Buprenorphine, a powerful mixed agonist-antagonist analgesic which shows promise of providing maintenance pharmacotherapy for heroin addicts, is metabolized in male human subjects to norbuprenorphine and to conjugated buprenorphine and... more
Buprenorphine, a powerful mixed agonist-antagonist analgesic which shows promise of providing maintenance pharmacotherapy for heroin addicts, is metabolized in male human subjects to norbuprenorphine and to conjugated buprenorphine and norbuprenorphine. Following subcutaneous, sublingual, and oral buprenorphine administration to a single subject, total metabolite excretion in urine was 2, 13.4, and 12.1%, respectively. No free parent drug was detected in urine. The amount of norbuprenorphine metabolite excreted in urine generally exceeded that of conjugated buprenorphine. In contrast, free and conjugated buprenorphine equaled or greatly exceeded total norbuprenorphine content in fecal samples following oral or sublingual administration. The greatest amount of drug and metabolite eliminated in feces occurred at 4 to 6 days following buprenorphine administration at times when there was very little urinary excretion of conjugated buprenorphine. This latter evidence indicates an enterohepatic circulation of buprenorphine in humans.
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Levo-alpha-acetylmethadol (LAAM) is a long-acting opioid agonist approved for use as a maintenance treatment for opioid dependence. Previous clinical studies report that the onset of the effects of LAAM is slower after parenteral... more
Levo-alpha-acetylmethadol (LAAM) is a long-acting opioid agonist approved for use as a maintenance treatment for opioid dependence. Previous clinical studies report that the onset of the effects of LAAM is slower after parenteral administration than oral administration; however, preclinical studies suggest otherwise. This study examined the pharmacodynamic and pharmacokinetic profile of LAAM when given orally and intravenously to humans. Opioid-experienced volunteers (n = 6), who were not physically dependent on opioids, received LAAM (20 and 40 mg/70 kg i.v. and p.o.) and placebo under double-blind, double-dummy conditions during five weekly experimental sessions. Behavioral, physiological, subjective and pharmacokinetic measures were collected before and for 96 hr after drug administration. Intravenous LAAM produced significant subjective and physiological effects that appeared within 5 min, whereas the effects of oral LAAM appeared more slowly within 1 to 2 hr after drug administration. Pharmacokinetic data indicate that the immediate effects of intravenous LAAM are largely attributable to the parent drug rather than the active metabolites, nor-LAAM and dinor-LAAM. LAAM produced prototypic opioid agonist effects (i.e., miosis, subjective ratings of high, nodding) that were of equal magnitude across routes, dose-related and of long duration (up to 60 hr). These data are in contrast to previous clinical reports and indicate that LAAM produces effects of immediate onset when administered parenterally, which suggests that intravenous LAAM possesses greater abuse potential than previously believed.
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A diuretic effect of the pentapeptide BW942C [Tyr-D-Met(O)-Gly-pNO2-Phe-Pro-NH2 HCl] was demonstrated in humans and rats; it was characterized pharmacologically using whole animal, isolated tissue and in vitro binding studies. A single... more
A diuretic effect of the pentapeptide BW942C [Tyr-D-Met(O)-Gly-pNO2-Phe-Pro-NH2 HCl] was demonstrated in humans and rats; it was characterized pharmacologically using whole animal, isolated tissue and in vitro binding studies. A single 2-mg dose of BW942C increased urine output 5-fold over control values in humans. In Long-Evans rats, BW942C produced a biphasic dose-response curve for urine output with lower doses increasing and higher doses suppressing output. Low doses of naltrexone antagonized the antidiuresis, and high doses antagonized the diuresis produced by BW942C. BW942C was less efficacious in producing diuresis than the full kappa agonists bremazocine and U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]- benzeneacetamide methanesulfonate, hydrate). Furthermore, BW942C antagonized the diuretic effects of bremazocine and U50,488H. Rats tolerant to U50,488H-induced diuresis were cross-tolerant to BW942C. In Brattleboro rats, which are unable to synthesize vasopressin, BW942C failed to produce a diuretic effect, demonstrating the necessity of vasopressin for its diuretic response. In the kappa-selective rabbit vas deferens bioassay, BW942C was less efficacious than a full agonist, it was antagonized by naloxone and BW942C in nondepressant doses antagonized a full agonist. In binding studies, BW942C had the highest affinity for mu and delta opioid receptors and an intermediate affinity for kappa opioid receptors. The data suggest that BW942C has the property of a partial kappa opioid agonist in addition to being a mu agonist.
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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... more
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.
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Aims. Examine the relationship between buprenorphine and norbuprenorphine plasma concentrations with subject‐reported withdrawalsymptomatology during buprenorphine dose induction, maintenance treatment (daily and alternate‐day dosing) and... more
Aims. Examine the relationship between buprenorphine and norbuprenorphine plasma concentrations with subject‐reported withdrawalsymptomatology during buprenorphine dose induction, maintenance treatment (daily and alternate‐day dosing) and withdrawal . Design. Two groups of randomly assigned subjects inducted onto buprenorphine and maintained on 8 mg daily by the sublingual route for 18 days. Group 1 continued to receive daily buprenorphine to day 36. Group 2 subjects received alternate‐day dosing of buprenorphine and placebo on days 19 to 36. Both groups received placebo on days 37 to 52 . Setting. Inpatient facilities at the Addiction Research Center, Intramural Research Center, NIDA, Baltimore, MD . Participants. Eleven male, heroin‐dependent volunteers participating in a research study . Intervention. Medications for treatment of withdrawal symptoms were prescribed as needed after day 39 (72 hours after the last dose of buprenorphine) . Measurements. Plasma concentrations of buprenorphine and norbuprenorphine, withdrawal symptomatology and pupil diameter . Findings. The mean steady‐state buprenorphine plasma concentration (24 hours) after daily administration of sublingual buprenorphine for study days 21‐35 was 0.80 ng/ml, and the mean alternate day steady‐state buprenorphine plasma concentration (24 hours) was 0.77 ng/ml. Daily and alternate day steady‐state norbuprenorphine plasma concentrations were 1.10 and 0.90 ng/ml, respectively. Predicted alternate day steady‐state buprenorphine and norbuprenorphine plasma concentrations at 48 hours were 0.49 ng/ml and 0.57 ng/ml, respectively. Withdrawal scores varied inversely with plasma concentration. There were no significant differences between Groups 1 and 2 during steady‐state (days 21‐35) with regard to withdrawal scale scores or pupillary diameter. The overall, mean terminal elimination half‐lives for buprenorphine and norbuprenorphine were 42 and 57 hours, respectively . Conclusions. During daily buprenorphine maintenance, plasma concentrations greater than 0.7 ng/ml of buprenorphine and norbuprenorphine were associated with minimal withdrawal symptoms. The long elimination half‐life of buprenorphine suggested that increasing the buprenorphine dose with alternate‐day administration may provide an effective, flexible therapy regimen for the treatment of opioid dependence.
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There is limited data on the comparative pharmacokinetics of cannabidiol (CBD) across oral and vaporized formulations. This within-subject, double-blind, double-dummy, placebo-controlled laboratory study analyzed the pharmacokinetic... more
There is limited data on the comparative pharmacokinetics of cannabidiol (CBD) across oral and vaporized formulations. This within-subject, double-blind, double-dummy, placebo-controlled laboratory study analyzed the pharmacokinetic profile of CBD, ∆9-tetrahydrocannabinol (∆9-THC) and related metabolites in blood and oral fluid (OF) after participants (n = 18) administered 100 mg of CBD in each of the following formulations: (1) oral CBD, (2) vaporized CBD and (3) vaporized CBD-dominant cannabis containing 10.5% CBD and 0.39% ∆9-THC (3.7 mg); all participants also completed a placebo condition. Oral CBD was administered in three formulations: (1) encapsulated CBD, (2) CBD suspended in pharmacy-grade syrup and (3) Epidiolex, allowing for pharmacokinetic comparisons across oral formulations (n = 6 per condition). An optional fifth experimental condition was completed for six participants in which they fasted from all food for 12 h prior to oral ingestion of 100 mg of CBD. Blood and OF...
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Oral cannabis products (a.k.a. “edibles”) have increased in popularity in recent years. Most prior controlled pharmacokinetic evaluations of cannabis have focused on smoked cannabis and included males who were frequent cannabis users. In... more
Oral cannabis products (a.k.a. “edibles”) have increased in popularity in recent years. Most prior controlled pharmacokinetic evaluations of cannabis have focused on smoked cannabis and included males who were frequent cannabis users. In this study, 17 healthy adults (8 females), with no cannabis use in at least the past 2 months, completed 4 double-blind outpatient sessions where they consumed cannabis brownies containing Δ9-tetrahydrocannabinol (THC) doses of 0, 10, 25 or 50 mg. Whole blood and oral fluid specimens were collected at baseline and for 8 h post-brownie ingestion. Enzyme-linked immunosorbent assay (ELISA) and liquid chromatography–tandem mass spectrometry (LC–MS-MS) were used to measure THC and relevant metabolites. In whole blood, concentrations of THC and 11-hydroxy-THC (11-OH-THC) peaked 1.5–2 h after brownie consumption, decreased steadily thereafter, and typically returned to baseline within 8 h. Blood concentrations for 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (...
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The market for products containing cannabidiol (CBD) is booming globally. However, the pharmacokinetics of CBD in different oral formulations and the impact of CBD use on urine drug testing outcomes for cannabis (e.g.,... more
The market for products containing cannabidiol (CBD) is booming globally. However, the pharmacokinetics of CBD in different oral formulations and the impact of CBD use on urine drug testing outcomes for cannabis (e.g., 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (Δ9-THCCOOH)) are understudied. This study characterized the urinary pharmacokinetics of CBD (100 mg) following vaporization or oral administration (including three formulations: gelcap, pharmacy-grade syrup and or Epidiolex) as well as vaporized CBD-dominant cannabis (containing 100 mg CBD and 3.7 mg Δ9-THC) in healthy adults (n = 18). A subset of participants (n = 6) orally administered CBD syrup following overnight fasting (versus low-fat breakfast). Urine specimens were collected before and for 58 h after dosing on a residential research unit. Immunoassay (IA) screening (cutoffs: 20, 50 and 100 ng/mL) for Δ9-THCCOOH was performed, and quantitation of cannabinoids was completed via LC–MS-MS. Urinary CBD concentrations (ng/mL...
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The US Food and Drug Administration (FDA) considers the development of abuse-deterrent formulations of solid oral dosage forms a public health priority and has outlined a series of premarket studies that should be performed prior to... more
The US Food and Drug Administration (FDA) considers the development of abuse-deterrent formulations of solid oral dosage forms a public health priority and has outlined a series of premarket studies that should be performed prior to submitting an application to the Agency. Category 1 studies are performed to characterize whether the abuse-deterrent properties of a new formulation can be easily defeated. Study protocols are designed to evaluate common abuse patterns of prescription medications as well as more advanced methods that have been reported on drug abuse websites and forums. Because FDA believes Category 1 testing should fully characterize the abuse-deterrent characteristics of an investigational formulation, Category 1 testing is time consuming and requires specialized laboratory resources as well as advanced knowledge of prescription medication abuse. Recent Advisory Committee meetings at FDA have shown that Category 1 tests play a critical role in FDA's evaluation of ...
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A series of compounds derived from phencyclidine (PCP) was examined in the sigma receptor and PCP receptor binding assays. The derivatives included compounds containing methylene, ethylene or carboxyl ethylene insertion between the... more
A series of compounds derived from phencyclidine (PCP) was examined in the sigma receptor and PCP receptor binding assays. The derivatives included compounds containing methylene, ethylene or carboxyl ethylene insertion between the cycloalkyl ring and the amine group of PCP. Various phenyl substitutions, cycloalkyl rings and amines of these derivatives were also examined. The methylene and ethylene insertions decreased the compounds' potencies at PCP receptors, whereas they increased the potencies at sigma receptors. The carboxyl ethylene insertion produced compounds with negligible potencies at PCP receptors while possessing high potencies for sigma receptors. One derivative (PRE-084; 2-(4-morpholino)ethyl 1-phenylcyclohexane-1-carboxylate hydrochloride) had an IC50 of 44 nM in the sigma receptor assay, an IC50 of more than 100,000 nM for PCP receptors and an IC50 higher than 10,000 nM in a variety of other receptor systems. In general, compounds with hydroxy-substituted phenyl...
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Research Interests: Chemistry, Analytical Chemistry, Chromatography, Medicine, Humans, and 13 moreAnalytical Toxicology, Male, Analytical, Urine, Saliva, Adult, Time Factors, Oxford university, Immunoassay, Gas Chromatography/mass Spectrometry, Reproducibility of Results, Marijuana abuse, and Pharmacology and pharmaceutical sciences
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In two separate studies, 5 drug-free male volunteers with a history of marijuana use were passively exposed to the sidestream smoke of 4 and 16 marijuana cigarettes (2.8% delta-9-tetrahydrocannabinol [THC]) for 1 h each day for 6... more
In two separate studies, 5 drug-free male volunteers with a history of marijuana use were passively exposed to the sidestream smoke of 4 and 16 marijuana cigarettes (2.8% delta-9-tetrahydrocannabinol [THC]) for 1 h each day for 6 consecutive days. A third study was similarly performed with 2 marijuana-naive subjects passively exposed to the smoke of 16 marijuana cigarettes. Passive smoke exposure was conducted in a small, unventilated room. Room air levels of THC and CO were monitored frequently. All urine specimens were collected and analyzed by EMIT d.a.u. assay, Abuscreen radioimmunoassay and GC/MS. The studies show that significant amounts of THC were absorbed by all subjects at the higher level of passive smoke exposure (eg., smoke from 16 marijuana cigarettes), resulting in urinary excretion of significant amounts of cannabinoid metabolites. However, it seems improbable that subjects would unknowingly tolerate the noxious smoke conditions produced by this exposure. At the lower level of passive marijuana-smoke exposure, specimens tested positive only infrequently or were negative. Room air levels of THC during passive smoke exposure appeared to be the most critical factor in determining whether a subject produced cannabinoid-positive urine specimens.
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Pharmaceutical risk management can be considered to be any strategies for minimizing risks and enabling the realization of the benefits of medications. Historically, risk management has been achieved through the drug label, which includes... more
Pharmaceutical risk management can be considered to be any strategies for minimizing risks and enabling the realization of the benefits of medications. Historically, risk management has been achieved through the drug label, which includes the US Controlled Substances Act (CSA) drug scheduling placement if abuse and dependence are considered sufficiently serious to warrant special restrictions. Since the late 1990s, additional strategies for addressing abuse- and dependence-related risks have been developed, including various postmarketing requirements for surveillance and reporting to the Food and Drug Administration. These strategies have been described in guidance documents and include risk assessment, risk management, and postmarketing surveillance. Preclinical abuse potential assessment provides early signals of potential risks and scheduling. Such studies are also considered in the premarket risk evaluation that guides recommendations concerning risk management strategies that go beyond drug scheduling along with the evaluation of abuse-deterrent drug products and how such evaluation might be informed by preclinical studies.
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Research Interests: Behavior, Medicine, Humans, Male, Smoke, and 4 moreCannabis, Pulse, Psychomotor Performance, and Dronabinol
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Research Interests: Psychology, Behavior, Performance, Medicine, Humans, and 15 moreProlactin, Hormones, Male, Cannabis, Aged, Middle Aged, Adult, Hormone, Adrenocorticotropic Hormone, Human Subjects, Luteinizing Hormone, Follicle stimulating hormone, hydrocortisone, Pharmacology and pharmaceutical sciences, and Dronabinol
Research Interests: Chemistry, Analytical Chemistry, Medicine, Sample Preparation, Quantitative analysis, and 15 moreHumans, Analytical Toxicology, Hair, Pharmacogenetics, Female, Male, Analytical, Buprenorphine, Atmospheric Pressure, Chemical Analysis, Adult, Retrospective Studies, Quantitative Analysis, Pharmacology and pharmaceutical sciences, and HPLC Chromatography
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Research Interests: Treatment, Pregnancy, Humans, Female, Infant, and 13 moreBuprenorphine, Health Status, Adult, Opioid Dependence, Pregnant Women, Prospective Study, Prenatal Care, Pregnancy Outcome, Outcome measure, Prenatal Exposure, Psychology and Cognitive Sciences, Pregnancy complications, and Medical and Health Sciences
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Examine the relationship between buprenorphine and norbuprenorphine plasma concentrations with subject-reported withdrawal symptomatology during buprenorphine dose induction, maintenance treatments (daily and alternate-day dosing) and... more
Examine the relationship between buprenorphine and norbuprenorphine plasma concentrations with subject-reported withdrawal symptomatology during buprenorphine dose induction, maintenance treatments (daily and alternate-day dosing) and withdrawal. Two groups of randomly assigned subjects inducted onto buprenorphine and maintained on 8 mg daily by the sublingual route for 18 days. Group 1 continued to receive daily buprenorphine to day 36. Group 2 subjects received alternate-day dosing of buprenorphine and placebo on days 19 to 36. Both groups received placebo on days 37 to 52. Inpatient facilities at the Addiction Research Center, Intramural Research Center, NIDA, Baltimore, MD. Eleven male, heroin-dependent volunteers participating in a research study. Medications for treatment of withdrawal symptoms were prescribed as needed after day 39 (72 hours after the last dose of buprenorphine). Plasma concentrations of buprenorphine and norbuprenorphine, withdrawal symptomatology and pupil diameter. The mean steady-state buprenorphine plasma concentration (24 hours) after daily administrations of sublingual buprenorphine for study days 21-35 was 0.80 ng/ml, and the mean alternate day steady-state buprenorphine plasma concentration (24 hours) was 0.77 ng/ml. Daily and alternate day steady-state norbuprenorphine plasma concentrations were 1.10 and 0.90 ng/ml, respectively. Predicted alternate day steady-state buprenorphine and norbuprenorphine plasma concentrations at 48 hours were 0.49 ng/ml and 0.57 ng/ml, respectively. Withdrawal scores varied inversely with plasma concentration. There were no significant differences between Groups 1 and 2 during steady-state (days 21-35) with regard to withdrawal scale scores or pupillary diameter. The overall, mean terminal elimination half-lives for buprenorphine and norbuprenorphine were 42 and 57 hours, respectively. during daily buprenorphine maintenance, plasma concentrations greater than 0.7 ng/ml of buprenorphine and norbuprenorphine were associated with minimal withdrawal symptoms. The long elimination half-life of buprenorphine suggested that increasing the buprenorphine dose with alternate-day administration may provide an effective, flexible therapy regimen for the treatment of opioid dependence.
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Page 110. CHAPTER 8 Interpreting Alternative Matrix Test Results Edward J. Cone, Ph. D., 1 Angela Sampson-Cone, Ph. D., 1 and Marilyn A. Huestis, Ph. D. 2* 1 ConeChem Research, Severna Park, Maryland 2 Chemistry ...
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Proposed changes to the Health and Human Services Guidelines for forensic urine drug testing will lower the required cannabinoid immunoassay cutoff concentration from 100 to 50 micrograms/L. We investigated the effect of this change on... more
Proposed changes to the Health and Human Services Guidelines for forensic urine drug testing will lower the required cannabinoid immunoassay cutoff concentration from 100 to 50 micrograms/L. We investigated the effect of this change on the sensitivity, specificity, and efficiency of eight cannabinoid immunoassays: Syva Emit d.a.u. 100; Syva Emit II 100; Syva Emit d.a.u. 50; Syva Emit II 50; Roche Abuscreen Online; Roche Abuscreen radioimmunoassay; Diagnostic Reagents; and Abbott ADx. All specimens also were assayed by gas chromatography/mass spectrometry. Lowering the cutoff concentration from 100 to 50 micrograms/L increased efficiencies and sensitivities for all immunoassays, with minor decreases in specificity (1.0-2.6%). There was a 23.2-53.6% increase in the number of true-positive specimens identified. Thus, lowering the cannabinoid immunoassay cutoff concentration from 100 to 50 micrograms/L resulted in detection of a substantial number of additional true-positive specimens, ...
Research Interests: Forensic Medicine, Comparative Study, Quantitative analysis, Cannabinoids, Clinical Chemistry, and 10 moreHumans, Medical Biotechnology, Male, Drug Addiction, Clinical Sciences, Immunoassay, Gas Chromatography/mass Spectrometry, Quantitative Analysis, Sensitivity and Specificity, and Medical biochemistry and metabolomics
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Qualitative urinalysis methods of monitoring cocaine use may over-detect frequency of use, possibly decreasing the ability of clinical trials to detect effective treatments. Quantitative urinalysis and newly developed criteria for... more
Qualitative urinalysis methods of monitoring cocaine use may over-detect frequency of use, possibly decreasing the ability of clinical trials to detect effective treatments. Quantitative urinalysis and newly developed criteria for identifying new cocaine use were evaluated as alternative measures of cocaine use. Urine specimens collected in a cocaine dosing study in non-treatment-seeking subjects (n = 5) and a cocaine treatment trial (n = 37) were analyzed for the cocaine metabolite, benzoylecgonine, with qualitative and quantitative methods. Pharmacokinetic criteria ('New Use' rules) were applied to quantitative data to identify occasions of new cocaine use. Results were compared to known cocaine administrations in the laboratory study and to self-reported drug use and qualitative urinalysis for subjects in the clinical trial. New Use criteria correctly identified cocaine administrations in the cocaine dosing study in all but a small number of specimens. In the clinical trial, quantitative urinalysis and estimated New Uses provided more information about patterns and frequency of use than qualitative urinalysis in the different treatment conditions in the clinical trial. Interpretation of quantitative urinalysis with New Use rules appears to be a useful method for monitoring treatment outcome and may be more accurate than traditional qualitative urinalysis in estimating frequency of cocaine use.
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ABSTRACT
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Despite their structural similarities, the natural products chelerythrine ( 5) and sanguinarine ( 6) target different binding sites on the pro-survival Bcl-X L protein. This paper details the synthesis of phenanthridine-based analogues of... more
Despite their structural similarities, the natural products chelerythrine ( 5) and sanguinarine ( 6) target different binding sites on the pro-survival Bcl-X L protein. This paper details the synthesis of phenanthridine-based analogues of the natural products that were used to probe this difference in binding profiles. The inhibitory constants for these compounds were then measured in a fluorescence polarization assay against Bcl-X L and the tagged Bak-BH3 peptide. The results led to structure-activity relationship studies, which identified the structural motifs required for binding-site specificity as well as inhibitory activity. We also identified synthetic analogues of the natural products that display similar binding modes but with more potent IC 50 values.
Research Interests: Pharmacology, Chemistry, Organic Chemistry, Medicinal Chemistry, Modeling, and 15 moreMagnetic Resonance Spectroscopy, Medicine, In Vitro, Computer Simulation, Mutation, Animals, Male, Phencyclidine, Medicinal, Molecular Model, Fluorescence polarization, Chemical Synthesis, Binding Site, Molecular Structure, and Pharmacology and pharmaceutical sciences
Oxymorphone was extensively metabolized by human, rat, dog, and guinea pig and to a lesser extent by rabbit. The most abundant metabolite in urine for all species was conjugated oxymorphone (12.7-81.7% administered dose) followed by 6... more
Oxymorphone was extensively metabolized by human, rat, dog, and guinea pig and to a lesser extent by rabbit. The most abundant metabolite in urine for all species was conjugated oxymorphone (12.7-81.7% administered dose) followed by 6 beta- and 6 alpha-carbinols produced by 6-keto reduction of oxymorphone. 6 beta-Oxymorphol (0.2-3.1%) was found in the urine of all species, whereas 6 alpha-oxymorphol (0.1-2.8%) was found only in human, rabbit, and guinea pig. Small amounts of free oxymorphone (less than or equal to 10%) were excreted by all species except rabbit, which excreted 31.7%. Overall recoveries of oxymorphone and metabolites from urine ranged from 15-96%, of which greater than 80% was excreted in the first 24 hr by all species except dog. Only 35% was excreted by dog during the first day. Stereoselectivity of 6-keto- reduction was observed for all species with the 6 beta-carbinol metabolite being most abundant in the urine of all but guinea pig. Considerable individual varia...
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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... more
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...