Giovanni Serpelloni

Abacavir use and cardiovascular disease events: a meta-analysis of published and unpublished data

Background:The use of abacavir (ABC) has been associated with an increased risk of cardiovascular disease in some cohort studies. However, no excess risk of myocardial infarction (MI) with ABC therapy has been observed in individual randomized clinical trials (RCTs) and in the aggregated clinical trials database maintained by the manufacturer of ABC. Objective:To combine all the evidence from RCTs by means of meta-analysis to estimate the effect of combined antiretroviral therapy (cART) containing ABC on MI and overall major cardiovascular events (CVEs). Methods:Primary outcomes included MI, CVE, adverse events requiring discontinuation of treatment, and overall mortality. We used a conventional Mantel–Haenszel method, with risk ratio and 95% confidence intervals (CIs) or, in the presence of heterogeneity, a random-effect model. Results:Data were from 28 primary RCTs (9233 participants) comparing ABC-containing cART (4376 participants) to other regimens not containing ABC (4857 controls). MI data were available from 18 trials (31 episodes in 7054 patients) and CVE data from 20 trials (79 episodes in 7899 patients). Compared to the controls, ABC use did not increase significantly the occurrence of MI (risk ratio 0.73, 95% CI 0.39–1.35; P = 0.31), CVE (risk ratio 0.95, 95% CI 0.62–1.44; P = 0.80), overall mortality (risk ratio 1.20, 95% CI 0.63–2.27; P = 0.58), and adverse events requiring discontinuation of treatment (risk ratio 0.82, 95% CI 0.67–1.00; P = 0.05). Conclusion:This meta-analysis of RCTs does not support the hypothesis that ABC-containing cART regimens carry a greater risk of MI or major cardiovascular events relative to comparator cART.

A Conceptual Review of Research on the Pathological Use of Computers, Video Games, and the Internet

Preliminary research studies suggest that some people who use computer, video games, and the Internet heavily develop dysfunctional symptoms, often referred to in the popular press as an “addiction.” Although several studies have measured various facets of this issue, there has been no common framework within which to view these studies. This paper aims to provide a conceptual framework of “impulse control disorders” and describe what is known currently based on a review of the international literature, and highlight what remains to be studied. We suggest the term “Pathological Technology Use” (PTU) rather than “internet addiction”, since there is robust construct validity (via convergent validity and comorbidity) for pathological computer, video game and Internet use, regardless of how individual researchers defined or measured it. Questions concerning diagnostic criteria are raised, and a common set of diagnostic criteria is proposed.

Serologic response to hepatitis B vaccine with high dose and increasing number of injections in HIV infected adult patients

Sixty-five HIV-infected patients received high-dose (40mug), short interval HBV vaccine. In non-responders to the initial immunization, 1-3 boosters were administered. Rate of response was 60.0% after primary vaccination, and 89.2% after boosters. However, 12 and 24 months after the last vaccination, only 63% and 32.7% of the responders, respectively, had persistence of protective anti-HBs titers (> or =10 IU/L). The results of logistic regression show that gender, CD4 count, and HIV viral load were significant predictors of vaccination outcome. This study suggests that in HIV-infected patients with relatively high CD4 count, response to high dose of HBV vaccine is suboptimal. Rate of response may be increased by vaccine boosts, but antibody titers are significantly lower in non-responders than in responders to primary vaccination. Since persistence of anti-HBs titers appears significantly related to antibody titers after the immunization procedure, monitoring of anti-HBs, particularly in patients with low level of protective antibody titers after primary vaccination or boosters, seems more than justified.

rTMS in the treatment of drug addiction: an update about human studies.

Drug addiction can be a devastating and chronic relapsing disorder with social, psychological, and physical consequences, and more effective treatment options are needed. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation technique that has been assessed in a growing number of studies for its therapeutic potential in treating addiction. This review paper offers an overview on the current state of clinical research in treating drug addiction with rTMS. Because of the limited research in this area, all studies (including case reports) that evaluated the therapeutic use of rTMS in nicotine, alcohol, or illicit drug addiction were included in this review. Papers published prior to December 2012 were found through an NCBI PubMed search. A total of eleven studies were identified that met review criteria. There is nascent evidence that rTMS could be effective in reducing cocaine craving and nicotine and alcohol craving and consumption and might represent a potential therapeutic tool for treating addiction. Further studies are needed to identify the optimal parameters of stimulation for the most effective treatment of drug addiction, to improve our comprehension of the treatment neurophysiological effects, and to conduct rigorous, controlled efficacy studies with adequate power.

Screening for synthetic cannabinoids in hair by using LC-QTOF MS: a new and powerful approach to study the penetration of these new psychoactive substances in the population

The current analytical technology for the determination of New Psychoactive Substances in biological samples is still largely inadequate, because the immunoassays are unsuitable for the detection of most of these compounds and the use of traditional gas chromatography–mass spectrometry techniques is hampered by the lack of chromatographic standards and mass fragmentation patterns. Taking advantage of the molecular recognition capability of high-resolution mass spectrometry, the present work aimed to apply liquid chromatography-quadrupole-time of flight mass spectrometry for the rapid identification of New Psychoactive Substances in the hair, a peculiar tissue which “keeps memory” of the recent history of drug intake of the subject. All the samples were screened for the presence of 50 different New Psychoactive Substances (synthetic cannabinoids, cathinones and phenethylamines), substances that had been reported officially by the National Early Warning System in the period 2009–2011. Among the 435 samples analyzed, 8 were found “positive” for the following compounds: JWH-018, JWH-073, JWH-081, JWH-250, JWH-122, in a broad range of concentrations (0.010–1.28 ng/mg). Results strongly support the use of hair analysis to monitor the diffusion of new psychoactive drugs in the community.

An analytical approach to the forensic identification of different classes of new psychoactive substances (NPSs) in seized materials

RATIONALE New psychoactive substances (NPSs) are rapidly spreading worldwide, and forensic laboratories are often requested to identify new substances for which no reference standards or analytical data are available. This article describes an analytical approach that was adopted in Italy by a few collaborative centres of the Italian Early Warning System for Drugs, which has contributed many alerts for the identification of different classes of NPSs in the last 24 months. METHODS Seized crystals and powders were initially analysed via single quadrupole gas chromatography/mass spectrometry (GC/MS), followed by liquid chromatography/high-resolution mass spectrometry (LC/HRMS) in the positive electrospray ionisation (ESI) mode at 100,000 full width at half maximum resolution (FWHM) without fragmentation to elucidate the elemental compositions of unknown molecules. Different fragmentation voltages during LC/HRMS were applied to study the accurate masses of the obtained characteristic fragments. Nuclear magnetic resonance (NMR) analyses were performed to identify specific isomers when necessary. RESULTS Some interesting examples of unknown NPSs from seizures later identified in our laboratories are reported, with special focus on those cases where analytical standards were not available during analyses. These cases include cathinones, such as 3-methylmethcathinone (3-MMC), methylone, bk-MBDB (butylone), 4-methylethcathinone (4-MEC), flephedrone, methylenedioxypyrovalerone (MDPV) and pentedrone, methoxetamine, apinaca or AKB48, benzydamine, meta-chlorophenylpiperazine (m-CPP), 5-MeO-N,N-dialkyl tryptamines, such as 5-MeO-DALT and 5-MeOMIPT, benzofurans, such as 6-APB and 4-APB, and diphenidine (identified for the first time in Europe). CONCLUSIONS The identification of NPSs in confiscated materials was successfully achieved via GC/MS coupled with LC/HRMS and, in a few cases, NMR analyses. The availability of GC/MS libraries is of great assistance in the identification of new drugs. Alternatively, the study of characteristic molecule fragments combined with the determination of their accurate masses can be a useful approach to identify unknown samples not previously analysed.

Neuropharmacology of New Psychoactive Substances (NPS): Focus on the Rewarding and Reinforcing Properties of Cannabimimetics and Amphetamine-Like Stimulants

New psychoactive substances (NPS) are a heterogeneous and rapidly evolving class of molecules available on the global illicit drug market (e.g smart shops, internet, “dark net”) as a substitute for controlled substances. The use of NPS, mainly consumed along with other drugs of abuse and/or alcohol, has resulted in a significantly growing number of mortality and emergency admissions for overdoses, as reported by several poison centers from all over the world. The fact that the number of NPS have more than doubled over the last 10 years, is a critical challenge to governments, the scientific community, and civil society [EMCDDA (European Drug Report), 2014; UNODC, 2014b; Trends and developments]. The chemical structure (phenethylamines, piperazines, cathinones, tryptamines, synthetic cannabinoids) of NPS and their pharmacological and clinical effects (hallucinogenic, anesthetic, dissociative, depressant) help classify them into different categories. In the recent past, 50% of newly identified NPS have been classified as synthetic cannabinoids followed by new phenethylamines (17%) (UNODC, 2014b). Besides peripheral toxicological effects, many NPS seem to have addictive properties. Behavioral, neurochemical, and electrophysiological evidence can help in detecting them. This manuscript will review existing literature about the addictive and rewarding properties of the most popular NPS classes: cannabimimetics (JWH, HU, CP series) and amphetamine-like stimulants (amphetamine, methamphetamine, methcathinone, and MDMA analogs). Moreover, the review will include recent data from our lab which links JWH-018, a CB1 and CB2 agonist more potent than Δ9-THC, to other cannabinoids with known abuse potential, and to other classes of abused drugs that increase dopamine signaling in the Nucleus Accumbens (NAc) shell. Thus the neurochemical mechanisms that produce the rewarding properties of JWH-018, which most likely contributes to the greater incidence of dependence associated with “Spice” use, will be described (De Luca et al., 2015a). Considering the growing evidence of a widespread use of NPS, this review will be useful to understand the new trends in the field of drug reward and drug addiction by revealing the rewarding properties of NPS, and will be helpful to gather reliable data regarding the abuse potential of these compounds.

Chronic THC during adolescence increases the vulnerability to stress-induced relapse to heroin seeking in adult rats

Cannabis derivatives are among the most widely used illicit substances among young people. The addictive potential of delta-9-tetrahydrocannabinol (THC), the major active ingredient of cannabis is well documented in scientific literature. However, the consequence of THC exposure during adolescence on occurrence of addiction for other drugs of abuse later in life is still controversial. To explore this aspect of THC pharmacology, in the present study, we treated adolescent rats from postnatal day (PND) 35 to PND-46 with increasing daily doses of THC (2.5-10mg/kg). One week after intoxication, the rats were tested for anxiety-like behavior in the elevated plus maze (EPM) test. One month later (starting from PND 75), rats were trained to operantly self-administer heroin intravenously. Finally, following extinction phase, reinstatement of lever pressing elicited by the pharmacological stressor, yohimbine (1.25mg/kg) was evaluated. Data revealed that in comparison to controls, animals treated with chronic THC during adolescence showed a higher level of anxiety-like behavior. When tested for heroin (20μg per infusion) self-administration, no significant differences were observed in both the acquisition of operant responding and heroin intake at baseline. Noteworthy, following the extinction phase, administration of yohimbine elicited a significantly higher level of heroin seeking in rats previously exposed to THC. Altogether these findings demonstrate that chronic exposure to THC during adolescence is responsible for heightened anxiety and increased vulnerability to drug relapse in adulthood.

Monitoring of chronic Cannabis abuse: an LC-MS/MS method for hair analysis.

An advanced analytical method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS), has been developed for the identification and determination in hair of Δ(9)-tetrahydrocannabinol together with its major metabolite 11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol. Since the latter is formed endogenously, it allows the assessment of chronic use excluding passive exposure to Cannabis. The sample pre-treatment procedure is based on a feasible incubative extraction followed by a liquid-liquid extraction step. Chromatographic separation was performed using a reversed-phase column and gradient elution with a formic acid/acetonitrile/water mobile phase. The limits of quantitation and of detection were 3pg/mg and 1pg/mg, respectively, for both analytes. The method was successfully applied to the analysis of hair samples from Cannabis abusers; the analyte concentrations found ranged from 55 to 100pg/mg for Δ(9)-tetrahydrocannabinol and from 5 to 10pg/mg for 11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol. Accuracy studies also gave satisfactory results (recovery>87%), thus confirming the suitability of the assay for chronic consumption monitoring.

Micellar electrokinetic chromatography: a new simple tool for the analysis of synthetic cannabinoids in herbal blends and for the rapid estimation of their logP values.

For the first time a capillary separation based on micellar electrokinetic chromatography (MEKC) with diode array detection (DAD) was developed and validated for the rapid determination of synthetic cannabinoids in herbal blends. Separations were carried out on a 30 μm(ID) × 40 cm uncoated fused silica capillaries. The optimized buffer electrolyte was composed of 25 mM sodium tetraborate pH 8.0, 30 mM SDS and n-propanol 20% (v/v). Separations were performed at 30 kV. Sample injection conditions were 0.5 psi, 10s. Diazepam and JWH-015 were used as internal standards. The determination of the analytes was based on the UV signal recorded at 220 nm, corresponding to the maximum wavelength of absorbance of the molecules, whereas peak identification and purity check were also performed on the basis of the acquisition of UV spectra between 200 and 400 nm wavelengths. Under the described conditions, the separation of the compounds was achieved in 25 min without any significant interference from the matrix. Linearity was assessed within a concentration range from 5 to 100 μg/mL. The intra-day and inter-day imprecision values were below 2.45% for relative migration times and below 10.75% for relative peak areas. The present method was successfully applied to the direct determination of synthetic cannabinoids in 15 different herbal blend samples requiring only sample dilution. In addition, the developed MEKC separation was also applied to estimate the octanol/water partition coefficients (logP) of these new and poorly known molecules.