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Biomedical subjects

K L Preston

Publications and source records attributed to K L Preston.

At least 37 records · Page 2Linked to original sources
PubMed1998

Broad beneficial effects of cocaine abstinence reinforcement among methadone patients.

Escalating reinforcement for sustained abstinence has been effective in treating cocaine abuse. Under this schedule, patients receive vouchers for cocaine-free urine samples; vouchers have monetary values that increase with the number of consecutive cocaine-free urine samples. Cocaine-abusing methadone patients were randomly assigned to receive vouchers for 12 weeks under (a) an escalating schedule (n = 20), (b) an escalating schedule with start-up bonuses (n = 20), or (c) a noncontingent schedule (n = 19). Start-up bonuses were designed to provide added reinforcement for initiating abstinence; however, they did not improve outcomes. Both contingent interventions significantly increased cocaine abstinence. In addition, the contingent interventions increased abstinence from opiates and decreased reports of cocaine craving. These results replicate the efficacy of cocaine abstinence reinforcement and show that it can have broad beneficial effects.

Adult↗
PubMed1998

Opioid discrimination in humans: discriminative and subjective effects of progressively lower training dose.

The purpose of this study was to examine the extent of covariation of subjective and discriminative drug effects as the dose of the discriminated training drug was progressively lowered. Six adult male volunteers with histories of opioid abuse, who were not currently physically dependent, were trained to discriminate the mu-receptor agonist hydromorphone (20 mg, oral) from placebo in daily sessions. They received financial reinforcement for correct responses. The hydromorphone training dose was then progressively reduced (20, 14, 10, 7, 5, and 3.5 mg) while the discrimination reinforcement contingencies remained in effect. Measures of subjective and physiological effects were concurrently collected during each discrimination session. As the training dose decreased, discriminative performance was generally well maintained, although the percent of drug-appropriate responses to hydromorphone did decline from 98% to 75%. The magnitude of the subjective and physiological effects of hydromorphone also decreased as the training dose decreased. At the lowest training dose, there were no physiological effects and few subjective effects of hydromorphone statistically different from placebo, although discrimination behavior remained statistically significant at all doses. These data indicate covariation of subjective effects and discrimination performance and suggest that discrimination behavior may be more sensitive for differentiating among drug conditions than traditional subjective effects measures.

Adult↗
PubMed1998

Site of opioid action in the human brain: mu and kappa agonists' subjective and cerebral blood flow effects.

OBJECTIVE: Humans experience the subjective effects of mu and kappa opioid agonists differently: mu agonists produce mainly euphoria, while kappa agonists are more likely to produce dysphoria. This study tested the hypothesis that these subjective effects would be associated with anatomically distinct changes in regional cerebral blood flow (CBF) relative to baseline as assessed with single photon emission computed tomography (SPECT). METHOD: Nine nondependent opioid abusers participated in the study. In the first phase of the study, the participants were acclimated to effects of the study drugs. In the second phase they underwent repeat challenges with the study drugs followed by an assessment of CBF with use of the SPECT tracer [99mTc]HMPAO. Medications tested were the prototypic mu agonist hydromorphone, the mixed agonist/antagonist butorphanol (which has a kappa agonist component of activity), and saline placebo. RESULTS: Subjective effects of the drugs were distinctly different. Hydromorphone produced increased ratings of "good effects," while butorphanol led to more "bad effects." Hydromorphone significantly increased regional CBF in the anterior cingulate cortex, both amygdalae, and the thalamus--all structures belonging to the limbic system. Butorphanol caused a less distinct picture of regional CBF increases, mainly in the area of both temporal lobes. CONCLUSIONS: This study demonstrates that opioids with different subjective effects also produce statistically significant patterns of change in regional CBF from baseline, and the regions of statistical significance appear in different brain regions. In addition, these results demonstrate the applicability of SPECT functional neuroimaging in the study of medications with potential abuse liability.

Amygdala↗
PubMed1997

Rapid liquid-liquid extraction of cocaine from urine for gas chromatographic-mass spectrometric analysis.

A novel, simple and economic liquid-liquid extraction method for isolating cocaine from urine was developed utilizing gas chromatography-mass spectrometry (GC-MS) for analysis and quantification. The use of a single nonpolar organic solvent allowed only nonpolar analytes to be extracted from the biological fluid, and consequently, no derivatization step was necessary before GC-MS analysis. Large numbers of specimens (>60) can be extracted in approximately 3 h with this procedure. The method is highly precise (C.V. <7%), accurate (>98%), sensitive (limit of detection of 5 ng/ml) and has a mean recovery of 48.8%.

Alkanes↗
PubMed1997

The effects of buprenorphine in buprenorphine-maintained volunteers.

Buprenorphine is a mu opioid partial agonist currently used as an analgesic, and being developed for the treatment of opioid dependence. The purpose of this study was to determine the abuse liability of parenteral buprenorphine in volunteers maintained on daily sublingual (SL) buprenorphine (8 mg). In a residential laboratory, eight volunteers underwent pharmacologic challenges two times per week. Medication challenges were 16 h after the daily dose of buprenorphine, and consisted of double-blind IM injections of buprenorphine (4, 8, 16 mg), the prototypic mu opioid agonist hydromorphone (9 and 18 mg), or saline. Assessments consisted of physiologic monitoring, subjects' self-reports, and a trained observer's ratings of drug effects, and were collected for 0.5 h before and 2.0 h following injection. Supplemental doses of IM buprenorphine produced opioid agonist-like effects, indicating some abuse potential of parenteral buprenorphine in buprenorphine-maintained patients. There was incomplete cross-tolerance to the effects of hydromorphone, suggesting that higher maintenance doses of buprenorphine may be needed to maximize clinical efficacy. However, there was a lack of graded dose-effects for hydromorphone, suggesting that buprenorphine's combination of partial agonist effects and high affinity for opioid receptors may limit the magnitude of effects of supplemental full agonists. Finally, participants tolerated cumulative doses of maintenance buprenorphine plus challenge buprenorphine without adverse effects, suggesting higher doses of buprenorphine can be safely administered to opioid dependent patients.

Adult↗
PubMed1997

Discriminative stimulus and subjective effects of opioids with mu and kappa activity: data from laboratory animals and human subjects.

Although a large and rich body of data is available regarding the discriminative stimulus effects of opioids in laboratory animals and human subjects, it has been difficult to reconcile the data obtained from these two different sources. Therefore, the purpose of this review is to bring together data from both animal and human laboratories and systematically to compare the discriminative stimulus effects of opioids, in particular those with activity at both mu and kappa opioid receptor types (i.e., the mixed action opioids). The data that can be collected from laboratory animals differ from the data that can be collected in human subjects. In general, the advantage of studies in laboratory animals is that they can investigate very broad dose ranges of opioids as well as some very selective opioids that are not available for investigation in human subjects. Although investigations in human subjects are limited by the compounds and doses available for examination, the advantage of these studies is that they can examine the subjective as well as the discriminative stimulus effects of opioids. Taken together, studies conducted in laboratory animals and human subjects indicate that the mixed action opioids are best classified as intermediate efficacy mu agonists with additional activity through other non-mu, possibly kappa opioid systems.

Animals↗
PubMed1997

Cocaine effects on digital blood flow and diffusing capacity for carbon monoxide among chronic cocaine users.

PURPOSE: To determine the acute effects of intravenous (i.v.) cocaine on primarily digital skin blood flow and diffusion capacity for carbon monoxide (CO), and secondarily on subjective and cardiovascular measures. PATIENTS AND METHODS: A double-blind, Latin-square, placebo-controlled, dose-response study was conducted in an inpatient general clinical research center and clinical pharmacology unit of a university teaching hospital. Twelve adult males with histories of illicit drug use including i.v. cocaine received 0, 25, and 50 mg of i.v. cocaine given as 1-minute infusions, on 3 consecutive test days. Digital cutaneous blood flow was determined via laser doppler flowmetry and skin temperature. Diffusing capacity for carbon monoxide (DCO) was measured with standard techniques. Subjective responses were measured by oral report of a numerical ranking of strength of drug effect. Heart rate and blood pressure responses were measured by electronic sphygmomanometer. RESULTS: A maximal decrease in skin blood flow occurred at 2 to 3 minutes after infusion, and was not distinguished among drug conditions. Blood flow returned to baseline more rapidly after placebo than after cocaine: 7 minutes (placebo), 35 minutes (25 mg cocaine), 50 minutes (50 mg cocaine). Skin temperature decreased by 1.25 degrees C after placebo and by 2.75 and 3.25 degrees C after 25 and 50 mg of cocaine, respectively. DCO changed by -1.02 (mean) +/- 0.25 (standard deviation), 0.16 +/- 1.22, and 0.21 +/- 1.63 ml/min/mm Hg following placebo, 25, and 50 mg of cocaine, respectively. Typical subjective, chronotropic, and pressor responses to cocaine were demonstrated, and these occurred in close temporal relationship to digital blood flow and skin temperature responses. CONCLUSIONS: The digital cutaneous circulation is highly sensitive to vasoconstrictor effects of cocaine. Pulmonary blood volume tends to be preserved after i.v. cocaine. Subjective effects and cardiovascular responses occur in concert with peripheral blood flow changes. The peripheral vasoconstrictor effects have implications for cocaine users with concurrent vasospastic or vasculopathic disorders.

Adult↗
PubMed1997

Comparison of self-reported drug use with quantitative and qualitative urinalysis for assessment of drug use in treatment studies.

The effectiveness of substance abuse treatment programs can be monitored by self-reported drug use and objectively measured by qualitative and quantitative urinalysis. The advantages and disadvantages of each of these three methods of assessing drug use are reviewed. Data collected in a clinical trial of a behavioral treatment for cocaine abuse are used to evaluate the relationships among qualitative and quantitative urinalysis for cocaine metabolite and self-reported cocaine use. Qualitative and quantitative urine testing showed greater rates of drug use than that shown by self-report, though there were significant correlations between self-reported use and urine toxicology results. Benzoylecgonine concentrations in urine specimens supported the suggestions that rates of drug use as determined by qualitative urinalysis are artificially high due to carryover and were informative about subjects' patterns of use.

Evaluation Studies as Topic↗
PubMed1997

Assessment of cocaine use with quantitative urinalysis and estimation of new uses.

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.

Adolescent↗
PubMed1996

Sustained cocaine abstinence in methadone maintenance patients through voucher-based reinforcement therapy.

BACKGROUND: Chronic cocaine abuse remains a serious and costly public health problem. This study assessed the effectiveness of a voucher-based reinforcement contingency in producing sustained cocaine abstinence. METHODS: A randomized controlled trial compared voucher-based reinforcement of cocaine abstinence to noncontingent voucher presentation. Patients were selected from 52 consecutively admitted injecting heroin abusers in a methadone maintenance treatment program. Patients with heavy cocaine use during baseline period (N = 37) participated. Except where otherwise indicated, the term cocaine abuse is used in this article in a generic sense and not according to the DSM-III-R definition. Patients exposed to abstinence reinforcement received a voucher for each cocaine-free urine sample (ie, negative for benzoylecgonine) provided three times per week throughout a 12-week period; the vouchers had monetary values that increased as the number of consecutive cocaine-free urine samples increased. Control patients received noncontingent vouchers that were matched in pattern and amount to the vouchers received by patients in the abstinence reinforcement group. RESULTS: Patients receiving vouchers for cocaine-free urine samples achieved significantly more weeks of cocaine abstinence (P = .007) and significantly longer durations of sustained cocaine abstinence (P = .001) than controls. Nine patients (47%) receiving vouchers for cocaine-free urine samples achieved between 7 and 12 weeks of sustained cocaine abstinence; only one control patient (6%) achieved more than 2 weeks of sustained abstinence. Among patients receiving vouchers for cocaine-free urine samples, those who achieved sustained abstinence ( > or = 5 weeks) had significantly lower concentrations of benzoylecgonine in baseline urine samples than those who did not achieve sustained abstinence (P < or = .01). Patients receiving voucher reinforcement rated the overall treatment quality significantly higher than controls (P = .002). CONCLUSION: Voucher-based reinforcement contingencies can produce sustained cocaine abstinence in injecting polydrug abusers.

Adult↗
PubMed1996

Enhancement of cocaine's abuse liability in methadone maintenance patients.

The present study was conducted to determine whether methadone maintenance alters the pharmacodynamic effects of single doses of cocaine. Twenty-two current users of IV cocaine who were not seeking treatment for their illicit cocaine use participated while living on a research unit. Eleven were maintained on methadone 50 mg PO daily as treatment for their opioid abuse; 11 were opioid abusers who were not physically dependent on opioids and who provided opioid-free urines throughout the study. Each subject received acute cocaine challenge doses of 0, 12.5, 25, and 50 mg intravenously in random order under double-blind conditions in separate test sessions. Physiologic and subject-rated responses were measured before injection and for 2 h after. In the methadone maintenance group, cocaine challenge sessions occurred 15.5 h after the daily methadone dose. There were significant differences between the methadone-dependent and nondependent groups: 1) baseline differences related to chronic methadone administration and not associated with cocaine administration (lower respiration rates and pupil diameter; higher skin temperature) and 2) differences in response to cocaine administration; cocaine-induced increases in subject ratings of Drug Effect, Rush, Good Effects, Liking, and Desire for Cocaine and in heart rate were greater in the methadone maintenance patients compared to the non-dependent group. These results indicate that the positive subjective effects and some physiological effects of cocaine are enhanced in methadone-maintained individuals, suggesting a pharmacological basis for the high rates of cocaine abuse among methadone maintenance patients.

Adult↗
PubMed1996

Absorption rate of methylxanthines following capsules, cola and chocolate.

OBJECTIVE: To compare caffeine and theobromine absorption after oral administration of capsules, cola beverage and chocolate candy. METHODS: Three males and four females who abstained from methylxanthines received five methylxanthine-containing treatments: caffeine in capsules (72 mg), administered twice; theobromine in capsules (370 mg); cola beverage (72 mg caffeine) and chocolate candy (72 mg caffeine and 370 mg theobromine). Plasma methylxanthine levels were assayed from samples collected before and 0.25, 0.50, 0.75, 1.0, 1.5, 2.0, and 3.0 h after caffeine capsule and cola treatments and, additionally, at 4.0 and 6.0 h after theobromine capsule and chocolate treatments. RESULTS: Caffeine plasma concentrations increased rapidly and peaked at approximately 30 min following both capsule treatments 1 (Cmax: 1.93 micrograms.ml-1); and 2 (Cmax: 2.05 micrograms.ml-1). Relative to capsules, caffeine absorption from cola and chocolate was delayed and produced lower maximum caffeine plasma concentrations which peaked 1.5-2.0 h after treatment (For cola, Cmax: 1.57 micrograms.ml-1); and for chocolate, Cmax: 1.50 micrograms.ml-1. Theobromine plasma concentrations peaked approximately 3 h after capsule administration (Cmax: 6.72 micrograms.ml-1). Relative to capsules, theobromine absorption from chocolate was more rapid and produced higher maximum theobromine plasma concentrations which peaked approximately 2 h after treatment (Cmax: 8.05 micrograms.ml-1). CONCLUSIONS: The results suggest that a usual dietary portion of the cola or chocolate used in this study would produce behaviorally discriminable plasma levels of caffeine in most subjects and of theobromine in at least one subject.

Absorption↗
PubMed1996

Increasing opiate abstinence through voucher-based reinforcement therapy.

Heroin dependence remains a serious and costly public health problem, even in patients receiving methadone maintenance treatment. This study used a within-subject reversal design to assess the effectiveness of voucher-based abstinence reinforcement in reducing opiate use in patients receiving methadone maintenance treatment in an inner-city program. Throughout the study subjects received standard methadone maintenance treatment involving methadone, counseling, and urine monitoring (three times per week). Thirteen patients who continued to use opiates regularly during a 5-week baseline period were exposed to a 12-week program in which they received a voucher for each opiate-free urine sample provided: the vouchers had monetary values that increased as the number of consecutive opiate-free urines increased. Subjects continued receiving standard methadone maintenance for 8 weeks after discontinuation of the voucher program (return-to-baseline). Tukey's posthoc contrasts showed that the percentage of urine specimens that were positive for opiates decreased significantly when the voucher program was instituted. (P < or = 0.01) and then increased significantly when the voucher program was discontinued during the return-to-baseline condition (P < or = 0.01). Rates of opiate positive urines in the return-to-baseline condition remained significantly below the rates observed in the initial baseline period (P < or = 0.01). Overall, the study shows that voucher-based reinforcement contingencies can decrease opiate use in heroin dependent patients receiving methadone maintenance treatment.

Adult↗
PubMed1996

Opioid antagonist effects of dezocine in opioid-dependent humans.

Dezocine is an opioid mu-partial agonist recently approved for use as an analgesic in the United States. This study characterized the relative agonist versus antagonist effects of dezocine in comparison to naloxone (an opioid antagonist), hydromorphone (an opioid mu-agonist), and placebo (saline solution) in opioid-dependent volunteers. In a residential laboratory, six volunteer male opioid abusers maintained on 30 mg/day oral methadone underwent pharmacologic challenges two to three times per week, 20 hours after the last dose of methadone. Challenges consisted of a double-blind intramuscular injection of dezocine (dose range, 7.5 to 60 mg), hydromorphone (5 and 10 mg), naloxone (0.1 and 0.2 mg), or saline solution. Measures included physiologic indexes, self-reports of drug effects, and observer ratings of drug effects. Naloxone and hydromorphone produced characteristic antagonist-like and agonist-like effects, respectively. Dezocine acted as an opioid antagonist, precipitating a withdrawal syndrome only slightly different from that produced by naloxone. Dezocine's antagonist effects were not directly dose related, but peaked at intermediate doses and declined at higher doses.

Adult↗
PubMed1996

Cocaine disposition in meconium from newborns of cocaine-abusing mothers and urine of adult drug users.

The analysis of meconium for cocaine and metabolites has proved to be a reliable method for the detection of fetal cocaine exposure. Better sensitivity and a larger gestational window of detection have been demonstrated for meconium testing as compared with neonatal urine testing. Cocaine and cocaine metabolites, including benzoylecgonine, ecgonine methyl ester, cocaethylene, norcocaine, benzoylnorecgonine, and m-hydroxybenzoylecgonine, have been identified in meconium. The origin of these metabolites, whether maternal or fetal, has not been established. This study was conducted to compare the disposition of cocaine and metabolites in meconium from fetuses exposed to cocaine with that of urine from cocaine abusers. Meconium specimens were obtained from six neonates of mothers positive for cocaine use by urinalysis or self-reporting or both during pregnancy. Urine specimens were obtained from 17 adult female and 17 adult male cocaine users enrolled in a treatment program. Specimens were analyzed by gas chromatography-mass spectrometry for cocaine and 12 related analytes. The following analytes were identified and measured in meconium and urine: anhydroecgonine methyl ester; ecgonine methyl ester; ecgonine ethyl ester; cocaine; cocaethylene; benzoylecgonine; norcocaine; norcocaethylene; benzoylnorecgonine; m-and p-hydroxycocaine; and m-and p-hydroxybenzoylecgonine. In addition, both m-and p-hydroxybenzoylecgonine were found to exhibit approximately equal cross-reactivity with benzoylecgonine in the EMIT and TDx assays. The presence of p-hydroxybenzoylecgonine in meconium suggested that this newly identified metabolite, like m-hydroxybenzoylecgonine, might serve as a valuable marker of fetal cocaine exposure during pregnancy. The presence of cocaine and anhydroecgonine methyl ester in meconium was attributed to transfer across the placenta from the mother. However, the origin of the hydrolytic and oxidative metabolites of cocaine could not be established because they were also identified in urine specimens of adult female cocaine users and could have arisen in meconium from either fetal or maternal metabolism.

Adult↗
PubMed1996

Buprenorphine, morphine and naloxone effects during ascending morphine maintenance in humans.

One purpose of this study was to characterize the acute effects of the partial mu-opioid agonist buprenorphine administered to human subjects undergoing maintenance treatment with ascending doses of morphine. A second purpose was to examine the development of tolerance, cross-tolerance and physical dependence under the same morphine maintenance conditions. Six opioid-dependent volunteers were treated chronically with ascending morphine doses of 15, 30, 60 and 120 mg/day. Each morphine dosing level was maintained for 2 weeks, with test drugs administered during the second week of maintenance of each morphine dose. Both morphine (30 mg i.m.) and buprenorphine (6 mg i.m.) constricted pupils and produced reports of opioid-like subjective effects. The magnitude of these effects was inversely related to the morphine maintenance dose, with no effects being detected at higher maintenance levels. Naloxone (0.3 mg) produced little effect at lower morphine maintenance doses but precipitated withdrawal at higher maintenance doses. Buprenorphine failed to precipitate withdrawal even when subjects were treated with 120 mg/day morphine. These findings indicate that dose-dependent tolerance to morphine, cross-tolerance to buprenorphine and physical dependence develop during morphine maintenance. The finding that buprenorphine does not act as an antagonist under these dosing conditions further supports the clinical observation that there are conditions under which patients dependent on short-acting opioids can be comfortably transferred directly to buprenorphine maintenance treatment.

Adult↗
PubMed1996

Effects of naltrexone on response to intravenous cocaine, hydromorphone and their combination in humans.

This study evaluated the effects of i.v. cocaine, hydromorphone and their combination, and assessed the ability of oral naltrexone, an opioid antagonist, to modulate these effects. Volunteers with cocaine and heroin abuse histories (n = 8) participated in this placebo-controlled, cross-over study while residing on a closed research unit. Daily treatment with capsules containing placebo or naltrexone in ascending doses (3.125, 12.5, 50 and 200 mg) were given for 7-day periods. In thrice weekly experimental sessions, cocaine, hydromorphone and their combination were given in random order. Drug doses were given in an ascending order 1 hr apart as follows: cocaine at 0,20 and 40 mg, hydromorphone at 0, 1.5 and 3.0 mg, and the combination of 0 and 0 mg, 20 mg cocaine and 1.5 mg hydromorphone and 40 mg cocaine and 3.0 mg hydromorphone. Hydromorphone and cocaine produced distinct pharmacodynamic profiles, and the combination produced effects similar to both drugs. In some cases, the magnitude of effects produced by the combination was greater than that produced by either drug alone. Naltrexone produced dose-related blockade of hydromorphone effects, but did not after any of the physiological or subjective effects of cocaine. All naltrexone doses partially attenuated the effects of the combination and this appeared to be attributable to selective opioid blockade. These data do not support the use of naltrexone as a treatment for cocaine abuse, but suggest it may be useful for treating patients with concurrent cocaine and heroin abuse.

Adult↗