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At least 829 records · Page 46Linked to original sources
PubMed1993

Solid-state stereochemistry and activity of 3-methylnefopam diastereomers: manipulation of eight-membered ring conformations in analogues of the non-narcotic analgesic drug.

The solid-state structures of (+/-)-(1R,3S,5S)/(1S,3R,5R)- and (+)/(-)-(1R,3R,5R)/(1S,3S,5S)-3-methylnefopam hydrochloride, epimeric 3-methyl derivatives of the non-narcotic analgesic drug, were determined by single-crystal X-ray diffraction analyses. (+/-)-(1R,3S,5S)/(1S,3R,5S)-3-Methylnefopam hydrochloride gave crystals belonging to the monoclinic space group P2(1)/c, and at ambient temperature, a = 7.993(2), b = 34.376(4), c = 11.785(2) A, beta = 93.06 degrees, V = 3234(2) A3, Z = 8, R(F = 0.070, and Rw(F) = 0.053. (+)/(-)-(1R,3R,5R)/(1S,3S,5S)-3-Methylnefopam hydrochloride gave chiral crystals belonging to the orthorhombic space group P2(1)2(1)2(1), and at 92 K, a = 9.261(2), b = 10.280(2), c = 16.668(4) A, V = 1587(1) A3, Z = 4, R(F) = 0.034, and Rw(F) = 0.035. The two molecules in the asymmetric unit of the (1R,3S,5S)/(1S,3R,5R)-racemic modification had twist-chair-(flattened chair) [TCfC] conformational geometries for the eight-membered ring. Both molecules are virtually identical as shown by a root mean squares fit of 0.077 A in the superimposition of all nonhydrogen atoms in both molecules. The (+)/(-)-(1R,3R,5R)/(1S,3S,5S)-epimers were found in the same boat-(flattened chair) [BfC] conformation previously noted for crystalline nefopam hydrochloride. The TCfC and BfC eight-membered ring conformations of the two 3-methylnefopam diastereomers differ in the -N+H(CH3)CH2CH-fragment chair or boat arrangement vis-a-vis the adjacent flattened region. In both 3-methyl diastereomers, the C(3)-methyl group was disposed in an equatorial orientation, the phenyl group resided in an exo-position, and the -OCH(Ph)-o-C6H4- fragment occupied the flattened region of the eight-membered ring.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1985

Continuous epidural narcotic analgesia for intractable pain due to malignancy.

Eighty consecutive cancer patients with severe pain, uncontrolled by conventional narcotic analgesics, received a 2-mg test dose of morphine epidurally. Thirty-four of them had significant pain relief and were thus selected to receive continuous treatment. This consisted of 2-6 mg of morphine administered every 8-24 hours through an indwelling epidural catheter. The duration of treatment was from 1 to 28 weeks with a median of 4 weeks. Twenty-five (76%) of the patients experienced complete relief of pain, while nine had only a partial analgesic response. Complications were minimal. No sepsis, hypotension, or respiratory depression occurred. It is recommended that cancer patients with intractable pain will be selected for continuous epidural analgesia by evaluating their response to a test dose of epidural morphine.

Adult↗
PubMed1991

A proposal for the molecular basis of mu and delta opiate receptor differentiation based on modeling of two types of cyclic enkephalins and a narcotic alkaloid.

The molecular basis underlying the divergent receptor selectivity of two cyclic opioid peptides Tyr-c[N delta-D-Orn2-Gly-Phe-Leu-] (c-ORN) and [D-Pen2,L-Cys5]-enkephalinamide (c-PEN) was investigated using a molecular modeling approach. Ring closure and conformational searching procedures were used to determine low-energy cyclic backbone conformers. Following reinsertion of amino acid side chains, the narcotic alkaloid 7 alpha-[(1R)-1-methyl-1-hydroxy-3-phenylpropyl]-6-14-endoethenotetrahy dro oripavine (PEO) was used as a flexible template for bimolecular superpositions with each of the determined peptide ring conformers using the coplanarity and cocentricity of the phenolic rings as the minimum constraint. A vector space of PEO, accounting for all possible orientations for the C21-aromatic ring of PEO served as a geometrical locus for the aromatic ring of the Phe4 residue in the opioid peptides. Although a vast number of polypeptide conformations satisfied the criteria of the opiate pharmacophore, they could be grouped into three classes differing in magnitude and sign of the torsional angle values of the tyrosyl side chain. Only class III conformers for both c-ORN and c-PEN, having tyramine dihedral angles chi 1 = 150 degrees +/- 30 degrees and chi 2 = -155 degrees +/- 20 degrees, had significant structural and conformational properties that were mutually compatible while respecting the PEO vector space. Comparison of these properties in the context of the divergent receptor selectivity of the studied opioid peptides suggests that the increased distortion of the peptide backbone in the closure region of c-PEN together with the pendant beta,beta-dimethyl group, combine to generate a steric volume which is absent in c-ORN and that may be incompatible with a restrictive topography of the mu receptor. The nature and stereochemistry of substituents adjacent to the closure region of the peptides could also modulate receptor selection by interacting with a charged (delta) or neutral (mu) subsite.

Computer Graphics↗
PubMed1975

The specificity of binding of the narcotic agonist etorphine in synaptic membranes of rat brain in vivo.

When 3H-etorphine was administered to rats in a pharmacologically effective dose (0.75 mug/kg intracisternally), the labeled drug was concentrated in synaptic membrane fractions isolated from the brains of rats killed 10 min after etorphine injection. Pretreatment of the animals with the narcotic antagonists naloxone, diprenorphine or l-cyclorphan, blocked the pharmacological responses to etorphine and reduced 3H-etorphine binding in the membrane fractions. The differences between 3H-etorphine bound in synaptic membranes of rats treated with d-cyclorphan (inactive isomer) and l-cyclorphan (active antagonist) were in the same range as the reductions in etorphine binding in antagonist-treated rats, indicating that stereospecific and pharmacologically-specific binding sites in synaptic membranes in vivo were of the same magnitude: about 0.04 pmol/g brain.

Animals↗
PubMed1978

Behavioral supersensitivity to apomorphine following chronic narcotic treatment in the guinea pig.

Male albino guinea pigs were treated for 3 weeks with methadone, morphine, haloperidol, or saline. One week and 5 weeks following termination of treatment they were challenged with the directly acting dopaminergic agonist apomorphine. At the week 1 test the haloperidol and saline groups did not differ, but behavioral supersensitivity was apparent in significantly elevated mean stereotypy scores of the methadone and morphine groups relative to the saline group. The source of differences in mean scores was a higher peak score rather than increased duration of action. At the week 5 test the scores of the methadone group were even higher, the morphine group's scores were equivalent to the saline group's, and the haloperidol group's scores were significant depressed. This study indicates that a 3-week treatment period with methadone or morphine is sufficient to induce dopaminergic supersensitivity and suggests that there may be different time courses for the retention or expression of supersensitivity following these narcotics.

Animals↗
PubMed1980

Narcotic analgesics and stereotyped behaviour in mice.

In this paper we have studied the effects of morphine, codeine, fentanyl, pentazocine, etorphine and fluphenazine (all drugs injected i.p.) on stereotyped behaviour induced by methylphenidate 60 mg/kg i.p., as well as induced by apomorphine 5 mg/kg s.c. in mice. It was found that all used analgesics and fluphenazine dose--dependently inhibited the intensity of methylphenidate--induced gnawing in mice. This effect of analgesics, but not that of fluphenazine was antagonized by naloxone (0.8 mg/kg i.p.) and nalorphine (10 mg/kg i.p.). Climbing behaviour induced by apomorphine was not reduced by narcotic analgesics, but fluphenazine inhibited this effect dose--dependently. These findings give the behavioural support that analgesics applied have antidopaminergic activity in mice.

Analgesics, Opioid↗
PubMed1986

Patient-controlled analgesia with nalbuphine, a new narcotic agonist-antagonist, for the treatment of postoperative pain.

Patient-controlled analgesia (PCA, intravenous self-application of narcotics) has been studied during the early postoperative period in 40 ASA I-III patients recovering from elective major and minor surgery (20 abdominal and 20 orthopaedic operations). Doses of 3.7 mg of the new agonist-antagonist opioid analgesic nalbuphine were available on demand, whenever the patients felt that pain relief was necessary, delivered by a microprocessor-controlled injection pump (On-Demand Analgesia Computer, ODAC) in response to use of a patient-controlled manual switch. The maximum dose/h was set at 28.2 mg, with a refractory time of 1 minute between successful demands. A continuous nalbuphine infusion (0.44 mg X h-1) was administered in addition in order to prevent obstruction of the catheter. The duration of the PCA period was 17.9 (0.4-28.0) h (median, range). During that time, 13.3 (1-45) demands per patient were recorded, resulting in median individual nalbuphine consumptions of 51.3 (8.1-1050.5) micrograms X kg-1 X h-1. Self-administration was characterized by considerable intra- and inter-individual variability. Following abdominal surgery significantly more nalbuphine was needed compared to orthopaedic patients, but it resulted in poorer pain relief. There were no statistically significant differences in drug requirements or pain scores between the sexes. Overall efficacy and patient acceptance proved to be good. When compared with previous conventional postoperative analgesia, the effectiveness of PCA was judged superior by about 57% of patients. Side effects (nausea, sweating) occurred in about 10% of patients but were usually of minor intensity. No serious circulatory or respiratory problems were observed during the period of PCA. Patient-controlled analgesia is a promising technique for the treatment of acute pain and for clinical pain research.

Adult↗
PubMed1988

Narcotic antagonism of seizures induced by a dopamine-derived tetrahydroisoquinoline alkaloid.

This paper describes experiments designed to evaluate whether the narcotic antagonist naloxone significantly interferes with seizures induced by tetrahydroisoquinolines (TIQs). In these experiments we found that naloxone significantly reduced seizure scores induced by intra-cranially infusing mice with 50 micrograms of the dopamine-derived tetrahydroisoquinoline (TIQ) alkaloid, 6,7-dihydroxy TIQ. These findings support an opioid involvement in the actions of TIQs and may lead to further understanding of opioid-mediated novel excitatory receptors.

Alcoholic Intoxication↗
PubMed2000

Effects of microwave radiation and strychnine on cerebral biopotentials in narcotized rats.

Strychnine and microwave radiation produced changes in spectral parameters of electrocorticogram, correlation dimension, and Kolmogorov entropy, parameters calculated by the methods of nonlinear dynamics opposite to those induced by urethane. The modulatory effect of microwaves on bioelectric cerebral activity in narcotized animals was similar to the effect of strychnine and probably related to enhanced excitability of brain structures and complication of bioelectric processes.

Animals↗
PubMed1989

Neuromuscular and cardiovascular effects of mivacurium chloride in surgical patients receiving nitrous oxide-narcotic or nitrous oxide-isoflurane anaesthesia.

The neuromuscular and cardiovascular effects of mivacurium chloride were studied during nitrous oxide-oxygen narcotic (fentanyl) (n = 90) and nitrous oxide-oxygen isoflurane (ISO) anaesthesia (n = 45). In addition, a separate group (n = 9) received succinylcholine during fentanyl anaesthesia to compare its neuromuscular effects with mivacurium. Mivacurium was initially administered as a single bolus in doses from 0.03 mg.kg-1 to 0.25 mg.kg-1 to study the dose-response relationships, as well as the cardiovascular effects of mivacurium. Neuromuscular block (NMB) was measured by recording the twitch response of the adductor pollicis muscle following ulnar nerve stimulation (0.15 Hz, 0.2 ms supramaximal voltage). The ED95 values for mivacurium were estimated to be 0.073 mg.kg-1 and 0.053 mg.kg-1 in the fentanyl and ISO groups respectively. The duration of block (time from injection to 95 per cent recovery) for a dose of 0.05 mg.kg-1 mivacurium was 15.3 +/- 1.0 min and 21.5 +/- 1.3 min for fentanyl and ISO anaesthesia, respectively. The recovery index (25-75 per cent) between initial bolus dose (6.1 +/- 0.5 min), repeat bolus doses (7.6 +/- 0.6 min), mivacurium infusion (6.7 +/- 0.7 min) and succinylcholine infusion (6.8 +/- 1.8 min) were not significantly different. There was minimal change in mean arterial pressure (MAP) or heart rate (HR) following bolus doses of mivacurium up to 0.15 mg.kg-1. Bolus administration of 0.20 mg.kg-1 or 0.25 mg.kg-1 of mivacurium decreased MAP from 78.2 +/- 2.5 to 64.0 +/- 3.2 mmHg (range 12-59 per cent of control) (P less than 0.05). The same doses when administered slowly over 30 sec produced minimal change in MAP or HR.

Adult↗
PubMed1999

Antisettlement and Narcotic Action of Analogues of Diterpene Marine Natural Product Antifoulants from Octocorals.

: Prevoius studies have determined that the octocorals Renilla reniformis and Leptogorgia virgulata contain diterpenes that are potent inhibitors of barnacle settlement. These antifoulants-the renillafoulins and pukalide-are, however, comparatively complex and thus are not amenable to commercial exploitation. The present study examined 19 analogues, based on the functional groups of lactone and furan rings in the parent molecules, for antisettlement activity and toxicity. The latter parameters are presented as EC(50) values for inhibition of cypris settlement and naupliar swimming, respectively. Assays of a subset of the analogues indicated that they were active in solution rather than when bound to a surface and that at relatively high concentrations they had a narcotic action. The mechanism whereby some of the analogues were able to inhibit settlement at nontoxic concentrations has yet to be explained but suggests that there is merit in the present approach to antifoulant development.

Journal Article↗
PubMed1997

Inert gas and raised pressure: evidence that motor decrements are due to pressure per se and cognitive decrements due to narcotic action.

The psychomotor and cognitive abilities of experienced professional divers participating in training and experimental dives in a hyperbaric chamber were investigated during experiments at high ambient pressure of either air or hydrogen-helium-nitrogen-oxygen mixtures. Decrements in psychomotor ability were not as large as decrements in cognitive ability: manual dexterity was 2-16%, number ordination 4-46% below control. To determine the respective roles of inert gases and pressure per se, the data were compared with lipid solubility theories of narcosis. This analysis indicated that impairment of cognitive ability was a consequence of the narcotic action of the inert gases, whereas impairment of motor ability was a consequence of the raised pressure per se.

Adult↗
PubMed1987

Continuous epidural anesthesia and postoperative epidural narcotics in vascular surgery.

A combination epidural technique using local anesthetics intraoperatively and morphine postoperatively is shown to offer many advantages. These benefits include inhibition of the surgical stress response, decreased cardiorespiratory depression, decreased blood loss, decreased intubation and pulmonary infection, decreased thromboembolism, decreased hyperglycemic and hypertensive response, nitrogen sparing, a stable resting metabolic rate, prevention of immunosuppression, simplification of cerebral status monitoring, and earlier ambulation and hospital discharge. The main disadvantage in patients undergoing vascular procedures is the risk of epidural hematoma. A review of the literature confirms the extreme rarity of this risk and, in view of the emerging benefits, argues for reconsideration of epidural technique in vascular patients. The addition of epidural morphine to this combined technique affords a postoperative pain-free continuum unmatched by any other method. This significantly decreased pain stress in cardiac patients increases safety and comfort. In conclusion, epidural anesthesia and postoperative epidural narcotics provide a safe and reliable method of management for patients undergoing vascular procedures.

Anesthesia, Epidural↗
PubMed1975

Localization of the central sympatho-inhibitory effect of a narcotic analgesic agent, fentanyl, in cats.

Fentanyl (10 and 30 mug/kg), a narcotic analgesic, induced in cats a decrease in blood pressure and heart rate and reduced spontaneous splanchnic nerve activity. Fentanyl reduced the pressor response to medullary stimulation, but did not change the pressor response to hypothalamic or cervical spinal cord stimulation. Fentanyl reduced the potential evoked in the splanchnic nerve by stimulation at low frequency of a pressor area of the medulla oblongata. The potentials evoked in the splanchnic nerve by hypothalamic or cervical spinal cord stimulation were only slightly changed. Nalorphine (0.5 mg/kg) or naloxone (30 mug/kg) induced a recovery in blood pressure, heart rate and spontaneous splanchnic discharges which had been reduced by fentanyl, but nalorphine or naloxone did not restore pressor response to medullary stimulation or potentials evoked in the splanchnic nerve by medullary stimulation, which had been decreased by fentanyl.

Animals↗
PubMed1975

Narcotic withdrawal like mouse jumping produced by amphetamine and L-DOPA.

Upward jumping in mice that resembled the narcotic-withdrawal syndrome was produced by a combination of amphetamine (4 mg/kg) and L-DOPA (400 mg/kg) administration. Neither drug alone caused that jumping. Pretreatment with haloperidol (0.16 mg/kg) or pimozide (0.08 mg/kg) but not with phentolamine (10mg/kg) effectively blocked amphetamine-dopa jumping. After DOPA there was an increase in the brain levels of DOPA, dopamine and norepinephrine. Amphetamine, ineffective in itself, enhanced DOPA-induced elevation of brain DOPA and dopamine without affecting brain norepinephrine levels.

Amphetamine↗
PubMed1993

Effects of rimcazole, a specific antagonist of sigma sites, on the antitussive effects of non-narcotic antitussive drugs.

We examined the effects of rimcazole, a specific antagonist of sigma sites, on the antitussive effects of dextromethorphan and noscapine in mice. Intraperitoneal injection of rimcazole, in doses from 1 to 10 mg/kg, significantly and dose dependently antagonized the cough depressant effect of N,N'-di(orthotolyl)guanidine (DTG), a sigma ligand. The cough depressant effects of dextromethorphan (3 mg/kg i.p.) and noscapine (10 mg/kg i.p.) were also significantly and dose dependently reduced by pretreatment with rimcazole. However, rimcazole (10 mg/kg i.p.) did not have a significant effect on the antitussive effect of morphine (3 mg/kg i.p.). Furthermore, rimcazole by itself (10 and 30 mg/kg i.p.) had no significant effect on the number of coughs. These results suggest that sigma sites may be involved in the antitussive mechanism of centrally acting non-narcotic antitussive drugs.

Animals↗
PubMed1985

The narcotic antagonist naltrexone has a biphasic effect on the nicotinic acetylcholine receptor.

It is known that narcotic antagonists interact with many cholinergic pathways but less in known about specific mechanisms. Using neonatal rat myoballs to study single channel behaviour of the acetylcholinegated nicotinic receptor, it was found that micromolar concentrations of naltrexone had no effect on channel conductance but caused open channel blockade by increasing the flickering from the open to the closed state in a concentration-dependent manner. At micromolar concentrations of naltrexone, the frequency of channel opening was decreased and bursts were grouped in clusters, whereas at nanomolar levels the frequency of opening was increased. The sequential model for ion-channel blockade cannot explain these effects, and an alternative allosteric mechanism of action is proposed.

Acetylcholine↗