Current Drug Metabolism - Volume 19, Issue 13, 2018

Background: Gamma-hydroxybutyrate (GHB or sodium oxybate) is both an exogenous and endogenous molecule with neuromodulator properties. In the United States, GHB is an approved drug for the treatment of narcolepsy and narcolepsy with cataplexy in adults. In some European Union countries, sodium oxybate is applied for the treatment of opioid and alcohol withdrawal. Objective: The aim of the present review was to describe the state of art of the pre-clinical research and the clinical evidence related to GHB used alone or in combination with other treatments in alcohol withdrawal syndrome and alcohol abstinence maintenance. Method: Internationally published pre-clinical findings and clinical studies investigating the effects of GHB on alcohol withdrawal syndrome and alcohol abstinence maintenance were collected and described considering seven clinical studies involving GHB in the treatment of alcohol withdrawal abstinence and five clinical studies involving GHB in the treatment of alcohol abstinence maintenance. Furthermore, GHB pharmacology and characteristics of abuse were briefly detailed. Results: Clinical evidence indicates that GHB is effective in reducing symptoms of alcohol withdrawal syndrome and produces beneficial effects comparable to those of benzodiazepines or chlometiazole. GHB proved effective in increasing alcohol abstinence maintenance and in reducing alcohol craving, but it did not show any influence in relapses of heavy drinkers when given alone. Conversely, it seems to be effective in reducing relapses in alcohol dependent patients when given in combination with naltrexone and escitalopram. Conclusion: Despite this bunch of evidence, studies are still limited and investigations including a larger number of patients are needed. In addition, some safety concerns, such as insufficiency against hallucinations in alcohol withdrawal and potential development of GHB dependence have to be more investigated.

Background: Gamma-hydroxybutyrate (γ-hydroxybutyrate or GHB) is a physiological compound of mammalians with specific receptors in central nervous system (CNS). Apart from an endogenous production, GHB is also an exogenous molecule found in pharmaceutical as well as in illicit formulations. Products manufactured and spread in these two fields, whose borders are all but strictly defined and traced, differ for the in vivo effects and for the potential of abuse. Illicit GHB gained public attention due to its use as a sexual assault facilitator. Notwithstanding its popularity, the effects on human performances, are still not completely understood and could be more complex than expected. Therefore, there is a real public safety concern regarding psychomotor functions and driving abilities due to GHB ingestion. Objective: To provide an updated and complete review on the effects of GHB on psychomotor, cognitive and driving performance that may be useful for judiciary expert forensic evaluation of driving under the influence of GHB (GHB-DUI). Method: Experimental animal-based and human-based studies and case series or epidemiological studies regarding driving under influence of GHB (and its precursors) were reviewed using main scientific databases. Results: The effects of GHB on cognitive, psychomotor and driving performance are dose-related in experimental studies. In real cases of driving under the influence of GHB, severe impairment is observed. In these cases, a wide range of blood GHB levels are found. Possible long-term effects are also reported. Conclusion: GHB causes cognitive and psychomotor impairment and risky driving behavior. Multiple aspects and variables are still waiting clarification, such as the harmful potential of illicit preparations, the effect of precursors and impairing dosages. GHB (and its precursors) must be considered a substantial personal and public risk even in the absence of a clear dose-effects correlation.

Background: Narcolepsy type 1 (NT1) is a chronic neurologic disorder defined by excessive daytime sleepiness, cataplexy, sleep paralysis, hallucinations and disrupted nocturnal sleep, typically with onset during childhood/ adolescence. Pediatric NT1 is associated with limitations on children's activities and achievements, especially poor performance at school, difficulty with peers due to disease symptoms and comorbidities including depression, obesity, and precocious puberty. Sodium oxybate (SO) is a sodium salt of γ-hydroxybutyric (GHB) acid and is greatly effective in treating cataplexy and excessive daytime sleepiness in NT1 and it can be helpful also for sleep disruption, hypnagogic hallucination and sleep paralysis in these patients. Method: We conducted a research of literature into bibliographic databases regarding NT1 features in childhood and the possible option treatment with SO in this kind of patient population. Results: We reported sixteen papers focusing on symptom presentation and on clinical and metabolic features of children affected with NT1. Furthermore, we reported 24 manuscripts focusing on SO biological actions and pharmacological properties and on the few but important available studies (8) conducted in NT1 children under SO therapy. Conclusion: Although in the majority of patients develop NT1 during childhood, there are no approved treatments for pediatric NT1. However, SO has been widely used off-label to treat narcolepsy symptoms in children and adolescents with NT1 in non-controlled studies, showing a similar safety profile and therapeutic response to adult patients. Ongoing pediatric therapy is based only on observational data shared among sleep disorders clinicians.

Background: Recently, Gamma-hydroxybutyrate (GHB) consumption in the recreational setting has been replaced by that of its prodrug Gamma-butyrolactone (GBL), cheaper and easier to obtain due to several legal industrial applications. Objective: The aim of the present paper was to report the most authoritative literature on the pharmacology and toxicology of GBL, dependence and abuse potential and the related public health issues together with the results of the analyses of several illicit liquid preparations containing GHB/GBL generally sold as “G”. Method: International literature concerning “Gamma-butyrolactone”, “GBL” “toxicology”, “pharmacology”, “abuse”, “dependence” and “GHB has been reviewed and liquid preparations containing GHB/GBL analysed by ultra-high performance liquid chromatography coupled to the tandem mass spectrometry validated methodology. Results: GBL for recreational purposes is orally administered in liquid form and rapidly transformed into GHB by lactonase enzymes present in the blood. As GBL shows a higher lipophilicity than GHB, it is absorbed more quickly, its bioavailability is higher and its effects are faster than those of GHB. Studies on rodents have shown that GBL has a low acute toxicity and only central nervous system depression has been highlighted. GBL abuse potential broadly mimics that of GHB, taking into account that it exerts its effects on the only after conversion into GHB. The analysis of 30 illicit preparations generally sold as “G” highlighted the presence of GBL in all of them at a mean concentration of 760.7 ±91.46 mg/mL (range: 588.5 - 899.3 mg/mL). Conclusion: GBL currently represents a growing public health issue since the substance is relatively cheaper and easier to obtain than GHB. Improvement and implementation of laws and policies to place GBL under control are needed to limit its diffusion, the eventual health threat for users and its non -negligible abuse liability and dependence risk.

Background: Misuse of gammahydroxybutrate (GHB) and its prodrugs gammabutyrolactone (GBL) and 1,4 butanediol (1,4-BD) has increased greatly since the early 1990s, particularly amongst lesbian, gay, bisexual and transgender (LGBT) individuals in recreational and sexual settings, e.g. ‘chemsex’. Objective and Method: This paper presents an overview of GHB pharmacotoxicology and provides analyses of cases in the LGBT population associated with the use of these substances extracted from the UK’s National Programme on Substance Abuse Deaths database, to which notification is voluntary. Results: From 1995 to September 2013, 21 GHB/GBL-associated fatalities were reported. None involved 1,4-BD. Typical victims were: Male (100%); White (67%), young (mean age 34 years); employed (90%); with a drug misuse history (81%). Most deaths were accidental (67%) or related to recreational drug use (19%), the remaining (potential) suicides. The majority of fatalities (83%) occurred in private residences, typically following recreational use; others occurred in specific ‘gay’-oriented locales including clubs and saunas. Three London boroughs accounted for 62% of all notified deaths, reflecting the concentration of both resident and visiting ‘gay’ individuals. However, this may be an artefact of the voluntary nature of the data submission procedure in particular areas. GHB/GBL alone was implicated in 10% of fatalities. The following substances were implicated either alone or in combination in the remaining cases (percentages may add to more than 100%): cocaine (38%); alcohol (33%); amphetamines (29%); ecstasy (29%); diazepam (24%); ketamine (24%); mephedrone (24%). Post-mortem blood levels: mean 660 (range 22 - 2335; S.D. 726) mg/L. Conclusion: Significant caution is needed when ingesting GHB/GBL, particularly with alcohol, benzodiazepines, stimulants, and ketamine. Risk of death is increased due to their CNS-depressant properties. Of these, ‘chemsex’ drugs such as cocaine, mephedrone and ketamine are of note. More awareness is needed in the ‘gay’ community about risks associated with the consumption of such substances.

Background: Essential oils are liquid extracts from aromatic plants, which have numerous applications in multiple industries. There are a variety of methods used for the extraction of essential oils, with each method exhibiting certain advantages and determining the biological and physicochemical properties of the extracted oils. Essential oils from different plant species contain more than 200 constituents which are comprised of volatile and non-volatile components. The application of essential oils as antimicrobial, anticancer, anti-inflammatory and anti-viral agents is due to their effective and efficient properties, inter alia. Method: Several advanced (supercritical fluid extraction, subcritical extraction liquid, solvent-free microwave extraction) and conventional (hydrodistillation, steam distillation, hydrodiffusion, solvent extraction) methods have been discussed for the extraction of essential oils. Advanced methods are considered as the most promising extraction techniques due to less extraction time, low energy consumption, low solvent used and less carbon dioxide emission. Conclusion: This manuscript reviewed the major research studies in the field and discussed several research findings on the chemical composition of essential oils, methods of oil extraction, and application of these oils in pharmaceutical and therapeutic fields. These essential oils can be used as anticancer, antimicrobial, antiviral, and as skin permeation enhancer agents.

Background: Ternary solid dispersions have been demonstrated to be an effective strategy in the improvement of drug absorption and bioavailability. Method: The applications of the combination of hydrophilic polymers with the potential of hydrophobic polymer incorporation at moderate concentrations have been discussed in recent publications. Results: In this paper, the general review of this specific type of solid dispersion will be provided with comprehensive understanding of polymer blends of either hydrophilic or hydrophobic polymers. A detailed description of miscible polymers has been developed in recent studies. In addition to dissolution rate improvement, the role of second polymers in crystal growth inhibition and in maintaining the amorphous state will be mentioned. Conclusion: We also present a summary of characterization techniques commonly used to evaluate solid dispersion and polymer miscibility.

Background: Patients with hypertension usually have to be treated with Angiotensin Converting Enzyme (ACE) inhibitors, and are therefore more exposed to drug-drug Interactions (DDIs) by various mechanisms, especially the mechanisms based on drug metabolizing enzymes and transporters. Objective: This review article focuses on the pharmacokinetic interaction mechanisms with ACE inhibitors based on drug metabolizing enzymes and transporters, and the identification of these underlying mechanisms would help physicians and patients to predict, detect and prevent DDIs. Method: To identify the pharmacokinetic interaction mechanisms based on drug metabolizing enzymes and transporters of ACE inhibitors. An electronic search of PubMed, Medline, Science Direct, and Springer-Link database was conducted (from 1950 to December, 2017), using drug interactions, cytochrome P450, carboxylesterase, names of transporters, names of ACE inhibitors and pharmacokinetics as keywords. Results and Conclusion: Inhibition of metabolizing enzymes and transporter system can markedly alter the concentrations of ACE inhibitors. The genetic polymorphisms in the enzymes in some of the specific isoforms seem to explain the inter-individual differences in ACE inhibitors metabolism, and also the inter-individual variation in the pharmacokinetics of ACE inhibitors may be caused by changes in transporter function. Understanding the knowledge of how ACE inhibitors are metabolized and transported is important in predicting and managing DDIs. The data on the roles of drug metabolizing enzymes and transporters in the DDIs of ACE inhibitors should be studied and the selection of ACE inhibitors should be individualized to prevent DDIs in clinic.

Background: Although it is believed widely that the various routes of xenobiotic metabolism are now all known and effectively understood, occasionally there emerges a metabolite that signals a novel biotransformation pathway, especially where the xenobiotic may in some way interact with the myriad processes of intermediary metabolism. There are a few reports in the literature where saturated short-chain dicarboxylic acids have been exploited as conjugating agents and these unusual xenobiotic metabolites subsequently excreted intact in the urine. Method: Initially suggested by unpublished observations bolstered by extensive experience of the authors and colleagues in the field of xenobiochemistry, this narrative review has been supplemented by a search of bibliographic databases and the subsequent scrutiny of numerous peer-reviewed research articles. The resultant sparse and widely dispersed information has been examined, analysed and presented in this review. Results: Xenobiotic conjugation with dicarboxylic acids has been demonstrated to occur within several domains of life; microorganisms, plants, invertebrates and mammals. However, considering the number of xenobiotic metabolism investigations that have been undertaken reports of such conjugations are exceedingly rare. Conclusion: Dicarboxylic acid condensation with xenobiotic molecules may occur at nitrogen centres, or more precisely with a primary or secondary amine, that is at nitrogen still possessing a replaceable hydrogen atom. Both aliphatic amines and arylamines may be substrates with many of the free amino groups being formed by previous Ndealkylation reactions. Hopefully, awareness of this metabolic route will be raised and researchers will be enthused to search for this type of conjugate.