| 1. |
- Blum, K., et al.
(author)
-
Common Neurogenetic Diagnosis and Meso-Limbic Manipulation of Hypodopaminergic Function in Reward Deficiency Syndrome (RDS): Changing the Recovery Landscape
- 2017
-
In: Current Neuropharmacology. - : Bentham Science Publishers Ltd.. - 1570-159X .- 1875-6190. ; 15:1, s. 184-194
-
Journal article (peer-reviewed)abstract
- Background: In 1990, Blum and associates provided the first confirmed genetic link between the DRD2 polymorphisms and alcoholism. This finding was based on an earlier conceptual framework, which served as a blueprint for their seminal genetic association discovery they termed "Brain Reward Cascade." These findings were followed by a new way of understanding all addictive behaviors (substance and non-substance) termed "Reward Deficiency Syndrome" (RDS). RDS incorporates a complex multifaceted array of inheritable behaviors that are polygenic. Objective: In this review article, we attempt to clarify these terms and provide a working model to accurately diagnose and treat these unwanted behaviors. Method: We are hereby proposing the development of a translational model we term "Reward Deficiency Solution System (TM)" that incorporates neurogenetic testing and meso-limbic manipulation of a "hypodopaminergic" trait/state, which provides dopamine agonistic therapy (DAT) as well as reduced "dopamine resistance," while embracing "dopamine homeostasis." Result: The result is better recovery and relapse prevention, despite DNA antecedents, which could impact the recovery process and relapse. Understanding the commonality of mental illness will transform erroneous labeling based on symptomatology, into a genetic and anatomical etiology. WC: 184.
|
|
| 2. |
- Busardo, Francesco P., et al.
(author)
-
GHB Pharmacology and Toxicology: Acute Intoxication, Concentrations in Blood and Urine in Forensic Cases and Treatment of the Withdrawal Syndrome
- 2015
-
In: Current Neuropharmacology. - : Bentham Science Publishers. - 1570-159X .- 1875-6190. ; 13:1, s. 47-70
-
Journal article (peer-reviewed)abstract
- The illicit recreational drug of abuse, gamma-hydroxybutyrate (GHB) is a potent central nervous system depressant and is often encountered during forensic investigations of living and deceased persons. The sodium salt of GHB is registered as a therapeutic agent (Xyrem (R)), approved in some countries for the treatment of narcolepsy-associated cataplexy and (Alcover (R)) is an adjuvant medication for detoxification and withdrawal in alcoholics. Trace amounts of GHB are produced endogenously (0.5-1.0 mg/L) in various tissues, including the brain, where it functions as both a precursor and a metabolite of the major inhibitory neurotransmitter.-aminobutyric acid (GABA). Available information indicates that GHB serves as a neurotransmitter or neuromodulator in the GABAergic system, especially via binding to the GABA-B receptor subtype. Although GHB is listed as a controlled substance in many countries abuse still continues, owing to the availability of precursor drugs, gamma-butyrolactone (GBL) and 1,4-butanediol (BD), which are not regulated. After ingestion both GBL and BD are rapidly converted into GHB (t1/2 similar to 1 min). The Cmax occurs after 20-40 min and GHB is then eliminated from plasma with a half-life of 30-50 min. Only about 1-5% of the dose of GHB is recoverable in urine and the window of detection is relatively short (3-10 h). This calls for expeditious sampling when evidence of drug use and/or abuse is required in forensic casework. The recreational dose of GHB is not easy to estimate and a concentration in plasma of similar to 100 mg/L produces euphoria and disinhibition, whereas 500 mg/L might cause death from cardiorespiratory depression. Effective antidotes to reverse the sedative and intoxicating effects of GHB do not exist. The poisoned patients require supportive care, vital signs should be monitored and the airways kept clear in case of emesis. After prolonged regular use of GHB tolerance and dependence develop and abrupt cessation of drug use leads to unpleasant withdrawal symptoms. There is no evidence-based protocol available to deal with GHB withdrawal, apart from administering benzodiazepines.
|
|
| 3. |
- Carlier, Jeremy, et al.
(author)
-
In Vitro Metabolite Profiling of ADB-FUBINACA, A New Synthetic Cannabinoid
- 2017
-
In: Current Neuropharmacology. - : BENTHAM SCIENCE PUBL LTD. - 1570-159X .- 1875-6190. ; 15:5, s. 682-691
-
Journal article (peer-reviewed)abstract
- Background: Metabolite profiling of novel psychoactive substances (NPS) is critical for documenting drug consumption. N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1-Hindazole-3-carboxamide (ADB-FUBINACA) is an emerging synthetic cannabinoid whose toxicological and metabolic data are currently unavailable. Methods: We aimed to determine optimal markers for identifying ADB-FUBINACA intake. Metabolic stability was evaluated with human liver microsome incubations. Metabolites were identified after 1 and 3 h incubation with pooled human hepatocytes, liquid chromatography-high resolution mass spectrometry in positive-ion mode (5600(+) TripleTOF (R), Sciex) and several data mining approaches (MetabolitePilot (TM), Sciex). Results: Metabolite separation was achieved on an Ultra Biphenyl column (Restek (R)); full-scan TOF-MS and information-dependent acquisition MS/MS data were acquired. ADB-FUBINACA microsomal half-life was 39.7 min, with a predicted hepatic clearance of 9.0 mL/min/kg and a 0.5 extraction ratio (intermediate-clearance drug). Twenty-three metabolites were identified. Major metabolic pathways were alkyl and indazole hydroxylation, terminal amide hydrolysis, subsequent glucuronide conjugations, and dehydrogenation. Conclusion: We recommend ADB-FUBINACA hydroxyalkyl, hydroxydehydroalkyl and hydroxylindazole metabolites as ADB-FUBINACA intake markers. N-dealkylated metabolites are not specific ADB-FUBINACA metabolites and should not be used as definitive markers of consumption. This is the first ADB-FUBINACA in vitro metabolism study; in vivo experiments enabling pharmacokinetic and pharmacodynamics studies or urine from authentic clinical/forensic cases are needed to confirm our results.
|
|
