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Biomedical subjects

E J Cone

Publications and source records attributed to E J Cone.

At least 127 records · Page 7Linked to original sources
PubMed1986

Diazepam and methadone blood levels following concurrent administration of diazepam and methadone.

Results of a previous study indicated that the opioid effects of methadone were enhanced by the concurrent administration of diazepam in methadone-maintained subjects. To determine whether a pharmacokinetic interaction might account for this methadone-diazepam interaction, the plasma levels of methadone, diazepam and diazepam metabolites were determined in blood samples collected during that study. Five adult male patients on methadone maintenance (50-60 mg/day) were administrated single doses of placebo, diazepam (20 and 40 mg), methadone (100%, 150% and 200% of the maintenance dose), and four diazepam-methadone dose combinations (20 and 40 mg diazepam in combination with 100% and 150% of the maintenance dose). The results showed that the concurrent administration of methadone and diazepam did not significantly change the time-course or areas under the plasma concentration-time curve of methadone, diazepam or N-desmethyl-diazepam compared to the levels following the administration of either drug alone. Thus, plasma drug level analysis does not indicate a pharmacokinetic interaction between diazepam and methadone.

Adult↗
PubMed1986

Contact highs and urinary cannabinoid excretion after passive exposure to marijuana smoke.

Five healthy men were passively exposed under pre- and postplacebo controlled conditions to sidestream smoke from four and 16 standard marijuana cigarettes (2.8% delta-9-tetrahydrocannabinol [delta-9-THC]) for 1 hour each day for 6 consecutive days. Subjective effects produced by the 16-cigarette exposure conditions were similar to those observed after active smoking of one 2.8% delta-9-THC marijuana cigarette. Effects after the four-cigarette condition were less pronounced. Concurrent physiologic measurements showed no clear trends or effects of smoke exposure for either condition. Daily mean plasma levels of delta-9-THC ranged from 2.4 to 7.4 ng/ml with an individual high of 18.8 ng/ml for the 16-cigarette condition. With the use of EMIT cannabinoid assays with 20 ng/ml (EMIT 20) and 100 ng/ml (EMIT 100) cutoffs, urines positive per subject under the four- and 16-cigarette passive exposure conditions were 4.6 +/- 2.2 and 35.2 +/- 3.8, respectively, for the EMIT 20 and 0.0 and 1.0 +/- 0.8, respectively, for the EMIT 100 assay. From the results of these studies, caution is clearly indicated for individuals who might be substantially exposed to heavy marijuana cigarette smoke environments and for those interpreting marijuana screening data.

Adult↗
PubMed1985

63Ni electron-capture gas chromatographic assay for buprenorphine and metabolites in human urine and feces.

A 63Ni electron-capture gas chromatographic assay is described for buprenorphine, a potent narcotic agonist--antagonist. In addition, the assay is useful for the measurement of the metabolite norbuprenorphine and demethoxybuprenorphine, a rearrangement product resulting when buprenorphine is exposed to acid and heat. An extraction procedure was developed which optimized recovery of buprenorphine from biological samples and produced minimal background interferences and emulsion problems. Extract residues were derivatized with pentafluoropropionic anhydride and assayed by gas chromatography. Samples were analyzed with and without enzyme hydrolysis, thus providing a selective and sensitive assay for both free and conjugated buprenorphine, norbuprenorphine and demethoxybuprenorphine. The lower limits of detection following extraction of a 1-ml sample were ca. 10 ng/ml for buprenorphine and demethoxybuprenorphine and 5 ng/ml for norbuprenorphine. Application of the assay to human samples following a 40-mg oral dose of buprenorphine produced no evidence for the presence of demethoxybuprenorphine in urine or feces. Norbuprenorphine (free and conjugated) was present in urinary and fecal samples; buprenorphine (free and conjugated) was found in high amounts only in feces and in trace amounts in urine as conjugated buprenorphine. The urinary and fecal excretion pattern observed for a human subject following oral dosing of buprenorphine suggests enterohepatic circulation of buprenorphine.

Adult↗
PubMed1985

Discriminative stimulus properties and schedule effects of fencamfamine in rats.

The behavioral properties of fencamfamine, a sympathomimetic central stimulant recently identified in alleged cocaine samples, were studied in two different paradigms. In Experiment I, rats were trained to discriminate between injections of saline (0.1 ml/kg, IP) and cocaine (3.0 mg/kg, IP) in a two-lever drug discrimination task on a fixed-ratio (FR) 10 schedule of water presentation. Fencamfamine (0.3-3.0 mg/kg, IP) produced cocaine-appropriate choice behavior and was slightly more potent than cocaine in producing this effect. In Experiment II, rats responded under a multiple fixed-interval (FI) 300 sec, FR 20 schedule of water presentation. Fencamfamine (0.1-10.0 mg/kg, IP) and cocaine (0.1-30.0 mg/kg, IP) produced qualitatively similar effects on responding under this schedule. With increasing doses of either drug, FI responses rates first increased, then decreased; FR response rates were only decreased. Fencamfamine was approximately three times more potent than cocaine in producing these effects. The results of these two experiments indicate that fencamfamine and cocaine have similar behavioral properties.

Amphetamine↗
PubMed1985

Effects of nicotine, cocaine and some of their metabolites on schedule-controlled responding by beagle dogs and squirrel monkeys.

The behavioral effects of nicotine were compared with those of its metabolites, nornicotine and cotinine, in beagle dogs and squirrel monkeys. Subjects responded under a multiple fixed-interval (FI) 300-sec, fixed-ratio (FR) 30 response schedule of food presentation. Nicotine (0.01-1.0 mg/kg i.m.) and nornicotine (0.03-3.0 mg/kg i.m.) produced qualitatively similar effects in both dogs and monkeys. Nicotine produced dose-related increases, then decreases in rates of responding during FI components; rates of responding during FR components were only decreased. Nornicotine produced only dose-dependent decreases in responding during both FI and FR components. In the dogs, cotinine (0.01-10.0 mg/kg i.m.) produced only dose-dependent decreases in rates of responding during both FI and FR components. In the squirrel monkeys, however, cotinine (0.1-3.0 mg/kg i.m.) increased responding during FI components; a high dose of 30.0 mg/kg decreased responding during both FI and FR components. The behavioral effects of cocaine (0.03-3.0 mg/kg i.m.) and its metabolite norcocaine (0.01-1.0 mg/kg i.m.) were compared in the dogs. FI rates of responding first increased and then decreased with increasing doses of each drug, whereas FR rates of responding only decreased in a dose-related manner. Norcocaine was slightly more potent than cocaine in producing these effects on schedule-controlled responding in dogs. These experiments indicate the metabolites of nicotine and cocaine are behaviorally active and may contribute to the pharmacological profile of the parent compounds.

Animals↗
PubMed1984

Stability of the 6,14-endo-ethanotetrahydrooripavine analgesics: acid-catalyzed rearrangement of buprenorphine.

Buprenorphine (I), a member of the 6,14-endo-ethanotetrahydrooripavine series of analgesics, undergoes an acid-catalyzed rearrangement reaction when exposed to acid and heat. The product was shown by 1H-NMR and GC-MS to have undergone overall elimination of a molecule of methanol with concurrent formation of a tetrahydrofuran ring at C(6)-C(7) of I. Short-term stability studies across a wide range of pH and temperature conditions indicate that I is stable in aqueous solution at pH greater than 3 for 24 h at 36-38 degrees C. Under the more extreme conditions of the autoclave, significant loss of I occurred. Long-term stability studies (10 weeks) of I in aqueous solution (pH 1 and pH 5) at 0-4 degrees C and 26-28 degrees C indicate only minor conversion (4%) to the rearrangement product. Eight other 6,14-endo-ethanotetrahydrooripavine derivatives were subjected to extremes of acid (pH 0) and temperature (autoclave) to determine if similar rearrangement reactions occur. GC-MS indicated that hydrolysis products were produced whose spectra were consistent with the proposed rearrangement structures.

Analgesics↗
PubMed1984

Morphine-like discriminative stimulus effects of buprenorphine and demethoxybuprenorphine in rats: quantitative antagonism by naloxone.

The interactions between the opioid antagonist naloxone and the opioids morphine, buprenorphine and demethoxybuprenorphine ( DMB ), an acid-catalyzed rearrangement product of buprenorphine, were evaluated quantitatively in rats trained to discriminate between saline and 3.0 mg/kg of morphine using a two-choice, shock avoidance procedure. Dose-effect curves for each of the three agonists were determined alone and in the presence of varying doses of naloxone (0.01-1.0 mg/kg). Buprenorphine and DMB produced dose-related increases in morphine-appropriate responding which plateaued over at least a 30-fold dose-range for each drug. On a molar basis, buprenorphine was approximately 140 times and DMB approximately 45 times more potent than morphine. Naloxone produced parallel shifts in the dose-effect curves for morphine, buprenorphine and DMB . Schild plots derived from the relative shifts in the dose-effect curves yielded regression lines with slopes which were not significantly different from -1, consistent with naloxone acting as a competitive antagonist of each of the three opioids. The apparent pA2 values for naloxone were 7.85 +/- 0.36 against morphine, 7.48 +/- 0.16 against buprenorphine and 7.17 +/- 0.27 against DMB . Because the 95% CLs overlapped for morphine and buprenorphine, but not for morphine and DMB , these results are consistent with the interpretation that naloxone is acting at the same receptor in antagonizing morphine and buprenorphine but naloxone may be acting in a more complex manner in antagonizing DMB . The effectiveness of naloxone in antagonizing equieffective doses of morphine (3.0 mg/kg), buprenorphine (0.03 mg/kg) and DMB (0.1 mg/kg) were also evaluated when naloxone was administered either 0 or 30 min after the agonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Structure-activity relationship studies of phencyclidine derivatives in rats.

Phencyclidine (PCP), a semirigid molecule containing a cyclohexane ring with vicinally attached aromatic and piperidine rings, produces characteristic discriminative stimulus properties and pupillary miosis in rats. The effectiveness of a series of aromatic and nitrogen substituted analogs of PCP in producing PCP-like discriminative stimuli and changes in pupil diameter was determined in rats trained to discriminate between saline and 3.0 mg/kg of PCP. Dexoxadrol and its optical isomer levoxadrol were also evaluated for purposes of comparison. Analogs in which the electron-density of the aromatic ring was increased (3NH2-PCP) or only slightly reduced (3F-PCP) retained PCP-like activity. A loss of PCP-like activity occurred with analogs in which the electron-density of the aromatic ring was greatly reduced (3NO2-PCP) or extended to a larger system (1NCP and 2NCP). PCP-like activity also was abolished in analogs in which the distance between the aromatic ring and the remainder of the molecule was systematically increased by one, two or three methylene units. In contrast, substitutions on the nitrogen atom altered the potency, but not the efficacy, of such analogs. Dexoxadrol produced PCP-like activity whereas its optical enantiomer levoxadrol was devoid of such activity. These findings suggest a drug receptor surface with multiple domains or subsites which recognize regions of structural overlap among the phencyclidines, dioxolanes and psychotomimetic benzomorphan derivatives.

Animals↗
PubMed1984

Phencyclidine analogs and precursors: rotarod and lethal dose studies in the mouse.

A series of phencyclidine (PCP) related analogs, carbonitrile synthetic precursors and two monohydroxylated metabolites were compared pharmacologically in mice for their ability to produce ataxia using the rotarod method and toxicologically for their acute 4-hr lethality. The slope of the PCP dose-ataxic response curve was steeper than those of diazepam, pentobarbital, morphine and ketocyclazocine but not the slope of the sigma agonist, N-allylnormetazocine curve. Responses for all analogs, metabolites and precursors produced curves parallel to that of PCP. Ataxia potencies of all PCP-related compounds ranged from 0.05 to 2.15 X PCP and durations of action ranged from 18 to 65 min. N-ethyl-1-phenylcyclohexylamine, 1-[1-(2-thienyl)-cyclohexyl]-piperidine and 1-[1-(2-thienyl)-cyclohexyl]-pyrrolidine were most potent and least potent were 1-(1-phenyl-cyclohexyl)-4-methylpiperidine, the phenyl and thienyl morpholines and 4-phenyl-4-piperidinocyclohexanol. Among the PCP analogs, modifying the piperidine or aromatic ring effected changes only in potency. Seizures and respiratory depression characterized the lethal effects of PCP, its analogs, metabolites and precursors. However, the precursors failed to elicit the stereotyped movements and hyperactivity that preceded seizures produced by the other compounds. Overall potencies for lethality relative to PCP covered a narrow range (0.16-1.83) with the carbonitrile precursors being most potent. Therapeutic indices indicated relatively large margins of safety for 1-[1-(2-thienyl)-cyclohexyl]-piperidine, 1-[1-(2-thienyl)-cyclohexyl]-piperidine, N-ethyl-1-phenylcyclohexylamine and ketamine and the smallest were for 1-(1-phenylcyclohexyl)-4-methylpiperidine, the metabolite 4-phenyl-4-piperidinocyclohexanol and the three precursors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Assay for codeine, morphine and ten potential urinary metabolites by gas chromatography--mass fragmentography.

A mass fragmentography (MF) assay is described for ten potential, minor urinary metabolites of codeine (C) and morphine (M). Samples were hydrolyzed, extracted, derivatized with Tri-Sil Z and analyzed by methane chemical ionization (CI)-MF. The method is sensitive to ca. 0.01 microgram/ml for all compounds with the exception of normorphine (NM) which was difficult to extract with chloroform. The sensitivity of the MF assay for NM was only ca. 0.10 microgram/ml. Various solvent systems were investigated for optimization of extraction efficiency of all metabolites. A separate method for the extraction of NM is reported which utilizes a solid buffer--solvent combination, i.e., potassium carbonate--isopropanol. This latter method provided the best overall recovery of NM (39.0 +/- 3.4%). Gas chromatographic (GC) retention times of C, M and metabolites are reported for three liquid phases (3%) on Gas-Chrom Q (100-120 mesh). Resolution of metabolites (as trisilyl derivatives) was best on Silar-5CP and this phase was used in metabolic studies of C and M. GC resolution was not complete for all compounds; however, selection of specific ions for monitoring by MF provided the required specificity for all compounds except the 6 alpha- and 6 beta-hydroxy isomers. CI spectra for all metabolites are reported. The MF assay was used for urinary analysis of samples from guinea pigs that received single doses of C (15 mg/kg) or M (8 mg/kg). Following C administration 6 alpha- and 6 beta-hydrocodol, 6 alpha, beta-hydromorphol (undifferentiated), HM and M were measured. Following M administration only 6 alpha, beta-hydromorphol was found. The amount of total metabolite as percent dose for each component was calculated as less than 1%.

Animals↗
PubMed1983

Effects of cycloalkyl ring analogs of phencyclidine on behavior in rodents.

The purpose of the present experiments was to evaluate the effects of eliminating or varying the size of the cycloalkyl ring of phencyclidine (PCP) from 3 to 8 carbons while leaving the composition of the benzene and piperidine rings unaltered. Compounds were evaluated for their effectiveness in producing PCP-like discriminative stimuli and changes in pupil diameter in the rat and impaired motor performance on the Rotarod in the mouse. All modifications of the cycloalkyl ring of PCP significantly reduced the relative potencies of the cycloalkyl analogs, shortened their duration of action and also modified their spectra of action, including their effectiveness in producing PCP-like discriminative stimuli and miosis in the rat as well as ataxia in the mouse. The present results demonstrate that the cyclohexyl moiety of PCP is an absolute requirement for producing a full PCP-like spectrum of activity.

Animals↗
PubMed1982

Detection and measurement of opium alkaloids and metabolites in urine of opium eaters by methane chemical ionization mass fragmentography.

A gas chromatographic-mass spectrometric assay for eight opium alkaloids in human urine following opium ingestion is described. The compounds were extracted from urine with methylene chloride-isopropanol (7:3, v/v) at pH 9.5, evaporated, derivatized with Tri-Sil Z and analyzed by methane chemical ionization mass fragmentography. The method in sensitive to ca. 0.01 microgram/ml for morphine and codeine and ca. 0.05 microgram/ml for the other compounds. Adsorption problems on the gas chromatography column prevented obtaining reproducible results for the measurement of noscapine. Extraction efficiencies over the pH range of 8-11 for the eight compounds are reported. Retention times of the opium alkaloids were determined using five different liquid phases (3%) on Gas-Chrom Q (100-120 mesh) and two column lengths (36 cm and 183 cm). The 36-cm column packed with OV-210 was selected for use in the assay. Ions were selected for monitoring for each component from their methane chemical ionization spectrum to provide the needed sensitivity and specificity for analysis of a multi-component mixture. The assay was used for the analysis of an "opium eater's" urine. Morphine, codeine, nomorphine, norcodeine and noscapine were detected; however, no evidence was obtained for thebaine, papaverine or oripavine. Unconjugated morphine (0.64 microgram/ml) was present at nearly twice the concentration of codeine (0.37 microgram/ml) and normorphine and norcodeine were present in equal amounts (ca. 0.15 microgram/ml).

Gas Chromatography-Mass Spectrometry↗
PubMed1982

Physiologic effects and plasma kinetics of beta-phenylethylamine and its N-methyl homolog in the dog.

Single i.v. doses of beta-phenylethylamine (PEA) and its N-methyl homolog (NMPEA) were administered to separate groups of five dogs. The dose- and time-related effects of these compounds were determined on pupil diameter, heart rate and body temperature. Blood samples were obtained concurrently with the physiologic measures and plasma levels of PEA and NMPEA were determined by gas chromatography. Both compounds dilated pupils, tended to produce an initial tachycardia followed by a bradycardia and elevated body temperature. The plasma pharmacokinetics of both PEA and NMPEA could be described by first-order kinetics which estimated half-lives of approximately 5 to 10 min. Plasma levels for both amines correlated significantly only with increases in pupil diameter. The present findings demonstrate that the endogenous trace amine PEA and NMPEA, which may be produced enzymatically by nonspecific N-methyl transferases, produce prominent physiologic effects of short duration when administered i.v. in the dog, suggesting that alterations in the metabolism of these amines which result in elevated plasma levels can produce pronounced effects on mammalian nervous system function.

Animals↗