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Biomedical subjects

E J Cone

Publications and source records attributed to E J Cone.

At least 91 records · Page 5Linked to original sources
PubMed1992

Efficacy of urinalysis in monitoring heroin and cocaine abuse patterns: implications in clinical trials for treatment of drug dependence.

Urinalysis can be used as an objective criterion for monitoring the outcome of a treatment program or a clinical trial. Important factors to consider when implementing a drug testing program include standardization of assay technology and cutoffs between participating centers and selection of identical testing schedules. Also, it is vitally important to minimize the amount of safe time (time that drug use can go undetected) occurring in a testing schedule. The detection times for cocaine and heroin have been shown to vary with selection of cutoff and with the drug dose. Obviously, the selection of cutoffs is under program control, whereas the amount of illicit drug use is under subject control. Fortunately, changes in the illicit drug dose by the subject demonstrate a log-linear relationship to detection time. Hence, a higher drug dose by the subject only extends the detection time slightly (and improves the probability of detection) without greatly increasing the risks of drug carryover from one urine test to another. The most efficient testing schedule for judging the outcome of clinical trials for cocaine and heroin appears to be a 3-days-a-week schedule (Monday, Wednesday, Friday or Tuesday, Thursday, Saturday). When different schedules were challenged by simulating random times at which cocaine use might occur during the week, the 3-days-per-week schedule was the most efficient without the risk of carryover. The 3-days-per-week schedule also performed better than 1-day-per-week when multiple random drug use was simulated. Overall, the 3-days-per-week testing schedule with specified assay technology and cutoffs was the best compromise for maximizing detection of drug use, minimizing carryover, and providing a standardized methodology for outcome comparison between programs.

Clinical Trials as Topic↗
PubMed1992

Characterization of the absorption phase of marijuana smoking.

Rapid blood collection, a paced smoking protocol and timely collection of physiologic and behavioral measures were used to characterize the absorption phase of marijuana smoking. Six healthy males smoked a single marijuana cigarette (placebo, 1.75%, or 3.55% delta-9-tetrahydrocannabinol) in a double-blind, randomized, Latin square study design. Rapid blood sampling with a continuous withdrawal pump allowed simultaneous collection with concurrent physiologic and behavioral measures. Mean plasma levels of 7.0 and 18.1 ng/ml delta-9-tetrahydrocannabinol were observed after the first inhalation of a 1.75% and 3.55% delta-9-tetrahydrocannabinol cigarette, respectively. Blood levels increased rapidly and peaked at 9 minutes, before initiation of the last puff sequence at 9.8 minutes. Three of six subjects reported increases in drug "liking" scores after the first puff, and all subjects responded by the second puff of a high dose cigarette. Significant increases in heart rate and diastolic blood pressure occurred shortly after peak blood levels. Previous studies have indicated that there is a substantial time delay between peak plasma levels of delta-9-tetrahydrocannabinol and drug-induced effects. This study showed that behavioral and physiologic effects appear concurrently or within minutes after the rapid appearance of delta-9-tetrahydrocannabinol in blood during marijuana smoking.

Absorption↗
PubMed1992

The effects of chronic buprenorphine treatment on cocaine and food self-administration by rhesus monkeys.

The goal of this study was to determine if buprenorphine continues to reduce cocaine self-administration over long periods of treatment, or if tolerance develops to this effect. The effects of 30 to 120 days of buprenorphine treatment (0.32 mg/kg/day) on cocaine and food self-administration were examined in six rhesus monkeys. Saline control treatment was studied for 15 days before and after buprenorphine treatment. Intravenous cocaine (0.05 or 0.10 mg/kg) and food (1 g banana pellet) self-administration were maintained on a FR 4 (VR 16:S) schedule of reinforcement. Cocaine self-administration decreased significantly (P less than .0001) and remained 60 to 97% below saline treatment baseline levels (52 +/- 2 injections/day) throughout 120 days of buprenorphine treatment (P less than .01). After substitution of saline for buprenorphine, cocaine self-administration resumed and averaged between 21 (+/- 3.6) and 56 (+/- 6.5) injections per day over 20 days. Buprenorphine plasma levels averaged 18 (+/- 2.84) ng/ml (range 10.9-30 ng/ml) during buprenorphine treatment. Buprenorphine plasma levels usually decreased by 50% or more within 27 hr after the last buprenorphine dose. Low levels of buprenorphine (0.10-0.19 ng/ml) were measured for 30 to 74 days after abrupt termination of daily buprenorphine treatment. Food self-administration was initially reduced (P less than .01-.05), but tolerance to buprenorphine's suppression of food-maintained responding developed over 30 to 70 days of treatment. Food self-administration returned to and significantly exceeded (P less than .05-.01) saline treatment base-line levels, whereas cocaine self-administration remained significantly suppressed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Sigma compounds derived from phencyclidine: identification of PRE-084, a new, selective sigma ligand.

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 groups tended to have decreased potency at sigma receptors, whereas methylphenyl and chlorophenyl substitutions increased potencies. Reduction of cycloalkyl ring size decreased potencies for sigma receptors and quaternized amine groups invariably lowered the compound's potencies. Conformational analysis indicated that PRE-084 fitted onto a pharmacophore model for the sigma ligands. The study describes a new, highly selective ligand for the sigma receptor. The results of this study also confirm distinctly different structural requirements for binding to sigma and PCP receptors and provide a new structural consideration for synthesizing sigma-selective compounds.

Animals↗
PubMed1991

Pharmacodynamic and pharmacokinetic actions of ketocyclazocine enantiomers in the dog: absence of sigma- or phencyclidine-like activity.

The effects of the optical isomers and the racemic form of ketocyclazocine (KC) were compared with morphine and U-50,488H in the chronic spinal dog. l-KC and dl-KC produced depression of nociceptive reflexes, miosis, relaxation of the nictitating membrane and sedation, whereas d-KC lacked pharmacological activity. Peak plasma levels and distribution phase half-lives for dl-, l- and d-KC were similar, indicating no major dispositional differences between the isomers of KC despite a trend for d-KC to have a longer elimination half-life, slower plasma clearance and a greater apparent volume of distribution than l-KC. Although a relatively low dose of naltrexone (0.01 mg/kg) was sufficient to shift morphine dose-effect curves to the right, this dose of naltrexone was not sufficient to shift the dose-effect curves of dl-KC to the right. A dose of 1 mg/kg of naltrexone was required, consistent with the view that the effects were mediated by kappa opioid receptors. The overall pharmacological profile of l-KC differed from that of the more selective kappa opioid agonist U-50,488H, which produced both stimulatory and sedative effects. Neither l-KC nor U-50,488H produced pharmacological profiles typical of the sigma agonist d-N-allylnormetazocine or phencyclidine. The data suggest that the pharmacological activity of KC resides in the l-enantiomer, that the effects are kappa opioid receptor-mediated and that the binding of d-KC to haloperidol-sensitive sigma receptors does not produce N-allylnormetazocine- or phencyclidine-like actions in the dog.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1990

Changes in mood, craving, and sleep during short-term abstinence reported by male cocaine addicts. A controlled, residential study.

We examined changes over 28 days in mood states, craving for cocaine, and sleep during short-term abstinence reported by 12 male, predominantly intravenous-using, cocaine-addicted subjects residing in a research facility. For comparison, we examined 10 nonaddicted control subjects. There were no significant differences between cocaine addicts and controls regarding demographics and selected DSM-III-R diagnoses other than psychoactive substance use disorder and antisocial personality disorder. There were significantly higher scores of psychiatric symptoms reported by cocaine addicts 1 week before admission. Mood-distress and depression scores recorded at admission and during short-term abstinence were significantly greater than those reported by controls. Addicts' mood-distress scores and craving for cocaine were greatest at admission and decreased gradually and steadily during the 28-day study. There were no significant differences between groups regarding reports of sleep other than difficulty falling asleep and clearheadedness on arising. Although there were significant differences in resting heart rate at admission and over time, there were no significant differences in weight gain or blood pressure. Given the absence of a classic "withdrawal" pattern, "short-term abstinence" may be a more appropriate classification of psychological and physical phenomena experienced by cocaine addicts who initiate abstinence in a controlled environment.

Adult↗
PubMed1990

Cocaine inhibition of ligand binding at dopamine, norepinephrine and serotonin transporters: a structure-activity study.

Structure-activity relationships for cocaine and analog binding at the dopamine, norepinephrine and serotonin transporters were determined. Cocaine inhibition of ligand binding to each of these sites has a stereospecific requirement for the levorotatory isomer. Binding potencies of cocaine derivatives involving N-substitution, C2 and C3 substituent modifications, however, revealed differences in structure-activity relationships for cocaine binding at the transporters. Removal of the N-methyl groups produced little change in binding potency at the dopamine transporter site but produced increases in binding potency at norepinephrine and serotonin transporter sites. Changes in structure at the C2 substituent produced changes in binding potency at the dopamine transporter which were generally similar in direction, but not necessarily in magnitude at the norepinephrine and serotonin transporters. Modifications to the C3 substituent, especially substitution of a hydroxyl moiety, produce changes in affinity at norepinephrine and serotonin transporters which are much larger than those observed at dopamine transporters. In general, our results indicate that unique structural requirements exist for each transporter site, but that cocaine binding at norepinephrine and dopamine transporters can be described by more similar structure-activity relationships than those found for the serotonin transporter. Requirements for cocaine binding to the dopamine transporter, which we have previously shown to be associated with the reinforcing effects of cocaine, include levorotatory stereospecificity, the benzene ring at C3, at least some portions of the tropane ring, and the presence of the C2 methyl ester group in the beta conformation.

Animals↗
PubMed1990

Phencyclidine binding to striatal cocaine receptors.

PCP and related compounds inhibit 3H-mazindol binding to the cocaine receptor on dopamine transporters. The relative potencies of these compounds are such that some of the behavioral effects of PCP could be related to its action at the cocaine receptor; however, the affinity of PCP at the cocaine site (Ki = 1.59 microM) is less than its affinity at its own receptor (Ki about 0.12 microM). More data will be needed to conclusively implicate the cocaine receptor in the action of PCP.

Animals↗
PubMed1990

Acute and residual effects of marijuana: profiles of plasma THC levels, physiological, subjective, and performance measures.

Three experienced marijuana smokers participated in four 2-day experimental sessions in which they smoked either 0, 1, or 2 marijuana cigarettes containing 2.57% delta 9-tetrahydrocannabinol (THC) at two different times on the first day. A battery of physiological, subjective, and performance measures was repeated throughout day 1 to assess acute effects and on day 2 to measure any residual effects of marijuana. Blood samples were also repeatedly collected to examine the relationship between plasma levels and pharmacological effects of THC. Acutely, marijuana increased heart rate and subjective ratings of drug effects and slightly impaired performance on a circular lights task in all subjects. Performance was also impaired (decreased accuracy and increased response time) on serial addition/subtraction and digit recall tasks on day 1 in two subjects. On day 2, tachycardia and subjective effects of marijuana were not observed. Performance remained impaired on the arithmetic and recall tasks on day 2, although the decrements were not as large as those observed on day 1. In general, plasma THC levels covaried with the other measures. These preliminary results suggest that marijuana can adversely affect complex human performance up to 24 hours after smoking.

Adult↗
PubMed1990

Kappa opioid partial agonist activity of the enkephalin-like pentapeptide BW942C based on urination and in vitro studies in humans and animals.

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.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1990

Validity testing of commercial urine cocaine metabolite assays: IV. Evaluation of the EMIT d.a.u. cocaine metabolite assay in a quantitative mode for detection of cocaine metabolite.

The EMIT d.a.u. cocaine metabolite assay (EMIT dau) was evaluated in a quantitative mode for analysis of clinical specimens obtained after controlled cocaine administration to human subjects. The quantitative results showed high concordance with those of gas chromatography/mass spectrometry (GC/MS) assays of the same specimens for benzoylecgonine, and no false positive or false negative results were obtained. The evaluation also included analysis of standardized solutions containing benzoylecgonine, cocaine, and other cocaine metabolites and isomers. The EMIT dau antibody demonstrated high selectivity for benzoylecgonine. The precision was somewhat less than that reported earlier for other commercial cocaine metabolite immunoassays. Quantitation of initial screening results from EMIT dau testing can serve as a useful guide for confirmation by GC/MS in forensic science urine testing.

Cocaine↗
PubMed1990

The association of hepatitis delta virus and hepatitis B virus in parenteral drug abusers. 1971 to 1972 and 1986 to 1987.

From 1971 to 1972 (N = 105) and 1986 to 1987 (N = 160), parenteral drug abusers seropositive for hepatitis B virus (HBV) markers were screened for antibodies to the hepatitis delta virus (anti-HD). In both time frames anti-HD was independently associated with the hepatitis B surface antigen. It was observed that 31% of those positive for hepatitis B surface antigen from the early sample and 20% of those from the latter sample had detectable anti-HD, as opposed to 10% and 7%, respectively, of those negative for hepatitis B surface antigen. Anti-HD seropositivity was unrelated to gender and ethnicity, and in the 1971 and 1972 nationwide sample, its presence was unrelated to geographic location. The probability of manifesting anti-HD increased with the more HBV markers detected, particularly the number of different HBV antibody markers. We conclude that anti-HD was wide-spread in parenteral drug abusers at least as early as 1971, and that its expression was associated with hepatitis B surface antigen and the intensity of the immune response to HBV as evidenced by the number of different circulating HBV antibodies.

Adolescent↗
PubMed1989

Use of buprenorphine in the treatment of opiate addiction. I. Physiologic and behavioral effects during a rapid dose induction.

A new, rapid dose-induction procedure was used in the evaluation of buprenorphine hydrochloride (buprenorphine) as a treatment for opiate dependence. Nineteen heroin-dependent men were given buprenorphine sublingually in ascending daily doses of 2, 4, and 8 mg and then maintained on 8 mg daily. The observations of the transition from heroin to buprenorphine for the first 4 days are described. During this period, subjects reported significantly elevated ratings of "good effects" and feelings of "overall well-being" and decreased ratings of "overall sickness." Data from subscales of the Addiction Research Center Inventory indicated increasing euphoria and decreasing dysphoria and sedation after buprenorphine administration. Subjects and observers consistently identified buprenorphine as an opiate and not as an opiate antagonist. These findings indicate that a rapid dose induction with buprenorphine is acceptable to heroin-dependent persons and that it causes minimal withdrawal symptoms.

Administration, Sublingual↗
PubMed1989

The Lexington addicts, 1971-1972: demographic characteristics, drug use patterns, and selected infectious disease experience.

The demographics, drug habits, and medical complications of a cohort of 1,129 addicts treated at Lexington in the period 1971-1972 were studied. These patients, admitted from 41 different states, had a mean period of addiction of 5.4 years. Over one-third of the sample had engaged in pimping or prostitution, and there were no differences by gender in terms of involvement. Eight-eight percent had shared injection equipment, and surprisingly, 78% admitted to some effort at sterilizing their "works." Hepatitis was the most common associated medical condition: 87% had serologic markers of hepatitis B virus (HBV) infection, 60% had evidence of hepatitis A virus (HAV) exposure, and 47% had abnormal liver function parameters. Gynecomastia was evident in 2% of male subjects. Thirteen percent of the sample had a reactive VDRL assay, but 64% of these were biologically false positive. Subtle abnormalities of immune function were also observed; 18% of the patients had recent unexplained weight loss, 6% had lymphadenopathy, 8% had leukopenia, and 2% had lymphocytopenia. We conclude that both HBV and HAV were important infectious disease risks in these addicts, and that many evidenced deficiencies in immune function well before AIDS became a major public health concern.

Adolescent↗