209, sufentanil, R 34 995. II. Comparative study on the epileptoid activity of the narcotics used in high and massive doses in curarised and mechanically ventilated dogs.

The experimental design, described in part I, was again used here. The electrocortical activity was registered with an EEG amplifier using a bipolar derivation of needle electrodes fixed in the scalp of a dog in the fronto-occipital position. In this situation the convlusion threshold for the 8 substances is as follows: pethidine 20 mg.kg-1 I.V., piritramide 30, morphine 180, phenoperidine 4, R 39 209 5, fentanyl 4, sufentanil 4 and R 34 995 10 mg.kg-1 I.V. Comparing the I.V. doses producing severe convulsions with the doses necessary for deep surgical analgesia a safety margin of neurological toxicity was calculated. This was for pethidine 2.2, for piritramide 6.6, for phenoperidine 16, for R 39 209 62.5, for morphine 72, for fentanyl 160, for sufentanil 1 000 and for R 34 995 10 000. It is concluded that for pure narcotics there exists an inverse relationship between analgesic potency and neurological toxicity which is always accompanied by a hyperactivity of the automatic nervous system. Factors modifying the convulsive level of the narcotics are still under investigation. In the meanwhile it can be stated that the association of a strong narcotic with flunitrazepam, droperidol or etomidate will increase the convulsion threshold of the morphinomimetics.

Acidosis↗
PubMed1980

Prescribing narcotics to habitual and addicted narcotic users. Medical and legal guidelines in California and some other Western states.

Confusion exists among physicians over the legal requirements and appropriate prescribing of narcotics to addicted or habitual users of narcotics. The result has often been either (1) the deprivation of appropriate treatment for patients who desire detoxification or adequate pain relief, or (2) illegal prescribing by physicians. Because most narcotics are potent and dangerous substances, certain legal restrictions are necessary to protect the general public. State-approved programs have been established to prescribe methadone and propoxyphene napsylate for addiction treatment. Current laws and regulations in California permit every practicing physician to provide effective and safe treatment for addiction and pain relief.

California↗
PubMed1985

Comparison of a narcotic (oxicone) and a non-narcotic anti-inflammatory analgesic (indoprofen) in the treatment of renal colic.

Intravenous indoprofen (400 mg), a cyclooxygenase inhibitor, was compared with intramuscular oxicodone hydrochloride (= oxicone 10 mg), a narcotic analgesic agent, in regard to efficacy and side effects in the treatment of renal colic. Oxicone was combined with papaverine (20 mg). Patients were randomized to either treatment, and the drugs were given in double-dummy fashion, i.e. one injection of active drug plus one placebo injection. Pain intensity before and after treatment was registered by the patient (visual analog scale) and by a nurse, who also registered side effects. Oxicone was given to 46 patients and indoprofen to 48. The groups did not differ in body weight, age, sex distribution, or pretreatment intensity of pain. More patients required additional treatment in the oxicone than in the indoprofen group (19 v. 10). At 2-5 min after injection, pain reduction was greater with indoprofen, and more patients in this group had pain relief after 3-5 hours. Side effects were less frequent with indoprofen than with oxicone (1 v. 20 patients), in particular from the central nervous system. This difference probably was related to indoprofen's slow and poor penetration of the blood-brain barrier. The study affirmed that non-narcotic cyclooxygenase inhibitors can replace narcotic analgesics for acute pain alleviation in renal colic. Indoprofen seems to be a useful alternative, with low risk of central nervous side effects.

Adult↗
PubMed1976

Discriminative stimulus properties of analgesic drugs: narcotic versus non-narcotic analgesics.

Using a food-reinforced two-lever operant procedure, rats (n=6) were trained to discriminate fentanyl (1.25 mg/kg, p.o., t-60') from solvent (1 ml/100 g B.W., p.o., t-60'). The administration of another narcotic analgesic (pethidine) produced a dose-related generalization with the standard fentanyl treatment; six non-narcotic analygesics (suprofen, acetylsalicylic acid, indomethacin, phenacetin, phenylbutazone, tolmetin) were found not to do so. It is concluded that the ability of drugs to produce analgesia is not a sufficient condition for the drugs to produce the narcotic cue as well.

Analgesics↗
PubMed1975

Microelectrometric titration measurement of the pKa's and partition and drug distribution coefficients of narcotics and narcotic antagonists and their pH and temperature dependence.

The pKa's, partition coefficients, and drug distribution coefficients (apparent partition coefficients) have been investigated for a number of narcotics and, where possible, for their congener narcotic antagonists. These studies were carried out by a microelectrometric titration technique as a function of temperature and pH. This method enables one to determine not only the dissociation constants to deconvolute overlapping pKa's, but also to determine the solubilities of oil-water distribution of these various drugs. The drug distribution coefficients displayed marked sensitivity to pH at values which span the range of attainable human physiological pH values. This has significant pharmacological implications for proper choice and scaling of drug dosages under various clinical situations. The partition coefficients and drug distribution coefficients were noticeably different at 20 degrees (where such measurements are customarily made) than at 37 degrees (body temperature). Furthermore, various drugs exhibit very nonequivalent increases in drug distribution coefficients with increasing temperature, ranginf from 21% for morephine to 200% for naltrexone. This nonregularity indicates that it will not be valid to extrapolate by any constant factor the measurements made at lower temperatures. Even the true partition coefficients increase with temperature from 20 degrees to 37 degrees. There is more of a difference in the drug distribution coefficients for naloxone and naltrexone than might have been expected from the similarities in their structures with naltrexone being significantly less lipophilic than naloxone. This would imply that this would lead to naloxone having a more rapid onset for antagonist activity and likewise a shorter duration of action than naltrexone.

Electrochemistry↗
PubMed1982

Discriminative stimulus properties of narcotic and non-narcotic drugs in rats trained to discriminate opiate kappa-receptor agonists.

The purpose of this study was to evaluate the discriminative stimulus properties of some narcotic and non-narcotic drugs in rats trained to discriminate the effect of the proposed opiate kappa-receptor agonists ethylketocyclazocine and bremazocine. Male Sprague-Dawley rats were trained in a two-lever food-reinforced paradigm to discriminate between the effect of ethylketocyclazocine (0.32 mg/kg) or bremazocine (0.04 mg/kg) and saline. Both groups of trained rats showed dose-dependent generalization to the effect of the proposed kappa-agonist MRZ-2033 and some animals generalized the effect of nalorphine and pentazocine. Some ethylketocyclazocine - but no bremazocine - trained rats generalized the effect of buprenorphine. The effect of dextrorphan, phencyclidine, and ketamine was generalized by some bremazocine -, but no ethylketocyclazocine-trained rats. Neither group of rats generalized the effect of etorphine, haloperidol, diazepam, or pentobarbital. These data suggest the usefulness of this procedure to evaluate the kappa-like properties of opioid drugs.

Animals↗
PubMed1986

Probes for narcotic receptor mediated phenomena. 13. Potential irreversible narcotic antagonist-based ligands derived from 6,14-endo-ethenotetrahydronororipavine with 7-(methoxyfumaroyl)amino, (bromoacetyl)amino, or isothiocyanate electrophiles: chemistry, biochemistry, and pharmacology.

N-Allyl-, N-(cyclopropylmethyl)-, and N-propyl-endo-ethenotetrahydronororipavines (N-substituted 6,14-endo-etheno-4,5-epoxy-3-hydroxy-6-methoxymorphinans) were synthesized with potential acylating or alkylating moieties at the C-7 position (isothiocyanato, (bromoacetyl)amino, and (methoxyfumaroyl)amino) and examined in vivo for their narcotic agonist and antagonist activities and for their ability to interact with opioid receptors in vitro. The N-(cyclopropylmethyl)-substituted compounds were found to have the highest affinity for opioid receptors among these N-substituted compounds, although all of them were found to be reasonably potent narcotic antagonists in the mouse tail flick vs. morphine assay. Their in vivo potency ranged from 1/8 to 4 times that of nalorphine on intravenous injection in mice. Rat brain membrane binding studies indicated that the compounds interacted with opioid receptors with potencies that ranged from 0.5 times that of morphine (8c, 9c, and 10c) to 0.017 that of morphine (8b). Among the compounds studied here, only the previously reported isothiocyanato compound (10c) and (methoxyfumaroyl)amino compound (8c) interacted irreversibly and selectively with mu or delta opioid receptors, respectively, in assays using NG108-15 neuroblastoma-glioma hybrid cells and/or in a rat brain membrane preparation. Both 8c and 10c were found to interact irreversibly, to a limited extent, with kappa opioid sites in rat brain membranes in which the mu and delta opioid receptors were depleted by interaction with the mu-selective irreversible ligand BIT and the delta-selective irreversible ligand FIT. Neither compound showed irreversible actions in the electrically stimulated mouse vas deferens preparation.

Animals↗
PubMed1983

Analgesic narcotic antagonists. 15. Potent narcotic agonist 7 beta-(arylalkyl)-4,5 alpha-epoxymorphinans.

Structure-activity correlations in 7 beta-(arylalkyl)-3-methoxy- or hydroxy-4,5 alpha-epoxymorphinans have been investigated. 6 beta-Hydroxy-7 alpha-hydroxymethyl compounds 7 with 7 beta-substituents CH2CH2R [a, R = H; b, R = CH2CH3; c, R = C6H5; d, R = CH2C6H5; f, R = CH2CH2C6H5; g, R = (CH2)3C6H5; h, R = (CH2)4C6H5] were prepared. Wittig condensations with previously reported 4,5 alpha-epoxy-7 beta-formyl-7 alpha-(hydroxymethyl)-6 beta, 7 alpha-O-isopropylidene-3-methoxy-17-methylmorphinan-6 beta-ol (3), followed by dilute acid removal of the blocking group and then hydrogenation, gave saturated compounds 7. Compounds with a 6 alpha, 7 alpha-oxymethylene ring. 18c,d,f,g, were prepared from 7 beta-formyl derivative 16 and the appropriate Wittig reagent, followed by hydrogenation. Both the 6 beta-hydroxy-7 alpha-hydroxymethyl and 6 alpha, 7 alpha-oxymethylene series containing 7 beta-arylalkyl groups with an alkyl chain length of 2 to 4 ar potent narcotic agonists. The most potent 17-methyl compound, 4,5 alpha-epoxy-7 alpha-(hydroxymethyl)-17-methyl-17 beta-(4-phenylbutyl)morphinan-3,6 beta-diol (8f) was 700 times more potent than morphine in the acetic acid induced mouse writhing assay. 17-Methyl compounds in the c, d, f, g series were converted to 17-cyclopropylmethyl (P series) or 17-cyclobutylmethyl (B series) derivatives. Narcotic antagonistic activity could not be demonstrated for these potent agonist 17-cycloalkylmethyl derivatives. These pharmacological results parallel those previously reported for tertiary alcohol derivatives of the endo-ethenotetrahydrooripavines. Structureal considerations confirm the existence of a lipophilic site extending upward and outward from where the C ring of morphine and congeners bind to opiate receptors.

Analgesics↗
PubMed1975

Bacteriological studies with morphine-like narcotics: relevance to narcotic actions in mammals?

A search for active bacterial growth inhibitors among seven highly potent morphine-like narcotics revealed that NIH 7591 and etorphine inhibited the rates of growth of Escherichia coli by 50% at 1.9 x 10(-4) M. Bacterial cultures escaped from growth inhibition by NIH 7591 after times which were proportional to the drug concentrations and inversely proportional to the initial bacterial densities. Populations of E. coli could adapt to resist and cross-resist growth inhibitions by NIH 7591 and phenazocine. Resistance was lost after growth in drug-free medium for a few doubling times. The agonist-antagonist pair, etorphine and diprenorphine, inhibited growth of E. coli additively without any indication of antagonism. Actions of narcotics in bacteria is considered a theme in its own right.

Drug Synergism↗
PubMed1975

On the narcotic cuing action of fentanyl and other narcotic analgesic drugs.

Using a food-reinforced two-levers operant procedure, rats could be trained to discriminate fentanyl (1.25 mg/kg, p.o., t-60') from solvent (1 ml/100 g B.W., p.o.,t60)treatment. The administration of the other narcotic analgesics bezitramide, dextromoramide, methadone and morphine produced a dose-related stimulus generalization with the standard fentanyl treatment. The results further evidence the validity of the narcotic cue.

Analgesics, Opioid↗
PubMedDate not supplied

[Effect of neuroleptics, narcotic analgesics and narcotic agents on the absorptive activity of the small intestine].

It was shown in experiments on preliminary operated on dogs that in conditions of analgesia achieved by the administration of neuroleptics and narcotic analgetics in doses applied for premedication, there are no significant disorders in the acid-alkaline state and the absorbing function of the small intestine. The administration of narcotic agents in doses providing the surgical stage of narcosis, inhibits the absorption in the intestine and the deeper the developing metabolic acidosis gets, the higher proves the inhibition. The obtained data show that the inhibition of absorption is not conditioned directly by the narcosis but is the result of disorders in the gaseous homeostasis with further disorders in metabolic processes in the intestine wall.

Acid-Base Equilibrium↗
PubMedDate not supplied

Central action of narcotic analgesics. I. Catalepsy and stereotypy in rats and narcotic analgesics.

The action of four analgesics, belonging to various pharmacological groups (morphine, codeine, fentanyl, pentazocine), was investigated in rats in tests for catalepsy and stereotypy, the tests depending on dopaminergic brain mechanisms. Interactions of the analgesics with a number of compounds known to affect dopaminergic brain functions in tests of catalepsy and stereotypy were also studied. In some experiments nalorphine, an antagonist of narcotic analgesics, was used. Morphine, codeine and fentanyl produced catalepsy, while pentazocine, at doses up to 60 microgram/kg, did not produce this effect. Reserpine, 2 mg/kg 3 hr before drugs, potentiated catalepsy produced by analgesics, while haloperidol, 0.2 mg/kg, 2 hr earlier, did not influence morphine and codeine catalepsy, but moderately potentiated fentanyl-induced catalepsy. alpha-methyl-p-tyrosine potentiated the cataleptogenic action of fentanyl and codeine, and also, less markedly, the action morphine. D-amphetamine (2.5-10 mg/kg) and apomorphine (5 mg/kg) moderately antagonized the catalepsy induced by analgesics, while atropine did not affect it. Nalorphine, 5 mg/kg, effectively abolished the catalepsy produced by narcotic analgesics, but did not affect that produced by neuroleptics. Morphine, codeine and fentanyl slightly inhibited apomorphine stereotypy, and evidently antagonized stereotypy produced by amphetamine. Pentazocine did not affect or slightly potentiated the both types of stereotypy. It is concluded that morphine, codeine and fentanyl, in contrast to pentazocine, inhibit behavioral activities depending on central dopaminergic functions in the rat. The mechanism of this action is most probably indirect, and seems to be related to the dopaminergic presynaptic functions.

Animals↗
PubMed1983

Probes for narcotic receptor mediated phenomena. 5. Narcotic antagonist irreversible ligands based on endoethenotetrahydrooripavine.

Nine new compounds have been synthesized as potential affinity ligands for specific opioid receptors. The biochemical properties of three of these compounds were examined in detail and one of them, N-cyclopropylmethyl-7 alpha-methylfumaroylamido-6, 14-endoethenotetrahydronororipavine (NIH 10236), was found to be a potent irreversible ligand for the delta opioid receptor. It had the properties of a narcotic antagonist, as determined by its effect on adenylate cyclase activity of NG108-15 neuroblastoma-glioma cell homogenates. It is, thus, the first delta specific alkylating ligand known which is a narcotic antagonist. A second compound, the N-cyclopropylmethyl-7 alpha-isothiocyanato-6, 14-endoethenotetrahydronororipavine (NIH 10235) was found to be a mu specific alkylating ligand in brain and a reversible antagonist in the NG108-15 cells.

Animals↗
PubMed1975

Narcotic antagonists. 4. Carbon-6 derivatives of N-substituted noroxymorphones as narcotic antagonists.

A series of new narcotic antagonists has been synthesized by modifying the C-6 carbonyl group in naloxone (Ia) and naltrexone (Ib). New functional units were introduced by reaction with various phosphorus and sulfur ylides and alkyllithium reagents. The activity of the new compounds were measured by the hot-plate and tail-clip tests after oral administration to mice. The majority of the new narcotic antagonists exhibited oral potencies considerably superior to the parent compounds, with 6-methylene derivatives IIa and IIb showing the most impressive increases.

Analgesia↗