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1.
J Anal Toxicol ; 44(5): 499-503, 2020 Apr 02.
Article in English | MEDLINE | ID: mdl-32049354

ABSTRACT

Phencyclidine (PCP) was first synthesized in 1926 and originally developed in 1950s as a general anesthetic agent. Abuse of PCP declined at the national level since its first illicit use in 1960s, but it continues in certain areas including Houston. This research evaluates PCP-positive cases of driving while intoxicated (DWI) in 2013-2018. The blood samples were collected from drivers, submitted by the Houston Police Department and analyzed for alcohol and drugs. Toxicological findings and demographic information were evaluated for the impaired driving cases tested positive for PCP in blood. Additionally, the Drug Recognition Expert (DRE) findings were examined for 12 cases in 2018. A total of 615 DWI cases positive for PCP in blood were identified in which the traffic offense occurred between August 2013 and December 2018. The mean (median, range) PCP concentration was 47 (43, 7-180) ng/mL. A total of 23% of those cases were females, and 77% were males; 85% were blacks, 10% were whites and 5% were other races/ethnicities as identified by the arresting officer. The mean age was 37 years. No significant differences in median and distribution of PCP concentrations (P's > 0.05) were observed across the offense years and among demographic cohorts. A total of 43% of the cases were positive for PCP only. Among the remaining 57%, cannabinoids are the most common concurrently detected analytes (35%), followed by cocaine/metabolite (14%) and ethanol (13%). The proportion of black male PCP-positive drivers decreased in younger age groups. Common indications observed by DRE officers included slurred speech, chemical breath odor, watery and/or bloodshot eyes, vertical/horizontal gaze nystagmus and impaired coordination/balance. This study provides valuable regional information to better understand the demographic patterns of PCP-impaired drivers in Houston, TX over 6 years. The findings may aid in designing and implementing regulations and prevention programs to reduce PCP-impaired driving.


Subject(s)
Driving Under the Influence/statistics & numerical data , Illicit Drugs/blood , Phencyclidine/blood , Substance Abuse Detection , Adolescent , Adult , Automobile Driving , Demography , Female , Humans , Male , Middle Aged , Texas
2.
Medicine (Baltimore) ; 98(52): e18295, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31876705

ABSTRACT

RATIONALE: 3-Methoxyphencyclidine (3-MeO-PCP) is a new psychoactive substance derived from phencyclidine. Although it can lead to severe intoxications, the main manifestations and optimal management have not been well characterized. Here, we report 2 cases of 3-MeO-PCP intoxication in the same patient, and summarize the manifestations of this intoxication reported in literature. PATIENT CONCERNS: A 17-year-old male purchased a bag of 3-MeO-PCP on the Internet but took an oral dose (200 mg) that corresponds to the less active isomer 4-MeO-PCP. He developed high blood pressure (158/131 mm Hg), tachycardia (100 bpm), and neurological manifestations (confusion, hypertonia, nystagmus, and then agitation). A maculopapular rash appeared, although this may have been related to the administration of midazolam. Hyperlactatemia (2.6 mmol/L) was the main laboratory finding. Seven days later, he returned to the emergency department after sniffing 50 mg of 3-MeO-PCP. High blood pressure, tachycardia, and neurological manifestations (psychomotor impairment and dysarthria) were present but less severe than after the first intoxication. DIAGNOSIS: In the first intoxication, the blood and urine 3-MeO-PCP concentrations were, respectively, 71.1 ng/mL and 706.9 ng/mL. Conventional toxicity tests were all negative. In the second intoxication, biological samples were not available. INTERVENTIONS: In the first intoxication, treatment consisted of intravenous hydration and midazolam. The patient was transferred to an intensive care unit for monitoring. After the second intoxication, he was monitored for 12 hours. OUTCOMES: The patient's condition improved quickly in both cases. LESSONS: These cases provide additional information on the manifestations of 3-MeO-PCP intoxication. These manifestations are mainly cardiovascular (high blood pressure, tachycardia) and neurological. The fact that second (50 mg) intoxication was less severe than the first (200 mg) is suggestive of a dose-effect relationship for 3-MeO-PCP. The first case also emphasizes the risk of dosing errors caused by the similarity between the names "3-MeO-PCP" and "4-MeO-PCP."


Subject(s)
Designer Drugs/poisoning , Phencyclidine/analogs & derivatives , Adolescent , Humans , Hypertension/chemically induced , Male , Phencyclidine/blood , Phencyclidine/poisoning , Phencyclidine/urine , Substance-Related Disorders/complications , Substance-Related Disorders/diagnosis , Tachycardia/chemically induced
3.
J Forensic Leg Med ; 65: 101-104, 2019 Jul.
Article in English | MEDLINE | ID: mdl-31129558

ABSTRACT

Structural analogs of classic drugs, also called designer drugs, are a booming market due to the easy accessibility on the internet and their legal status. One of those 'legal highs' is an analog of phencyclidine, namely 3-methoxyphencyclidine (3-MeO-PCP). Very few fatalities have been reported where 3-MeO-PCP contributed to the death of an individual. We present the first fatal case in the Netherlands and one of the few worldwide. Postmortem biological samples and the presumed abused unknown substance, sold as ant poison, were obtained. 3-MeO-PCP was detected, and the resulting concentration was 152 µg/l in whole blood. The presumed taken unknown sample was identified as 3-MeO-PCP and thus linked to the victim. The cause of death was a combination of 3-MeO-PCP, amphetamine, and alcohol. Improved diagnostic skills are necessary to face these emerging novel psychoactive substances also in light of public health and social risks.


Subject(s)
Designer Drugs/poisoning , Phencyclidine/analogs & derivatives , Psychotropic Drugs/poisoning , Adult , Amphetamine/blood , Blood Alcohol Content , Chromatography, Liquid , Designer Drugs/analysis , Humans , Male , Mass Spectrometry/methods , Netherlands , Phencyclidine/blood , Phencyclidine/poisoning , Psychotropic Drugs/blood , Substance-Related Disorders/blood
4.
J Anal Toxicol ; 43(4): 321-324, 2019 May 01.
Article in English | MEDLINE | ID: mdl-30476158

ABSTRACT

In this article, two fatal cases related to the use of 3-methoxyphencyclidine (3-MeO-PCP) are described. This compound is a new psychoactive substance that belongs to the phencyclidine family. In the recent period, this dissociative drug has gained interest because of its proposal as a legally available alternative to phencyclidine in some countries. The scientific literature related to 3-MeO-PCP is very poor. Using standard ultra-performance liquid chromatography-mass spectrometry and ultra-performance liquid chromatography-tandem mass spectrometry, the authors focused on the detection of 3-MeO-PCP and its metabolites in human urine. 3-MeO-PCP metabolism was studied in vitro after drug incubation with human liver microsomes and the identified metabolites were investigated in the urine of the two forensic cases. 3-MeO-PCP metabolites, including O-demethyl-3-MeO-PCP, piperidine-hydroxy-3-MeO-PCP, O-demethyl-piperidine-di-hydroxy-3-MeO-PCP and piperidine-di-hydroxy-3-MeO-PCP, were detectable in the urine from both cases and the ratio between metabolites and parent 3-MeO-PCP, always lower than 1, were calculated to estimate the proportionality of metabolites. At this stage, one can conclude that testing for 3-MeO-PCP metabolites does not increase the window of detection of the drug.


Subject(s)
Drug Overdose/blood , Drug Overdose/urine , Hallucinogens/blood , Hallucinogens/urine , Phencyclidine/analogs & derivatives , Substance Abuse Detection , Adult , Autopsy , Chromatography, Liquid , Designer Drugs , Fatal Outcome , Female , Femoral Artery , Forensic Toxicology , Humans , Illicit Drugs/blood , Illicit Drugs/urine , In Vitro Techniques , Male , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Osmolar Concentration , Phencyclidine/blood , Phencyclidine/urine , Tandem Mass Spectrometry
5.
J Anal Toxicol ; 41(6): 503-507, 2017 07 01.
Article in English | MEDLINE | ID: mdl-28830118

ABSTRACT

3- and 4-methoxyphencyclidine (3-MeO-PCP, 4-MeO-PCP), structural analogs of phencyclidine (PCP), were among the first legal PCP alternatives to show up on the novel psychoactive substances (NPS) market in Europe in the 2000s. Their structural similarities to PCP and ketamine likely contribute to their demonstrated dissociative anesthetic effects. Limited information exists in the literature about toxic and lethal concentrations of these drugs in biological samples. This case report presents the first two death cases in Washington State in which 3-MeO-PCP was identified. Alkaline drug screen analysis by gas chromatography-mass spectrometry (GC-MS) revealed a peak with a retention time similar to PCP and base peak of m/z 230. Certified reference materials for 3-and 4-MeO-PCP were obtained and the isomers were able to be distinguished based on different retention times and mass spectra. A quantitative GC-MS method was developed and validated for casework, utilizing a dynamic range of 10-1,000 ng/mL and a limit of detection of 1 ng/mL. Postmortem (peripheral/central) blood samples were analyzed using this method and the resulting concentrations were 0.63 and 3.2 mg/L of 3-MeO-PCP. Methamphetamine (0.11 mg/L) was additionally detected in the blood of one of the decedents; while the second decedent was additionally positive for ethanol (0.047 g/100 mL), bupropion (1.8 mg/L), delorazepam, paroxetine and mitragynine. The results presented in this case report are higher than previously reported concentrations in fatal cases, but the presence of polysubstance abuse is consistent with previously reported NPS intoxications. Both of these individuals were in drug rehabilitation facilities prior to their deaths; however, users continue to be drawn to 3-MeO-PCP due to its dissociative effects and its accessibility on the internet.


Subject(s)
Drug Overdose/diagnosis , Phencyclidine/analogs & derivatives , Psychotropic Drugs/poisoning , Substance Abuse Detection/methods , Drug Overdose/mortality , Humans , Illicit Drugs , Phencyclidine/blood , Phencyclidine/poisoning , Psychotropic Drugs/blood , Washington
6.
J Psychoactive Drugs ; 49(4): 289-293, 2017.
Article in English | MEDLINE | ID: mdl-28590798

ABSTRACT

BACKGROUND: Methoxetamine and 3-methoxy-phencyclidine are novel arylcyclohexylamines whose use and clinical toxicity are poorly reported in the medical literature. We report a case of analytically confirmed use of both methoxetamine and 3-methoxy-phencyclidine. CASE REPORT: A 27-year-old male presented 10 hours after insufflating an Internet-obtained powder. He was hypertensive, tachycardic, and demonstrated dissociated affect, a delayed verbal response to questions, ataxia, and vertical nystagmus. A urine drug screen was positive for phencyclidine and 11-nor-delta9-THC-9-carboxylic acid. He was admitted and his mental status and blood pressure normalized eight hours later. Blood samples (0, 2, and 3 hours from arrival) and the powders were analyzed by liquid chromatography-quadrupole time-of-flight mass spectrometry. Methoxetamine and 3-methoxy-phencyclidine were detected in all samples (279 ng/ml, 205 ng/ml, and 180 ng/ml for methoxetamine; 167 ng/mL, 131 ng/mL, and 90 ng/ml for 3-methoxy-phencyclidine at 0, 2, and 3 hours, respectively). No phencyclidine or tetrahydrocannabinol was detected. Two powders contained methoxetamine while one contained 3-methoxy-phencyclidine. CONCLUSION: The literature regarding methoxetamine and 3-methoxy-phencyclidine toxicity is limited. Methoxetamine use is associated with altered mental status, ataxia, and hypertension. Toxicity from 3-methoxy-phencyclidine is poorly described. There is no prior case describing serial qualitative analysis. Health care providers should be aware of the novel arylcyclohexylamines and their toxicity.


Subject(s)
Illicit Drugs/adverse effects , Ketamine/blood , Phencyclidine/blood , Adult , Cyclohexanones/blood , Cyclohexylamines/blood , Dronabinol/blood , Humans , Male , Substance Abuse Detection/methods
7.
J Anal Toxicol ; 40(7): 504-10, 2016 Sep.
Article in English | MEDLINE | ID: mdl-27339479

ABSTRACT

We present in this case report a validated method for accurate quantitative analysis of 3-methoxy phencyclidine (3-MeO-PCP) to determine postmortem blood concentrations of this PCP analog. A 29-year-old male with a history of illicit drug use was found unresponsive in his bed with a bag of white powder next to him. Resuscitation efforts were unsuccessful and the individual was pronounced dead 9 minutes after arrival to the hospital. Initial ELISA screening suggested the presence of PCP in the decedent's blood. However, confirmatory testing revealed no detectable PCP. Instead, a large peak corresponding to a m/z 274.218 species with retention time similar to PCP was present on a LC-TOF-MS drug screen, suggesting a possible PCP analog. This mass corresponds specifically to a methoxy-PCP analog, several of which are available for purchase online. Standards for 3-MeO-PCP and 4-MeO-PCP were obtained and injected on the same instrument. Although the 3- and 4-MeO-PCP analogs have identical masses and retention times, they are still distinguishable through their mass spectra. The peak from the decedent's sample matched both the mass spectrum and the retention time of 3-MeO-PCP. A quantitative LC-MS-MS method was subsequently developed and validated for casework. Analysis using this method revealed a concentration of 139 ± 41 µg/L 3-MeO-PCP in the decedent's blood. Diphenhydramine (4.1 ± 0.7 mg/L), marijuana metabolite (presumptive positive, confirmation not performed) and a small amount of amphetamine (<0.10 mg/L) were also found in the decedent's blood. The cause of death was determined to be combined 3-MeO-PCP, diphenhydramine and amphetamine toxicity. The manner of death was certified as an accident.


Subject(s)
Drug Overdose/diagnosis , Phencyclidine/analogs & derivatives , Substance Abuse Detection/methods , Adult , Drug Overdose/blood , Enzyme-Linked Immunosorbent Assay , Fatal Outcome , Forensic Toxicology , Humans , Male , Phencyclidine/blood , Phencyclidine/poisoning
8.
Clin Toxicol (Phila) ; 53(9): 856-64, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26295489

ABSTRACT

BACKGROUND: 3-Methoxy-phencyclidine (3-MeO-PCP) and 4-methoxy-phencyclidine (4-MeO-PCP) are analogs of and drug substitutes for the dissociative substance PCP ("Angel dust"), a recreational drug that was most popular in the 1970s. In Sweden, use of methoxylated PCP analogs was noted starting in mid-2013, according to statistics from the Poisons Information Centre. The objective of this case series was to present clinical and bioanalytical data from analytically confirmed non-fatal intoxications associated with 3-MeO-PCP and/or 4-MeO-PCP within the STRIDA project. STUDY DESIGN: Observational case series of consecutive patients with self-reported or suspected exposure to new psychoactive substances (NPS) and who require hospital care. PATIENTS AND METHODS: Blood and urine samples were collected from intoxicated patients presenting at emergency departments (ED) or intensive care units (ICU) all over Sweden. NPS analysis was performed by multicomponent liquid chromatographic-tandem mass spectrometric (LC-MS/MS) and LC-high-resolution MS (LC-HRMS) methods. Data on clinical features were collected during Poisons Information Centre consultations and retrieved from medical records. RESULTS: The Poisons Information Centre registered its first call related to methoxylated PCP analogs in July 2013, while analytically confirmed cases first appeared in October 2013. From July 2013 to March 2015, 1243 cases of suspected NPS intoxication originating from ED or ICU were enrolled in the STRIDA project. During the 21-month period, 56 (4.5%) patients tested positive for 3-MeO-PCP and 11 (0.9%) for 4-MeO-PCP; 8 of these cases involved both substances. The 59 patients were aged 14-55 (median: 26) years and 51 (86%) were men. Co-exposure to other NPSs and/or classical drugs of abuse was common with only 7 cases (12%) indicated to be 3-MeO-PCP single-substance intoxications; prominent clinical signs seen in the latter cases were hypertension (systolic blood pressure ≥ 140 mmHg; 7 cases), tachycardia (≥ 100/min; 5 cases), and altered mental status (4 cases) including confusion, disorientation, dissociation, and/or hallucinations. Mixed-drug users displayed not only the same clinical features, but also more sympathomimetic effects including agitation (38%) and dilated pupils (33%). Patients testing positive for 3-/4-MeO-PCP were typically under medical care for 1-2 days (85%), and 37% of all cases were graded as severe intoxications (Poisoning Severity Score 3). Besides standard supportive therapy, 49% of the patients were treated with benzodiazepines and/or propofol. CONCLUSION: Laboratory analysis constitutes an important basis for the assessment of NPS hazard and availability. The adverse effects noted in cases of acute intoxications involving 3- and/or 4-MeO-PCP resembled those of other dissociatives such as PCP, ketamine, and methoxetamine. However, similar to intoxications involving other NPS, poly-substance use was found to be common.


Subject(s)
Phencyclidine Abuse/epidemiology , Phencyclidine/analogs & derivatives , Phencyclidine/poisoning , Adolescent , Adult , Biomarkers/blood , Biomarkers/urine , Chromatography, Liquid , Drug Overdose , Female , Hospitalization , Humans , Male , Middle Aged , Phencyclidine/blood , Phencyclidine/urine , Phencyclidine Abuse/diagnosis , Phencyclidine Abuse/physiopathology , Phencyclidine Abuse/therapy , Poison Control Centers , Predictive Value of Tests , Severity of Illness Index , Substance Abuse Detection/methods , Sweden/epidemiology , Tandem Mass Spectrometry , Time Factors , Young Adult
9.
J Anal Toxicol ; 38(8): 569-74, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25217548

ABSTRACT

In December 2012, the possession and private use of limited quantities of marijuana and marijuana products became legal in the state of Washington. At the same time, the state's driving under the influence statutes were amended to include a per se level of 5 ng/mL delta(9)-tetrahydrocannabinol (THC) in whole blood for drivers aged 21 years and older. The aim of this study was to assess the effect of marijuana legalization on the prevalence of marijuana in suspected impaired driving cases. The prevalence of both active THC and its metabolite carboxy-THC detected in such cases pre-legalization was compared with the prevalence post-legalization. In 2009-2012, the average yearly percentage of cases positive for THC and carboxy-THC was 19.1% (range: 18.2-20.2%) and 27.9% (range: 26.3-28.6%), respectively. In 2013, the percentages had significantly increased to 24.9 and 40.0%, respectively (P < 0.05). The median THC concentration over the 5-year period ranged from 5.2 to 6.3 ng/mL, with individual concentrations ranging up to 90 ng/mL. An average of 56% of cases were at or >5 ng/mL over the 5-year period. The prevalence of alcohol and the majority of other drugs in this same population of suspected impaired drivers submitted for testing did not change during this same 5-year period-marijuana was the only drug to show such an increase in frequency. Further, this observed increase remained after the data had been normalized to account for changes in laboratory testing procedures that occurred during this time period. Future studies need be conducted to ascertain whether the observed increase has had any effect on the incidence of crashes, serious injuries and/or traffic fatalities.


Subject(s)
Automobile Driving , Cannabis/chemistry , Substance Abuse Detection/methods , Adolescent , Adult , Aged , Aged, 80 and over , Amphetamines/blood , Antidepressive Agents, Tricyclic/blood , Barbiturates/blood , Benzodiazepines/blood , Cannabinoids/blood , Cocaine/blood , Dextropropoxyphene/blood , Female , Humans , Male , Methadone/blood , Middle Aged , Phencyclidine/blood , Washington , Young Adult
10.
J Forensic Leg Med ; 19(2): 77-82, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22281215

ABSTRACT

The use of psychoactive substances to improve social relations and increase body energy, in Rave Culture, has raised many legal and health public concerns, both for illicit trade and consumption. Therefore, forensic toxicology plays an important role in this area, mainly linked to the detection and quantitation of these substances, both in vivo and in post-mortem samples. In fact, at the moment, forensic sciences have been under public authorities' scrutiny and critical look, due to the increasing attention of the media and public opinion, always applying for the use of scientific knowledge to help solving forensic cases. However, forensic toxicology results are only reliable to solve legal cases if all the analytical methodologies used are appropriately validated. In this work, a methodology for the extraction and analysis of 7-aminoflunitrazepam, buprenorphine, flunitrazepam, ketamine, methadone, phencyclidine (PCP) and d-propoxyphene was developed for whole blood samples, with solid phase extraction (SPE), using OASIS(®) MCX SPE columns, and gas chromatography coupled to mass spectrometry. The procedure presented here proved to be reliable, specific, selective and sensitive, with good LODs and LOQs and good precision.The adoption of a SPE procedure with an automatic SPE extraction device, allowed an increased level of automation in sample treatment, being contemporarily less time-consuming, increasing productiveness, and allowing good recovery and appropriate selectivity being, also, simple and reproducible. The simultaneous detection and quantitation of all compounds by the same extraction and detection methodology is crucial and has a great potential for forensic toxicology and clinical analysis.


Subject(s)
Illicit Drugs/blood , Narcotics/blood , Buprenorphine/blood , Dextropropoxyphene/blood , Flunitrazepam/analogs & derivatives , Flunitrazepam/blood , Forensic Toxicology , Gas Chromatography-Mass Spectrometry , Humans , Ketamine/blood , Limit of Detection , Methadone/blood , Phencyclidine/blood , Solid Phase Extraction
12.
Methods Mol Biol ; 603: 461-7, 2010.
Article in English | MEDLINE | ID: mdl-20077098

ABSTRACT

Phencyclidine (PCP) is a cycloalkylamine and is classified as a dissociative anesthetic. In the 1950s, PCP was tested as an intravenous anesthetic but due to its severe side effects, it was withdrawn from the clinical use. Since then PCP has become an illegal street drug making its laboratory analysis forensically essential. PCP can be detected in urine, serum, or plasma by immunoassays and quantified by gas or liquid chromatography mass spectrometry. In the method described here, a deuterated internal standard is added to the sample and the drug is extracted under alkaline conditions. Analysis is conducted using gas chromatography mass spectrometry (GC-MS). Quantitation of PCP is done by comparing the responses of unknown samples to the standards using selected ion monitoring.


Subject(s)
Gas Chromatography-Mass Spectrometry/methods , Phencyclidine/blood , Phencyclidine/urine , Humans , Reproducibility of Results
13.
Anal Bioanal Chem ; 393(2): 709-18, 2009 Jan.
Article in English | MEDLINE | ID: mdl-18982317

ABSTRACT

An analytical procedure for the simultaneous determination in human plasma and oral fluids of several illicit drugs belonging to different chemical and toxicological classes is presented. Amphetamine, methamphetamine, morphine, 6-monoacetylmorphine, methylenedioxyamphetamine, methylenedioxyethylamphetamine, methylenedioxymethamphetamine, cocaine, benzoylecgonine, tetrahydrocannabinol, carboxytetrahydrocannabinol, ketamine, and phencyclidine have been quantified in real samples using a very rapid sample treatment, basically a protein precipitation. The quantitative analysis was performed by liquid chromatography-tandem mass spectrometry and has been fully validated. All the analytes were detected in positive ionization mode using a TurboIonSpray source, except carboxytetrahydrocannabinol, which was detected in negative ionization mode. The use of a diverter valve between the column and the mass spectrometer allows the preservation of the ion source performances for high-throughput analysis.


Subject(s)
Body Fluids/chemistry , Chromatography, High Pressure Liquid/methods , Illicit Drugs/blood , Tandem Mass Spectrometry/methods , 3,4-Methylenedioxyamphetamine/blood , Amphetamine/blood , Calibration , Cocaine/analogs & derivatives , Cocaine/blood , Dronabinol/analogs & derivatives , Dronabinol/blood , Humans , Ketamine/blood , Methamphetamine/blood , Morphine/blood , Morphine Derivatives/blood , N-Methyl-3,4-methylenedioxyamphetamine/blood , Phencyclidine/blood , Sensitivity and Specificity , Time Factors
14.
Prog Neuropsychopharmacol Biol Psychiatry ; 32(2): 414-22, 2008 Feb 15.
Article in English | MEDLINE | ID: mdl-17945407

ABSTRACT

In a putative model of acute phencyclidine (PCP)-induced psychosis we evaluated effects of the drug on locomotor activity (LMA) and immediate early gene (IEG) induction in the rat using two routes of drug administration, intraperitoneal (i.p.) and subcutaneous (s.c.). Adult male rats received saline or PCP (1.0-5.0 mg/kg) either i.p or s.c. and were assessed for LMA for 60 min. At the end of the LMA testing animals were culled and blood and brain samples were collected for PCP concentration analysis. Separate cohorts of animals received 5.0 mg/kg PCP (i.p. or s.c.) and were used to investigate (1) the pharmacokinetics of PCP or (2) induction of IEG (Arc, c-fos, BDNF, junB, Krox-20, sgk-1, NURR1, fra-2, Krox-24, and egr-3) mRNA expression in the prefrontal cortex (PFC). Administration of PCP resulted in locomotor hyperactivity which was more robust and longer-lasting in animals dosed s.c. compared to i.p.-treated-animals. Differences in hyperlocomotion were paralleled by higher concentrations of PCP in the blood and in the brain of s.c.-treated animals compared to i.p.-treated animals. The differences in the concentration of PCP between the two routes of administration were detected 30 min after dosing and persisted for up to 4 h. Administration of PCP via the s.c. route resulted in induction of more IEGs and consistently larger magnitudes of induction than that via the i.p. route. Therefore, we have outlined the dosing conditions to induce rapid and robust effect of acute PCP on behaviour, gene induction, and pharmacokinetic profile, to allow investigation of this as a potential animal model of acute psychosis.


Subject(s)
Behavior, Animal/drug effects , Gene Expression Regulation/drug effects , Motor Activity/drug effects , Phencyclidine/administration & dosage , Phencyclidine/pharmacokinetics , Psychoses, Substance-Induced/etiology , Schizophrenia/chemically induced , Animals , Behavior, Animal/physiology , Brain/drug effects , Brain/metabolism , Disease Models, Animal , Genes, Immediate-Early/drug effects , Genes, Immediate-Early/genetics , Injections, Intraperitoneal , Injections, Subcutaneous , Male , Motor Activity/physiology , Phencyclidine/blood , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction , Transcriptional Activation
16.
J Mass Spectrom ; 40(1): 19-24, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15584009

ABSTRACT

A liquid chromatographic/tandem mass spectrometric method is described for the determination of phencyclidine (PCP) in small volumes of rat serum (e.g. 50 microl). Samples were extracted using a mixed-mode strong cation-exchange column and then separated isocratically using a narrow-bore (2.1 mm i.d.) 3 microm Hypersil phenyl column and a mobile phase consisting of an ammonium formate buffer (pH 2.7) with 60% (v/v) methanol. Detection was accomplished using positive ion electrospray ionization in the multiple reaction monitoring mode. Mass spectra were obtained and peaks were observed at an m/z (% abundance) of 244 (100), 159 (25), and 86 (89). Tandem mass spectra were also obtained from the m/z 244 precursor ion with peaks observed at m/z 159 (100), 86 (96), and 91 (11). Optimum serum PCP sensitivity and precision were obtained at a transition of m/z 244 --> 159. Matrix-associated ion suppression did not significantly affect the accuracy (100-112%) or precision (CV < or =8%) of the assay. The lower limit of quantitation was 1 ng ml(-1) in 50 microl of serum. The method was used to study the serum pharmacokinetics of PCP in rats after an intravenous bolus dose of PCP.


Subject(s)
Hallucinogens/blood , Phencyclidine/blood , Spectrometry, Mass, Electrospray Ionization/methods , Substance Abuse Detection/methods , Animals , Chromatography, High Pressure Liquid , Hallucinogens/administration & dosage , Hallucinogens/pharmacokinetics , Injections, Intravenous , Male , Phencyclidine/administration & dosage , Phencyclidine/pharmacokinetics , Rats , Rats, Sprague-Dawley , Reproducibility of Results , Sensitivity and Specificity
17.
Neuropsychopharmacology ; 29(2): 300-7, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14560321

ABSTRACT

N-methyl-D-aspartate (NMDA) receptors may play a critical role in the pathophysiology of schizophrenia. In rodents, NMDA receptor antagonists, such as phencyclidine (PCP), induce dopaminergic dysregulation that resembles the pattern observed in schizophrenia. The present study investigates the degree to which concurrent treatment with NMDA modulators, such as glycine and the recently developed glycine transport antagonist N[3-(4"-fluorophenyl)-3-(4"-phenylphenoxy)propyl]sarcosine (NFPS) prevents dopaminergic dysregulation observed following chronic (3 months) or subchronic (2 weeks) PCP administration. Both chronic and subchronic treatment with PCP in the absence of glycine or NFPS led to significant potentiation of amphetamine-induced dopamine release in the prefrontal cortex and striatum, similar to that observed in schizophrenia. Treatment with either high-dose glycine or NFPS along with PCP prevented PCP effects. These findings demonstrate effective doses of glycine for use in animal models of schizophrenia, and support recent clinical studies showing the effectiveness of NMDA agonists in the treatment of persistent symptoms of schizophrenia.


Subject(s)
Dopamine/blood , Excitatory Amino Acid Agonists/pharmacology , Glycine/metabolism , Phencyclidine/pharmacology , Receptors, N-Methyl-D-Aspartate/agonists , Sarcosine/analogs & derivatives , Amphetamine/pharmacology , Animals , Behavior, Animal , Brain/anatomy & histology , Brain/drug effects , Brain/metabolism , Brain Chemistry , Central Nervous System Stimulants/pharmacology , Chromatography, High Pressure Liquid , Dose-Response Relationship, Drug , Drug Administration Routes , Drug Administration Schedule , Drug Interactions , Electrochemistry , Glycine/antagonists & inhibitors , Male , Microdialysis/methods , Phencyclidine/blood , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/metabolism , Sarcosine/pharmacology , Time Factors
18.
J Pharmacol Exp Ther ; 306(3): 1092-8, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12829731

ABSTRACT

The range of medical effects and complications resulting from excessive use of drugs of abuse like phencyclidine (PCP) has hindered the development of effective medications. Drug-specific monoclonal antibodies (mAbs) provide an appealing medication approach since they can be selective for the drug, without concern for the sites of action of the drug. The use of mAb medications has been considered impractical because it is commonly believed that very large doses of mAb would be required to treat the adverse medical effects resulting from excessive drug use. In this study, a single dose of an anti-PCP mAb was found to significantly reduce the negative health impact of excessive, prolonged PCP treatment in rats (18 mg/kg/day for 2 weeks). The protective effects were mAb dose-dependent, and mAb doses as low as 1/100th the molar equivalent amount of the PCP body burden were effective at preventing PCP-induced deaths, reducing PCP-induced behaviors, reducing PCP brain concentrations, and improving the general health status of the animals. They also show that treatment with monoclonal antibody medications can have medically important outcomes without the need to neutralize the entire dose of the offending drug. These results could help establish the feasibility of using carefully designed monoclonal antibody medications to treat drug abuse and addiction, a chronic and re-occurring illness of the central nervous system.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Motor Activity/drug effects , Phencyclidine/adverse effects , Animals , Brain/metabolism , Excitatory Amino Acid Antagonists/adverse effects , Excitatory Amino Acid Antagonists/blood , Excitatory Amino Acid Antagonists/immunology , Excitatory Amino Acid Antagonists/pharmacokinetics , Male , Phencyclidine/blood , Phencyclidine/immunology , Phencyclidine/pharmacokinetics , Protein Binding , Rats , Rats, Sprague-Dawley , Receptors, Phencyclidine , Testis/metabolism , Tissue Distribution
19.
Neuropsychopharmacology ; 28(1): 34-44, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12496938

ABSTRACT

Functional dopaminergic hyperactivity is a key feature of schizophrenia. Etiology of this dopaminergic hyperactivity, however, is unknown. We have recently demonstrated that subchronic phencyclidine (PCP) treatment in rodents induces striatal dopaminergic hyperactivity similar to that observed in schizophrenia. The present study investigates the ability of PCP to potentiate amphetamine-induced dopamine release in prefrontal cortex (PFC) and nucleus accumbens (NAc) shell. Prefrontal dopaminergic hyperactivity is postulated to underlie cognitive dysfunction in schizophrenia. In contrast, the degree of NAc involvement is unknown and recent studies have suggested that PCP-induced hyperactivity in rodents may correlate with PFC, rather than NAc, dopamine levels. Rats were treated with 5-20 mg/kg/day PCP for 3-14 days by osmotic minipump. PFC and NAc dopamine release to amphetamine challenge (1 mg/kg) was monitored by in vivo microdialysis and HPLC-EC. Doses of 10 mg/kg/day and above produced serum PCP concentrations (50-150 ng/ml) most associated with PCP psychosis in humans. PCP-treated rats showed significant, dose-dependent enhancement in amphetamine-induced dopamine release in PFC but not NAc, along with significantly enhanced locomotor activity. Enhanced response was observed following 3-day, as well as 14-day, treatment and resolved within 4 days of PCP treatment withdrawal. These findings support the concept that endogenous NMDA receptor dysfunction could account for the pattern of dopaminergic dysfunction observed in schizophrenia, and suggest that even short duration abuse of PCP-like agents may greatly potentiate behavioral effects of psychostimulants in drug abuse situations. Finally, these studies provide a model system in which to evaluate effects of potential psychotherapeutic agents.


Subject(s)
Amphetamine/pharmacology , Central Nervous System Stimulants/pharmacology , Dopamine/metabolism , Excitatory Amino Acid Antagonists/pharmacology , Phencyclidine/pharmacology , Prefrontal Cortex/metabolism , Animals , Behavior, Animal/drug effects , Drug Synergism , Excitatory Amino Acid Antagonists/administration & dosage , Excitatory Amino Acid Antagonists/blood , Homovanillic Acid/metabolism , Hyperkinesis/chemically induced , Hyperkinesis/psychology , Male , Microdialysis , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Phencyclidine/administration & dosage , Phencyclidine/blood , Prefrontal Cortex/drug effects , Rats , Rats, Sprague-Dawley
20.
Chudoku Kenkyu ; 15(1): 47-52, 2002 Jan.
Article in Japanese | MEDLINE | ID: mdl-11977736

ABSTRACT

In our country, abuse of methamphetamine has increased. Furthermore, dealings of other drugs by using internet have increased. But, the poison cases of 3,4-methylenedioxymethamphetamine (MDMA) and phencyclidine (PCP) have never been reported in our country. We report an MDMA poison case and a PCP poison case. We could detect MDMA, MDA or PCP by GC-MS from urine and serum of patients admitted to the critical care medical center of Nippon Medical School. Case 1: A 23-year-old foreign female was admitted to our hospital because of disturbance of consciousness. Her friend said that she had been found lying on the floor of the bathroom after taking a tablet. The screening test by Triage showed AMP positive. Not methamphetamine but MDMA and MDA were detected from urine and serum of the patient by GC-MS. Case 2: A 27-year-old foreign female was admitted to our hospital because of restlessness and excitement. Her friend said that she had become restless and excited after taking 15-30 tablets of Tylenol. The screening by Triage showed BZO and PCP positive. Not acetaminophen but PCP was detected in the patient's sample by GC-MS. Drug abuse has expanded to Japan over the border. New responses to abuse drugs with respect to medical treatment and drug analyses should be established.


Subject(s)
Gas Chromatography-Mass Spectrometry , N-Methyl-3,4-methylenedioxyamphetamine/blood , N-Methyl-3,4-methylenedioxyamphetamine/poisoning , Phencyclidine/blood , Phencyclidine/poisoning , Substance Abuse Detection/methods , Adult , Critical Care , Emergency Service, Hospital , Female , Humans , Japan
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