Publications by authors named "Francesco Paolo Busardo"

130 Publications

Editorial: Psychiatric and Pharmacotoxicological Insights on Appearance and Performance Enhancing Drugs.

Front Psychiatry 2022 26;13:918482. Epub 2022 May 26.

Section of Legal Medicine, Department of Excellence of Biomedical Sciences and Public Health, Polytechnic University of Marche, Ancona, Italy.

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http://dx.doi.org/10.3389/fpsyt.2022.918482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9178271PMC
May 2022

Ultra-high-performance liquid chromatography-tandem mass spectrometry assay for quantifying THC, CBD and their metabolites in hair. Application to patients treated with medical cannabis.

J Pharm Biomed Anal 2022 Aug 20;217:114841. Epub 2022 May 20.

Marche Polytechnic University, Department of Excellence of Biomedical Sciences and Public Health, Section of Legal Medicine, Unit of Forensic Toxicology, Via Tronto 10/a, 60126 Ancona, Italy. Electronic address:

Recently, several countries approved the use of cannabis flowering tops with standardized amount of ∆9-tetrahydrocannabinol (THC), cannabidiol (CBD) to treat several diseases. Therapeutic monitoring of medical cannabis products administered to patients for the established pathologies is rarely carried out. Previous few investigations have been developed in conventional matrices like blood and urine. This is the first study involving hair analysis of THC, CBD and their metabolites in patients treated with medical cannabis. An ultra-high-performance liquid chromatography-tandem mass spectrometry method to quantify THC, CBD, and metabolites, i.e., 11-nor-9-carboxy-THC (THC-COOH), 11-hydroxy-THC (11-OH-THC) cannabidiol-7-oic acid (7-COOH-CBD), 7-hydroxycannabidiol (7-OH-CBD), 6-α-hydroxycannabidiol (6-α-OH-CBD) and 6-β-hydroxycannabidiol (6-β-OH-CBD) in hair samples was developed and fully validated. The validation results indicated that the method was accurate (average inter/intra-day error, <10%), precise (inter/intra-day imprecision, <10%), and fast (10 min run time). Average hair concentrations in four patients treated with different formulations of medical cannabis were 2.75 ng/mg THC, 2.87 ng/mg 11-OH-THC, and 0.32 ng/mg THC-COOH (n = 3); 1.65 ng/mg CBD, 2.73 ng/mg 7-OH-CBD, 1.29 ng/mg 7-COOH-CBD, 0.35 ng/mg 6-α-OH-CBD, and 0.03 ng/mg 6-β-OH-CBD. The proposed method proved suitable for a fast and sensitive determination of all target compounds allowing high throughput testing in individuals monitored for medical cannabis treatments.
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http://dx.doi.org/10.1016/j.jpba.2022.114841DOI Listing
August 2022

Liquid Chromatography High Resolution Mass Spectrometry in Forensic Toxicology: What Are the Specifics of Method Development, Validation and Quality Assurance for Comprehensive Screening Approaches?

Curr Pharm Des 2022 May 26. Epub 2022 May 26.

Institute of Forensic Medicine, Jena University Hospital, Jena, Germany.

The use of High Resolution Mass Spectrometry (HRMS) has increased over the past decade in clinical and forensic toxicology, especially for comprehensive screening approaches. Despite this, few guidelines of this field have specifically addressed HRMS issues concerning compound identification, validation, measurement uncertainty and quality assurance. To fully implement this technique, certainly in an era in which the quality demands for laboratories are ever increasing due to various norms (e.g. the International Organization for Standardization's ISO 17025), these specific issues need to be addressed. This manuscript reviews 26 HRMS-based methods for qualitative systematic toxicological analysis (STA) published between 2011 and 2021. Key analytical data such as samples matrices, analytical platforms, numbers of analytes and employed mass spectral reference databases/libraries as well as the studied validation parameters are summarized and discussed. The article further includes a critical review of targeted and untargeted data acquisition approaches, available HRMS reference databases and libraries as well as current guidelines for HRMS data interpretation with a particular focus on identification criteria. Moreover, it provides an overview on current recommendations for the validation and determination measurement uncertainty of qualitative methods. Finally, the article aims to put forward suggestions for method development, compound identification, validation experiments to be performed, and adequate determination of measurement uncertainty for this type of wide-range qualitative HRMS-based methods.
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http://dx.doi.org/10.2174/1381612828666220526152259DOI Listing
May 2022

Toxicological Characterization of GHB as a Performance-Enhancing Drug.

Front Psychiatry 2022 18;13:846983. Epub 2022 Apr 18.

Department of Excellence of Biomedical Sciences and Public Health, "Politecnica delle Marche" University of Ancona, Ancona, Italy.

Performance-enhancing drugs (PEDs) are represented by several compounds used to ameliorate the image, the appearance, or an athletic or non-athletic performance. Gamma-hydroxybutyrate (GHB) is an endogenous molecule first used as anesthetic and then marketed as a nutritional supplement with a wide diffusion in the bodybuilding community. The aim of the present work is to provide a toxicological characterization of the use of GHB as a PED, including the scientific basis for its use, the patterns of use/abuse, and the health risks arising from its consumption in this peculiar recreative setting. A literature search was performed on multiple databases including experimental studies on humans and animals as well as epidemiological reports and forensic case reports/series. Experimental studies demonstrated that the use of GHB as a PED is motivated by the release of growth hormone and the induction of sleep. However, the panel of desired performance-related effects was much wider in real cases and epidemiological studies. Even though the use of GHB among bodybuilders has decreased, its use to enhance some kind of performance, particularly sexual ones or social-communicative ones, as well as means to increase mood and perceived energy, is still common.
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http://dx.doi.org/10.3389/fpsyt.2022.846983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9058118PMC
April 2022

Synthetic Benzimidazole Opioids: The Emerging Health Challenge for European Drug Users.

Front Psychiatry 2022 25;13:858234. Epub 2022 Mar 25.

Unit of Forensic Toxicology, Section of Legal Medicine, Department of Excellence of Biomedical Sciences and Public Health, Marche Polytechnic University, Ancona, Italy.

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http://dx.doi.org/10.3389/fpsyt.2022.858234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8990956PMC
March 2022

Molecular Insights on New Psychoactive Substances (NPSs).

Int J Mol Sci 2022 Mar 18;23(6). Epub 2022 Mar 18.

Department of Excellence of Biomedical Sciences and Public Health, "Politecnica delle Marche" University of Ancona, Via Tronto 10/a, 60126 Ancona, Italy.

Currently, more than 1000 molecules have been classified as New Psychoactive Substances (NPSs), and it is reported that, every year, this number increases with new classes of compounds and/or newer generations of NPS families [...].
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http://dx.doi.org/10.3390/ijms23063282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8948614PMC
March 2022

Acute Intoxications and Fatalities Associated with Benzimidazole Opioid (Nitazene Analog) Use: A Systematic Review.

Ther Drug Monit 2022 Feb 9. Epub 2022 Feb 9.

Marche Polytechnic University, Department of Excellence of Biomedical Sciences and Public Health, Section of Legal Medicine, Unit of Forensic Toxicology, Ancona, Italy Brain&Care, Neuromodulation and Clinical Research Unit, Rimini, Italy Istituto Superiore di Sanità, National Centre on Addiction and Doping, Rome, Italy Sapienza University of Rome, Department of Anatomical, Histological, Forensic, and Orthopedic Sciences, Section of Legal Medicine, Unit of Forensic Toxicology, Rome, Italy.

Purpose: Synthetic benzimidazole opioids (BO) are highly potent µ-opioid receptor agonists with heroin-like effects. Isotonitazene was first available in 2019 in the drug market, while new analogs have multiplied recently. The authors aimed to identify BO use trends and gather toxicological data from BO-related cases to assist in clinical and forensic investigations.

Methods: A systematic literature search was conducted according to the PRISMA guidelines. PubMed and Scopus databases were accessed in October 2021 to identify scientific reports of BO-related intoxication and fatalities. Publication dates, case descriptions, symptoms, autopsy findings, and concentrations of BOs and metabolites in biological matrices were compiled.

Results: Data from 8 case reports with 93 fatalities involving isotonitazene (n = 65), metonitazene (n = 20), etonitazepyne (N-pyrrolidino etonitazene) (n = 8), flunitazene (n = 4), and/or butonitazene (n = 1), and 1 acute intoxication involving etonitazepyne were collected. Autopsy findings included pulmonary congestion/high lung weight (66%), cardiomegaly/high cardiac weight (39%), cerebral edema (22%), gastric contents in the airways (22%), and organ congestion (22%). Median peripheral blood concentrations were 1.7 ng/mL for isotonitazene (0.4-9.5 ng/mL, n = 13), 5.4 ng/mL for metonitazene (0.52-33 ng/mL, n = 17), 5.4 ng/mL for etonitazepyne (2.4-8.3 ng/mL, n = 2), 1.3 ng/mL for flunitazene (0.58-2.1 ng/mL, n = 2), and 3.2 ng/mL for butonitazene (n = 1). Central nervous system depressants were almost always co-administered.

Conclusion: Isotonitazene was predominant in cases from 2019 to mid-2020 and was replaced by metonitazene after scheduling in the USA. Typical findings on opioid overdoses have been reported. Peripheral blood concentrations were consistent with a potency similar to that of fentanyl. These results must be interpreted carefully, considering the scarcity of reports on BO-related cases and drug co-exposures.
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http://dx.doi.org/10.1097/FTD.0000000000000970DOI Listing
February 2022

Evaluating the risk of toxicity and adverse drug interactions involving recreational GHB use and prescribed drugs.

Expert Opin Drug Metab Toxicol 2021 Dec 20;17(12):1445-1454. Epub 2022 Jan 20.

Unit of Forensic Toxicology, Section of Legal Medicine, Department of Excellence of Biomedical Sciences and Public Health, Marche Polytechnic University of Ancona, Ancona, Italy.

Introduction: GHB is a small molecule and is present in the human CNS. Exogenously, GHB is administered orally in the form of sodium oxybate to treat cataplexy and excessive daytime sleepiness in patients with narcolepsy, and to manage alcohol withdrawal and detoxification in alcoholics. GHB shows a biphasic effect and dose-dependent pharmacokinetics and may interact with neuronal systems different from GABAergic one. The compound is also highly abused among bodybuilders and is associated with drugs of abuse.

Areas Covered: This article provides an overview of the risks associated with the recreational consumption of GHB and its analogues, including pharmaceuticals mostly encountered in GHB-related emergency department admissions and postmortem investigations. A literature search was performed using PubMed, Scopus, Google Scholar, and Web of Science databases to identify scientific reports concerning the recreational use of GHB and analogs with prescribed drugs. Further articles were retrieved after consulting international health and regulatory authorities' reports.

Expert Opinion: Due to its dual nature, interpreting and distinguishing GHB concentrations in biological fluid represents a challenge in forensic toxicology. To demonstrate recent exposure, a quick collection of samples is necessary to maximize the chance of detecting an exogenous GHB intake, especially in cases of GHB-facilitated sexual assaults.
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http://dx.doi.org/10.1080/17425255.2021.2029404DOI Listing
December 2021

Ethical and Legal Challenges of Telemedicine in the Era of the COVID-19 Pandemic.

Medicina (Kaunas) 2021 Nov 30;57(12). Epub 2021 Nov 30.

School of Law, Camerino University, 62032 Camerino, Italy.

: Telemedicine or telehealth services has been increasingly practiced in the recent years. During the COVID-19 pandemic, telemedicine turned into and indispensable service in order to avoid contagion between healthcare professionals and patients, involving a growing number of medical disciplines. Nevertheless, at present, several ethical and legal issues related to the practice of these services still remain unsolved and need adequate regulation. This narrative review will give a synthesis of the main ethical and legal issues of telemedicine practice during the COVID-19 pandemic. : A literature search was performed on PubMed using MeSH terms: Telemedicine (which includes Mobile Health or Health, Mobile, mHealth, Telehealth, and eHealth), Ethics, Legislation/Jurisprudence, and COVID-19. These terms were combined into a search string to better identify relevant articles published in the English language from March 2019 to September 2021. : Overall, 24 out of the initial 85 articles were considered eligible for this review. Legal and ethical issues concerned important aspects such as: informed consent (information about the risks and benefits of remote therapy) and autonomy (87%), patient privacy (78%) and confidentiality (57%), data protection and security (74%), malpractice and professional liability/integrity (70%), equity of access (30%), quality of care (30%), the professional-patient relationship (22%), and the principle of beneficence or being disposed to act for the benefit of others (13%). : The ethical and legal issues related to the practice of telehealth or telemedicine services still need standard and specific rules of application in order to guarantee equitable access, quality of care, sustainable costs, professional liability, respect of patient privacy, data protection, and confidentiality. At present, telemedicine services could be only used as complementary or supplementary tools to the traditional healthcare services. Some indications for medical providers are suggested.
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http://dx.doi.org/10.3390/medicina57121314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8705012PMC
November 2021

Fourth generation of synthetic cannabinoid receptor agonists: A review on the latest insights.

Curr Pharm Des 2021 Nov 15. Epub 2021 Nov 15.

School of law, Camerino University, Camerino. Italy.

Background: Over the past few years, an emerging number of new psychoactive substances (NPSs) entered the illicit market. NPSs are designed to resemble the effects of classical drugs of abuse, reinforcing their effects and duration. Among the most abused NPS, synthetic cannabinoids are cannabinoid receptor agonists (SCRAs) and mimic the effect of the main psychotropic phytocannabinoid Δ9-tetrahydrocannabinol (THC).

Methods: We herein reviewed the international literature to provide available information on the newest SCRAs generation.

Results: Compared to the previous SCRAs generations, the structures of the last generation result in increased affinity for and efficacy at cannabinoid CB1 receptors, which are thought to be mainly responsible for the psychoactive effects of THC and its analogues. Accordingly, these more potent cannabimimetic effects may increase the number of adverse reactions such as neurological disorders (e.g., psychosis, agitation, irritability, paranoia, confusion, and anxiety), psychiatric episodes (e.g., hallucinations, delusions, self-harm), other physical conditions (e.g., tachycardia, hypertension, arrhythmia, chest pain, nausea, vomiting, and fever) and deaths. In the last decade, more than a hundred SCRAs from different chemical classes emerged on the illicit web market. SCRAs have been thoroughly studied: they were physico-chemically characterized and pharmaco-toxicological characteristics were investigated. The last SCRAs generations include increasingly potent and toxic compounds, posing a potential health threat to consumers.

Conclusion: From November 2017 to February 2021, at least 20 new "fourth-generation" SCRAs were formally reported to international drug agencies. Our understanding about the neurotoxicity of these compounds is still limited due to the lack of global data, but their potency and their toxicity are likely higher than those of the previous generations.
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http://dx.doi.org/10.2174/1381612827666211115170521DOI Listing
November 2021

In silico prediction, LC-HRMS/MS analysis, and targeted/untargeted data-mining workflow for the profiling of phenylfentanyl in vitro metabolites.

Talanta 2021 Dec 28;235:122740. Epub 2021 Jul 28.

Unit of Forensic Toxicology, Section of Legal Medicine, Department of Excellence of Biomedical Sciences and Public Health, Marche Polytechnic University, 60126, Ancona, Italy; Unit of Forensic Toxicology, Section of Legal Medicine, Department of Anatomical, Histological, Forensic, and Orthopedic Sciences, Sapienza University of Rome, 00198, Rome, Italy.

Illicit fentanyl and analogues have been involved in many fatalities and cases of intoxication across the United States over the last decade, and are becoming a health concern in Europe. New potent analogues emerge onto the drug market every year to circumvent analytical detection and legislation, and little pharmacological/toxicological data are available when the substances first appear. However, pharmacokinetic data are crucial to determine specific biomarkers of consumption in clinical and forensic settings, considering the low active doses and the rapid metabolism of fentanyl analogues. Phenylfentanyl is a novel analogue that was first detected in seized material in 2017, and little is currently known about this substance and its metabolism. We studied phenylfentanyl metabolic fate using in silico predictions with GLORYx freeware, human hepatocyte incubations, and liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS). We applied a specific targeted/untargeted workflow using data-mining software to allow the rapid and partially automated screening of LC-HRMS/MS raw data. Approximately 90,000 substances were initially individuated after 3-h incubation with hepatocytes, and 115 substances were automatically selected for a manual check by the operators. Finally, 13 metabolites, mostly produced by N-dealkylation, amide hydrolysis, oxidation, and combinations thereof, were identified. We suggest phenylnorfentanyl as the main biological marker of phenylfentanyl use, and we proposed the inclusion of its fragmentation pattern in mzCloud and HighResNPS online libraries. Other major metabolites include N-Phenyl-1-(2-phenylethyl)-4-piperidinamine (4-ANPP), 1-(2-phenylethyl)-4-piperidinol, and other non-specific metabolites. Phase II transformations were infrequent, and the hydrolysis of the biological samples is not required to increase the detection capability of non-conjugated metabolites. The overall workflow is easily adaptable for the metabolite profiling of other novel psychoactive substances.
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http://dx.doi.org/10.1016/j.talanta.2021.122740DOI Listing
December 2021

Acute Pharmacological Effects and Oral Fluid Concentrations of the Synthetic Cannabinoids JWH-122 and JWH-210 in Humans After Self-Administration: An Observational Study.

Front Pharmacol 2021 19;12:705643. Epub 2021 Aug 19.

Clinical Pharmacology Unit, Hospital Universitari Germans Trias i Pujol, Institut de Recerca Germans Trias i Pujol (HUGTiP-IGTP), Barcelona, Spain.

Synthetic cannabinoids (SCs) are a group of new psychoactive drugs used recreationally with potential health risks. They are monitored by the EU Early Warning System since 2010 due to severe adverse effects on consumers. JWH-122 and JWH-210 are naphthoylindole SCs and potent cannabinoid receptor CB1 and CB2 agonists. Information about the effects of SCs usually is available from intoxication cases and surveys, and few studies on humans after controlled administration or observational/naturalistic studies using standardized measures of cardiovascular and subjective effects are available. The aim of this study was to evaluate the acute pharmacological effects of JWH-122 and JWH-210 recreational consumption in a 4 h observational study and assess their disposition in oral fluid (OF). Sixteen volunteers self-administered 1 mg dose of JWH-122 ( = 8) or 2.25 mg mean dose of JWH-210 (range 2-3 mg, = 8) by inhalation (smoking). Physiological parameters including blood pressure (systolic and diastolic), heart rate (HR), and cutaneous temperature were measured. A set of visual analog scales, the 49-item short-form version of the Addiction Research Center Inventory (ARCI), and the Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) were used for the evaluation of subjective effects. OF was collected at baseline and at 10, 20, and 40 min and 1, 2, 3, and 4 h after self-administration. Statistically significant increases in systolic blood pressure (SBP), diastolic blood pressure (DBP), and HR were observed after JWH-122 self-administration but not after JWH-210 self-administration. JWH-210 self-administration produced significant changes in subjective drug effects, similar to those induced by THC (intensity, high, good effects, and hunger). The subjective effects following JWH-122 consumption were minimal. The maximal effects were mostly observed 20 min after intake. JWH-122 and JWH 210 OF concentration reached a peak 20 min after administration and could not be detected after 3 h. The results demonstrated a different pattern of effects of these two SCs. Due to the limitations of our observational study, further research with a larger sample and controlled studies are needed to better define the acute pharmacological effect and health risk profile of JWH-122 and JWH-210.
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http://dx.doi.org/10.3389/fphar.2021.705643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417402PMC
August 2021

Optimization of a rapid sample pretreatment for the quantification of COCAINE and its main metabolites in hair through a new and validated GC-MS/MS method.

J Pharm Biomed Anal 2021 Sep 24;204:114282. Epub 2021 Jul 24.

Department of Excellence of Biomedical Science and Public Health, University "Politecnica Delle Marche" of Ancona, Via Tronto 71, 60124, Ancona, Italy. Electronic address:

We developed and validated a new rapid and sensitive gas chromatography-tandem mass spectrometry method for the determination of cocaine and its metabolites benzoylecgonine, norcocaine, ecgonine methyl esther and cocaethylene in hair of consumers. Hair samples were firstly decontaminated with three subsequent dichloromethane washes, then incubated for one hour with M3® buffer to promote analytes solubilization and stabilization and finally solid phase extracted. All extracts were derivatized and injected into GC-MS/MS with electron impact ionization. Multiple Reaction Monitoring was used for the acquisition of characteristic analytes ion transitions reaching a high sensitivity 0.01 ng/mg COC and metabolites limit of quantification. The method was linear in the COC and metabolites calibration ranges (LLOQ-10 ng/mg and LLOQ-1 ng/mg, respectively). Intra-assay and inter-assay precision were always lower than 15 %, accuracy never exceeded ± 6.6 %. The main advantages of the presented method are the fast, simple and innovative pretreatment procedure together with the instrumental sensitivity that allowed to measure also less concentrated metabolites.
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http://dx.doi.org/10.1016/j.jpba.2021.114282DOI Listing
September 2021

UHPLC-MS/MS Analysis of Cannabidiol and Its Metabolites in Serum of Patients with Resistant Epilepsy Treated with CBD Formulations.

Pharmaceuticals (Basel) 2021 Jun 29;14(7). Epub 2021 Jun 29.

Department of Excellence-Biomedical Sciences and Public Health, Università Politecnica delle Marche, 60121 Ancona, Italy.

Cannabidiol (CBD) is a promising therapeutic agent with analgesic, myorelaxant, and anti-epileptic actions. Recently, a purified form of CBD (Epidiolex) has been approved by the European Medicines Agency (EMA) for the treatment of two highly-refractory childhood-onset epilepsies (Dravet and Lennox-Gastaut syndrome). Given the interindividual response and the relationship between the dose administered and CBD blood levels, therapeutic drug monitoring (TDM) is a valuable support in the clinical management of patients. We herein report for the first time a newly developed and validated method using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) to evaluate CBD and its metabolites (i.e., cannabidiol-7-oic acid (7-COOH-CBD), 7-hydroxycannabidiol (7-OH-CBD), 6-α-hydroxycannabidiol (6-α-OH-CBD) and 6-β-hydroxycannabidiol (6-β-OH-CBD)) in serum samples. The method reached the sensitivity needed to detect minimal amounts of analytes under investigation with limits of quantification ranging from 0.5 to 20 ng/mL. The validation results indicated in this method were accurate (average inter/intra-day error, <15%), precise (inter/intra-day imprecision, <15%), and fast (8 min run time). The method resulted to be linear in the range of 1-10,000 ng/mL for CBD-COOH, 1-500 ng/mL for 7-OH-CBD and CBD and 1-25 ng/mL for 6-α-OH-CBD and 6-β-OH-CBD. Serum levels of CBD (88.20-396.31 and 13.19-170.63 ng/mL) as well as of 7-OH-CBD (27.11-313.63 and 14.01-77.52 ng/mL) and 7-COOH-CBD (380.32-10,112.23 and 300.57-2851.82 ng/mL) were significantly higher ( < 0.05) in patients treated with GW pharma CBD compared to those of patients treated with galenic preparations. 6-α-OH-CBD and 6-β-OH-CBD were detected in the first group and were undetectable in the second group. 7-COOH-CBD was confirmed as the most abundant metabolite in serum (5-10 fold higher than CBD) followed by 7-OH-CBD. A significant correlation ( < 0.05) between the dose administrated and a higher bioavailability was confirmed in patients treated with a GW pharma CBD preparation.
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http://dx.doi.org/10.3390/ph14070630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308640PMC
June 2021

Designer Benzodiazepines: A Review of Toxicology and Public Health Risks.

Pharmaceuticals (Basel) 2021 Jun 11;14(6). Epub 2021 Jun 11.

Department of Excellence of Biomedical Sciences and Public Health, Marche Polytechnic University of Ancona, Via Tronto 10, 60126 Ancona, Italy.

The rising use of designer benzodiazepines (DBZD) is a cat-and-mouse game between organized crime and law enforcement. Non-prohibited benzodiazepines are introduced onto the global drug market and scheduled as rapidly as possible by international authorities. In response, DBZD are continuously modified to avoid legal sanctions and drug seizures and generally to increase the abuse potential of the DBZD. This results in an unpredictable fluctuation between the appearance and disappearance of DBZD in the illicit market. Thirty-one DBZD were considered for review after consulting the international early warning database, but only 3-hydroxyphenazepam, adinazolam, clonazolam, etizolam, deschloroetizolam, diclazepam, flualprazolam, flubromazepam, flubromazolam, meclonazepam, phenazepam and pyrazolam had sufficient data to contribute to this scoping review. A total of 49 reports describing 1 drug offense, 2 self-administration studies, 3 outpatient department admissions, 44 emergency department (ED) admissions, 63 driving under the influence of drugs (DUID) and 141 deaths reported between 2008 and 2021 are included in this study. Etizolam, flualprazolam flubromazolam and phenazepam were implicated in the majority of adverse-events, drug offenses and deaths. However, due to a general lack of knowledge of DBZD pharmacokinetics and toxicity, and due to a lack of validated analytical methods, total cases are much likely higher. Between 2019 and April 2020, DBZD were identified in 48% and 83% of postmortem and DUID cases reported to the UNODC, respectively, with flualprazolam, flubromazolam and etizolam as the most frequently detected substances. DBZD toxicology, public health risks and adverse events are reported.
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http://dx.doi.org/10.3390/ph14060560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230725PMC
June 2021

The complex and constantly evolving public health threat of new psychoactive substances in Italy: addressing the main functions of a national observatory of drugs.

Ann Ist Super Sanita 2021 Apr-Jun;57(2):144-150

Centro Nazionale Dipendenze e Doping, Istituto Superiore di Sanità, Rome, Italy.

At the end of the 90s in Europe, the new psychoactive substances (NPS) phenomenon was limited to a small number of molecules created to mimic the actions and psychoactive effects of licensed medicines and existing drugs that are controlled by the United Nations drug conventions and therefore traded as their "legal" replacements. NPS were mostly circulating in rave parties and electronic music festivals. The globalization, the evolution of e-commerce and the growing popularity of NPS, facilitated the development of a wide illegal market in constant expansion. The dynamic nature of this phenomenon has led to an evolution in the prevention and monitoring of NPS trafficking within the European Union. The European legislative system has been amended with the aim of creating a faster and more effective regulatory system to tackle NPS diffusion and ban their sale and circulation. At the end of 2008, in compliance with the European Council Decision 2005/387/JHA, the Anti-Drug Policies Department of the Presidency of the Council of Ministers activated the National Early Warning System to promote a rapid exchange of information on NPS between Italy and the EU.
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http://dx.doi.org/10.4415/ANN_21_02_06DOI Listing
December 2021

Development and validation of a fast ultra-high-performance liquid chromatography tandem mass spectrometry method for determining carbonic anhydrase inhibitors and their metabolites in urine and hair.

Drug Test Anal 2021 Aug 16;13(8):1552-1560. Epub 2021 Jul 16.

Department of Excellence of Biomedical Sciences and Public Health, University "Politecnica delle Marche" of Ancona, Ancona, Italy.

A new, rapid, sensitive, and comprehensive ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method for quantifying diuretics (acetazolamide, brinzolamide, dorzolamide, and their metabolites) in human urine and hair was developed and fully validated. Twenty-five milligrams of hair were incubated with 500-μl M3® buffer reagent at 100°C for 1 h for complete digestion. After cooling, 1-μl supernatant was injected onto chromatography system. Urine samples were simply diluted before injection. The chromatographic run time was short (8 min) through a column with a mobile phase gradient. The method was linear (determination coefficients always higher than 0.99) from limit of quantification (LOQ) to 500 ng/ml in urine and from LOQ to 10 ng/mg in hair. LOQs ranged from 0.07 to 1.16 ng/ml in urine and from 0.02 to 0.15 ng/mg in hair. No significant ion suppression due to matrix effect was observed, and process efficiency was always higher than 80%. Intra- and inter-assay precision was lower than 15%. The suitability of the methods was tested with six urine and hair specimens from patients treated with acetazolamide, dorzolamide, or brinzolamide for ocular diseases or systemic hypertension. Average urine concentrations were 266.32 ng/ml for dorzolamide and 47.61 ng/ml for N-deethyl-dorzolamide (n = 3), 109.27 ng/ml for brinzolamide and 1.02 ng/ml for O-desmethyl-brinzolamide (n = 2), and finally, 12.63 ng/ml for acetazolamide. Average hair concentrations were 5.94 ng/mg for dorzolamide and 0.048 ng/mg for N-deethyl-dorzolamide (n = 3), 3.26 ng/mg for brinzolamide (n = 2), and 2.3 ng/mg for acetazolamide (n = 1). The developed method was simple and fast both in the extraction procedures making it eligible in high-throughput analysis for clinical forensic and doping purposes.
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http://dx.doi.org/10.1002/dta.3055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456811PMC
August 2021

Acute Pharmacological Effects and Oral Fluid Biomarkers of the Synthetic Cannabinoid UR-144 and THC in Recreational Users.

Biology (Basel) 2021 Mar 24;10(4). Epub 2021 Mar 24.

Clinical Pharmacology Unit, Hospital Universitari Germans Trias i Pujol and Institut de Recerca Germans Trias i Pujol (HUGTiP-IGTP), 08916 Badalona, Spain.

Synthetic cannabinoids (SCs) are one of the most frequent classes of new psychoactive substances monitored by the EU Early Warning System and World Health Organization. UR-144 is a SC with a relative low affinity for the CB1 receptor with respect to that for the CB2 receptor. As with other cannabinoid receptor agonists, it has been monitored by the EU Early Warning System since 2012 for severe adverse effects on consumers. Since data for UR-144 human pharmacology are very limited, an observational study was carried out to evaluate its acute pharmacological effects following its administration using a cannabis joint as term of comparison. Disposition of UR-144 and delta-9-tetrahydrocannibinol (THC) was investigated in oral fluid. Sixteen volunteers smoked a joint prepared with tobacco and 1 or 1.5 mg dose of UR-144 ( = 8) or cannabis flowering tops containing 10 or 20 mg THC ( = 8). Physiological variables including systolic and diastolic blood pressure, heart rate and cutaneous temperature were measured. A set of Visual Analog Scales (VAS), the Addiction Research Centre Inventory (ARCI)-49-item short form version and the Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) were administered to evaluate subjective effects. Oral fluid was collected at baseline, 10, 20, 40 min and 1, 2, 3 and 4 h after smoking, for UR-144 or THC concentration monitoring. Results showed significant statistical increases in both systolic and diastolic blood pressure and heart rate after both UR-144 and cannabis smoking. Both substances produced an increase in VAS related to stimulant-like and high effects, but scores were significantly higher after cannabis administration. No hallucinogenic effects were observed. Maximal oral fluid UR-144 and THC concentrations appeared at 20 and 10 min after smoking, respectively. The presence of UR-144 in oral fluid constitutes a non-invasive biomarker of SC consumption. The results of this observational study provide valuable preliminary data of the pharmacological effects of UR-144, showing a similar profile of cardiovascular effects in comparison with THC but lower intensity of subjective effects. Our results have to be confirmed by research in a larger sample to extensively clarify pharmacological effects and the health risk profile of UR-144.
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http://dx.doi.org/10.3390/biology10040257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064062PMC
March 2021

Died with or Died of? Development and Testing of a SARS CoV-2 Significance Score to Assess the Role of COVID-19 in the Deaths of Affected Patients.

Diagnostics (Basel) 2021 Jan 28;11(2). Epub 2021 Jan 28.

Department of Excellence of Biomedical Sciences and Public Health, University "Politecnica delle Marche" of Ancona, via Conca 71, 60126 Ancona, Italy.

Since December 2019, a new form of coronavirus, SARS-CoV-2, has spread from China to the whole word, raising concerns regarding Coronavirus Disease 2019 (COVID-19) endangering public health and life. Over 1.5 million deaths related with COVID-19 have been recorded worldwide, with wide variations among countries affected by the pandemic and continuously growing numbers. The aim of this paper was to provide an overview of the literature cases of deaths involving COVID-19 and to evaluate the application of the COVID-19 Significance Score (CSS) in the classification of SARS CoV-2-related fatalities, comparing it with the Hamburg rating scale. The results obtained allowed us to highlight that CSS used after a complete accurate post-mortem examination, coupled to the retrieval of in vivo data, post-mortem radiology, histology and toxicology, as well as to additional required analyses (e.g., electronic microscopy) is a useful and concise tool in the assessment of the cause of death and the role played by this virus. A shared use of this scale might hopefully lower the inhomogeneities in forensic evaluation of SARS CoV-2-related fatalities.
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http://dx.doi.org/10.3390/diagnostics11020190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912253PMC
January 2021

Disposition of Phytocannabinoids, Their Acidic Precursors and Their Metabolites in Biological Matrices of Healthy Individuals Treated with Vaporized Medical Cannabis.

Pharmaceuticals (Basel) 2021 Jan 13;14(1). Epub 2021 Jan 13.

Clinical Pharmacology Unit, Hospital Universitari Germans Trias i Pujol and Institut de Recerca Germans Trias i Pujol (HUGTiP-IGTP), 08916 Badalona, Spain.

Inhalation by vaporization is a useful application mode for medical cannabis. In this study, we present the disposition of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), their acidic precursors, and their metabolites in serum, oral fluid, and urine together with the acute pharmacological effects in 14 healthy individuals treated with vaporized medical cannabis. THC and CBD peaked firstly in serum and then in oral fluid, with higher concentrations in the first biological matrices and consequent higher area under the curve AUCs. Acidic precursors Δ-9-tetrahydrocannabinolic acid A (THCA) and cannabidiolic acid (CBDA) showed a similar time course profile but lower concentrations due to the fact that vaporization partly decarboxylated these compounds. All THC and CBD metabolites showed a later onset with respect to the parent compounds in the absorption phase and a slower decrease to baseline. In agreement with serum kinetics, THC-COOH-GLUC and 7-COOH-CBD were the significantly most excreted THC and CBD metabolites. The administration of vaporized medical cannabis induced prototypical effects associated with the administration of cannabis or THC in humans, with a kinetic trend overlapping that of parent compounds and metabolites in serum. The pharmacokinetics of cannabinoids, their precursors, and their metabolites in biological fluids of individuals treated with vaporized medical cannabis preparations showed a high interindividual variability as in the case of oral medical cannabis decoction and oil. Inhaled medical cannabis was absorbed into the organism earlier than decoction and oil. Cannabinoids reached higher systemic concentrations, also due to the fact that the acid precursors decarboxylated to parent cannabinoids at high temperatures, and consequently, the physiological and subjective effects occurred earlier and resulted with higher intensity. No serious adverse effects were observed.
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http://dx.doi.org/10.3390/ph14010059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828520PMC
January 2021

Disposition of Cannabidiol Metabolites in Serum and Urine from Healthy Individuals Treated with Pharmaceutical Preparations of Medical Cannabis.

Pharmaceuticals (Basel) 2020 Dec 12;13(12). Epub 2020 Dec 12.

Clinical Pharmacology Unit, Hospital Universitari Germans Trias i Pujol and Institut de Recerca Germans Trias i Pujol (HUGTiP-IGTP), 08916 Badalona, Spain.

The use of cannabis flowering tops with standardized amounts of active phytocannabinoids was recently authorized in several countries to treat several painful pathological conditions. The acute pharmacological effects and disposition of Δ-9-tetrahydrocannabinol (THC), cannabidiol (CBD), their acidic precursors and THC metabolites after oil and decoction administration have been already described. In this study, the disposition of CBD metabolites: 7-carboxy-cannabidiol (7-COOH-CBD), 7-hydroxycannabidiol (7-OH-CBD), 6-α-hydroxycannabidiol (6-α-OH-CBD), and 6-β-hydroxycannabidiol (6-β-OH-CBD) in the serum and urine of healthy volunteers was presented. Thirteen healthy volunteers were administered 100 mL of cannabis decoction in the first experimental session and, after 15 days of washout, 0.45 mL of oil. Serum and urine samples were collected at different time points, and the CBD metabolites were quantified by ultra-high-performance liquid chromatography-tandem mass spectrometry. The most abundant serum metabolite was 7-COOH-CBD, followed by 7-OH-CBD, 6-β-OH-CBD, and6-α-OH-CBD, after decoction and oil. Both 7-OH-CBD and the 6-α-OH-CBD showed similar pharmacokinetic properties following administration of both cannabis preparations, whereas 7-COOH and 6-α-OH-CBD displayed a significant higher bioavailability after decoction consumption. All CBD metabolites were similarly excreted after oil and decoction intake apart from 6-α-OH-CBD, which had a significantly lower excretion after oil administration. The pharmacokinetic characterization of CBD metabolites is crucial for clinical practice since the cannabis herbal preparations are increasingly used for several pathological conditions.
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http://dx.doi.org/10.3390/ph13120459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763054PMC
December 2020

Determination of the Synthetic Cannabinoids JWH-122, JWH-210, UR-144 in Oral Fluid of Consumers by GC-MS and Quantification of Parent Compounds and Metabolites by UHPLC-MS/MS.

Int J Mol Sci 2020 Dec 10;21(24). Epub 2020 Dec 10.

National Centre on Addiction and Doping, Istituto Superiore di Sanità, V.Le Regina Elena 299, 00161 Rome, Italy.

The consumption of synthetic cannabinoids (SCs) has significantly increased in the last decade and the analysis of SCs and their metabolites in human specimens is gaining interest in clinical and forensic toxicology. A pilot study has been carried out using a combination of an initial last generation gas chromatography-mass spectrometry (GC-MS) screening method for the determination of JWH-122, JWH-210, UR-144) in oral fluid (OF) of consumers and an ultra-high performance liquid chromatography high resolution mass spectrometry (UHPLC-HRMS) confirmatory method for the quantification of the parent compounds and their metabolites in the same biological matrix. OF samples were simply liquid-liquid extracted before injecting in both chromatographic systems. The developed methods have been successfully validated and were linear from limit of quantification (LOQ) to 50 ng/mL OF. Recovery of analytes was always higher than 70% and matrix effect always lower than 15% whereas intra-assay and inter-assay precision and accuracy were always better than 16%. After smoking 1 mg JWH-122 or UR-144 and 3 mg JWH-210, maximum concentration of 4.00-3.14 ng/mL JWH-122, 8.10-7.30 ng/mL JWH-210 ng/mL and 7.40 and 6.81 ng/mL UR-144 were measured by GC-MS and UHPLC-HRMS respectively at 20 min after inhalation. Metabolites of JWH 122 and 210 were quantified in OF by UHPLC-HRMS, while that of UR144 was only detectable in traces. Our results provide for the first time information about disposition of these SCs and their metabolites in consumers OF. Last generation GC-MS has proven useful tool to identify and quantify parent SCs whereas UHPLC-HRMS also confirmed the presence of SCs metabolites in the OF of SCs consumers.
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http://dx.doi.org/10.3390/ijms21249414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764284PMC
December 2020

UHPLC-MS/MS analysis of cannabidiol metabolites in serum and urine samples. Application to an individual treated with medical cannabis.

Talanta 2021 Feb 14;223(Pt 2):121772. Epub 2020 Oct 14.

Department of Excellence-Biomedical Sciences and Public Health, University Politecnica Delle Marche, Ancona, Italy.

No analytical assay is currently available for the simultaneous determination of CBD major metabolites in serum or urine samples of individuals treated with medical cannabis or CBD-based pharmaceuticals. We developed and validated a method using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) for quantifying cannabidiol (CBD) and its metabolites, cannabidiol-7-oic acid (7-COOH-CBD), 7- hydroxycannabidiol (7-OH-CBD), 6-alpha-hydroxycannabidiol (6-α-OH-CBD) and 6-beta-hydroxycannabidiol (6-β-OH-CBD) in serum and urine samples of an individual treated with medical cannabis. The ionization was performed by electrospray in negative mode to reach the sensitivity required to detect trace amounts, with limits of quantification ranging from 0.05 to 0.1 ng/mL. The method is accurate (average inter/intra-day error, <15%), precise (inter/intra-day imprecision, <15%) and fast (8 min run time) and it is an essential tool to investigate CBD pharmacokinetics and pharmacodynamics in individuals treated with medical cannabis or with CBD-based medical preparations.
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http://dx.doi.org/10.1016/j.talanta.2020.121772DOI Listing
February 2021

Toxicology and Analysis of Psychoactive Tryptamines.

Int J Mol Sci 2020 Dec 4;21(23). Epub 2020 Dec 4.

Institute of Emerging Health Professions, Thomas Jefferson University, 1020 Walnut St, Philadelphia, PA 19144, USA.

Our understanding of tryptamines is poor due to the lack of data globally. Tryptamines currently are not part of typical toxicology testing regimens and their contribution to drug overdoses may be underestimated. Although their prevalence was low, it is increasing. There are few published data on the many new compounds, their mechanisms of action, onset and duration of action, toxicity, signs and symptoms of intoxication and analytical methods to identify tryptamines and their metabolites. We review the published literature and worldwide databases to describe the newest tryptamines, their toxicology, chemical structures and reported overdose cases. Tryptamines are 5-HT receptor agonists that produce altered perceptions of reality. Currently, the most prevalent tryptamines are 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DiPT), 5-methoxy-N,N- diallyltryptamine (5-MeO-DALT) and dimethyltryptamine (DMT). From 2015 to 2020, 22 new analytical methods were developed to identify/quantify tryptamines and metabolites in biological samples, primarily by liquid chromatography tandem mass spectrometry. The morbidity accompanying tryptamine intake is considerable and it is critical for clinicians and laboratorians to be informed of the latest data on this public health threat.
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http://dx.doi.org/10.3390/ijms21239279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730282PMC
December 2020

The Difficult Interpretation of GHB Values in Postmortem Samples: What Strategies Should Be Followed?

J Anal Toxicol 2021 Jan;44(9):e11-e12

Department of Excellence-Biomedical Sciences and Public Heath, University Politecnica delle Marche, Ancona, Italy.

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http://dx.doi.org/10.1093/jat/bkaa130DOI Listing
January 2021

Intensive and pharmacological care in times of COVID-19: A "special ethics" for emergency?

BMC Med Ethics 2020 11 19;21(1):117. Epub 2020 Nov 19.

Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy.

Background: The Authors have laid out an analysis of Italian COVID-19 confirmed data and fatality rates, pointing out how a dearth of health care resources in northern regions has resulted in hard, ethically challenging decisions in terms of granting patient access to intensive care units (ICU).

Main Text: Having to make such decisions certainly entails substantial difficulties, and that has led many health care professional to seek ethical guidance. The Italian Society of Anesthesia, Analgesia, Resuscitation and Intensive Care (SIAARTI) has attempted to meet that growing need by a set of recommendations, applying "clinical soundness" as a beacon standard; that approach tends to prioritize patients with higher life expectancy, which could be characterized as a "moderately utilitarian" approach. Yet, such a selection has engendered daunting ethical quandaries. The authors believe it can only be warranted and acceptable if rooted in a transparent decision-making process and verifiable, reviewed criteria. Moreover, the authors have stressed how clinical experimentation in a pandemic setting is a subtext of great interest from an ethical perspective. In Italy, no drug therapy and trials were undertaken for COVID-19 patients for a rather long period of time. When the epidemic was already circulating, an intervention proved necessary on the system of administrative procedures, aimed at expediting the authorization and validation of protocols, then bogged down by bureaucracy. A new system has since been instituted by a government decree that was signed about one month after the first Covid-19 case was officially recorded in the country. Such a swift implementation, which took just a few weeks, is noteworthy and proves that clinical trials can be initiated in a timely fashion, even with a pandemic unfolding. The concerted, action of supportive care and RCTs is the only way to attain effective forms of treatments for COVID-19 and any other future outbreak.

Conclusions: The authors have arrived at the conclusion that the most effective and ethically sound response on the part of any national health care system would be to adequately reconfigure its organizational mechanisms, by making clinical trials and all related administrative procedures consistent with the current state of emergency.
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http://dx.doi.org/10.1186/s12910-020-00562-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675378PMC
November 2020

Pharmacology of Herbal Sexual Enhancers: A Review of Psychiatric and Neurological Adverse Effects.

Pharmaceuticals (Basel) 2020 Oct 14;13(10). Epub 2020 Oct 14.

Unit of Forensic Toxicology, Section of Legal Medicine, Department of Excellence of Biomedical Sciences and Public Health, Marche Polytechnic University, 60126 Ancona, Italy.

Sexual enhancers increase sexual potency, sexual pleasure, or libido. Substances increasing libido alter the concentrations of specific neurotransmitters or sex hormones in the central nervous system. Interestingly, the same pathways are involved in the mechanisms underlying many psychiatric and neurological disorders, and adverse reactions associated with the use of aphrodisiacs are strongly expected. However, sexual enhancers of plant origin have gained popularity over recent years, as natural substances are often regarded as a safer alternative to modern medications and are easily acquired without prescription. We reviewed the psychiatric and neurological adverse effects associated with the consumption of herbal aphrodisiacs L., L., L., Jack., Walp., Korth., C. A. Mey, L., (K. Schum.) Pierre ex Beille, G. Forst., Benth., (L.) N. E. Brown, Willd. ex. Schult., Stapf ex Scott-Elliot, and (L.) Dunal. A literature search was conducted on the PubMed, Scopus, and Web of Science databases with the aim of identifying all the relevant articles published on the issue up to June 2020. Most of the selected sexual enhancers appeared to be safe at therapeutic doses, although mild to severe adverse effects may occur in cases of overdosing or self-medication with unstandardized products. Drug interactions are more concerning, considering that herbal aphrodisiacs are likely used together with other plant extracts and/or pharmaceuticals. However, few data are available on the side effects of several plants included in this review, and more clinical studies with controlled administrations should be conducted to address this issue.
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http://dx.doi.org/10.3390/ph13100309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602496PMC
October 2020

Pharmacology and legal status of cannabidiol.

Ann Ist Super Sanita 2020 Jul-Sep;56(3):285-291

Dipartimento di Scienze Biomediche e Sanità Pubblica, Università Politecnica delle Marche, Ancona, Italy.

Cannabidiol (CBD) is the second most abundant cannabinoid present in Cannabis sativa L. It is not associated with psychotropic activity and is capable to mitigate the psychotomimetic effects produced by tetrahydrocannabinol (THC). The latest cannabis decriminalization policies and the high applicability in therapeutic and technologic-industrial fields, have determined an exponential marketing growth of foods, cosmetics and in particularly medicinal products containing CBD, which are easily available for consumers. Most importantly, on 2018 United States Food and Drug Administration approved CBD oral solution with the trade name of Epidiolex® for the treatment of two rare and severe forms of epilepsy, "Lennox-Gastaut syndrome" and "Dravet syndrome", in pediatric patients. The aim of this review was to focus on pharmacology and on legal status of CBD, to highlight the lack of harmonization of international regulatory laws over the marketing authorization of CBD-based products.
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http://dx.doi.org/10.4415/ANN_20_03_06DOI Listing
September 2021

Medicinal Cannabis and Synthetic Cannabinoid Use.

Medicina (Kaunas) 2020 Sep 7;56(9). Epub 2020 Sep 7.

Department of Excellence of Biomedical Sciences and Public Health, "Politecnica delle Marche" University of Ancona, Via Tronto 10/a, 60126 Ancona, Italy.

Cannabis products have been used for centuries by humans for recreational and medical purposes. Resent research, proposed the promising therapeutic potential of cannabis and related cannabinoids for a wide range of medical conditions, including psychiatric and neurological diseases. This Special Issue presents the latest updates on medicinal cannabis and synthetic cannabinoids pharmacology, toxicology and new analytical methods to identify and quantify these compounds in conventional and non-conventional biological matrices. Moreover, it provides current data regarding their adverse effects, safety, application for medical purposes and their harmful effects.
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http://dx.doi.org/10.3390/medicina56090453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7558594PMC
September 2020

A 2017-2019 Update on Acute Intoxications and Fatalities from Illicit Fentanyl and Analogs.

J Anal Toxicol 2021 Jul;45(6):537-554

Department of Excellence of Biomedical Sciences and Public Health, University "Politecnica delle Marche" of Ancona, Via Tronto 71, Ancona, Italy.

The aim of this review was to report the most recent cases of acute intoxication, fatalities and "driving under the influence" cases, involving illicit fentanyl and its newest analogs. When available, information on age, sex, circumstances of exposure, intoxication symptoms, cause of death (if applicable) and toxicology results from biological fluid testing was described. Scientific publications reporting fatalities or acute intoxications involving use of fentanyl derivatives were identified from PubMed, Scopus and institutional/governmental websites from January 2017 up to December 2019. The search terms, used alone and in combination, were as follows: fentanyl, street fentanyl, analogs, compounds, derivatives, abuse, fatality, fatalities, death, toxicity, intoxication and adverse effects. When considered relevant, reports not captured by the initial search but cited in other publications were also included. Of the 2890 sources initially found, only 44 were suitable for the review. Emergent data showed that the most common analogs detected in biological samples and seized materials are acetylfentanyl, acrylfentanyl, butyrfentanyl, carfentanil, cyclopropylfentanyl, fluorofentanyl, 4-fluorobutyrfentanyl, 4-fluoroisobutyrfentanyl, furanylfentanyl, 2-methoxyacetylfentanyl, 3-methylfentanyl and ocfentanil. These compounds were frequently administered in association with other illicit substances, medicinal drugs and/or alcohol; patients and the victims often had a previous history of drug abuse. The trend of fentanyl analogs is rapidly evolving with illicit market fluctuations. Since information about potency and lethal dosage are frequently unknown, it is important to identify the new trends for further investigation on therapeutic use, toxicity and fatal doses, and implement public health measures. Recently marketed fentanyl analogs such as crotonylfentanyl and valerylfentanyl were not involved in intoxications to date, but should be carefully monitored. Many intoxications and fatalities might have gone unnoticed, and research efforts should focus on metabolite identification studies and the implementation of updated and comprehensive analytical methods.
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http://dx.doi.org/10.1093/jat/bkaa115DOI Listing
July 2021
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