Enrico Marinelli

Hepatotoxicity Induced by “the 3Ks”: Kava, Kratom and Khat

The 3Ks (kava, kratom and khat) are herbals that can potentially induce liver injuries. On the one hand, growing controversial data have been reported about the hepatotoxicity of kratom, while, on the other hand, even though kava and khat hepatotoxicity has been investigated, the hepatotoxic effects are still not clear. Chronic recreational use of kratom has been associated with rare instances of acute liver injury. Several studies and case reports have suggested that khat is hepatotoxic, leading to deranged liver enzymes and also histopathological evidence of acute hepatocellular degeneration. Numerous reports of severe hepatotoxicity potentially induced by kava have also been highlighted, both in the USA and Europe. The aim of this review is to focus on the different patterns and the mechanisms of hepatotoxicity induced by “the 3Ks”, while trying to clarify the numerous aspects that still need to be addressed.

When “Chems” Meet Sex: A Rising Phenomenon Called “ChemSex”

Background: The term “chemsex” was coined to indicate the voluntary intake of psychoactive and non psychoactive drugs in the context of recreational settings to facilitate and/or to enhance sexual intercourses mostly among men who have sex with other men (MSM). Objective: The authors aimed to review the mechanisms of action, the toxicity and the pattern of use and abuse of substances involved in “chemsex” practice together with the sociocultural background underlying it and the health-related consequences that they may have. Results: Gamma-hydroxybutyrate, gamma-butyrolactone,1,4-butanediol, mephedrone, methamphetamine, sildenafil, tadalafil, vardenafil and alkyl nitrites have been described in their role of “chemsex drugs” including pharmacological action and in their implication to impair capacities to chose sexual partners and consensual sex. Moreover, it has been demonstrated that sexual activity over protracted length of time under the influence of chemsex drugs can result in rectal trauma or penile abrasions and a significant increase of the risk of transmission of sexual transmitted diseases, especially in case of condomless intercourses, which are frequent in this context, representing therefore a serious health threat. Conclusion: One of the major problems to establish health policy priority interventions for chemsex is the lack of available epidemiological data on the issue. Finally, social actions should be taken in order to break down the barriers that currently exist among chemsex drug users in accessing services, including the shame and stigma often associated with drug use. In conclusion, more specific resources to face high risks of infections and HIV transmission are required in bisexual and homosexual individuals having SUID: sex under the influence of drugs.

Determination of GHB levels in breast milk and correlation with blood concentrations.

The sodium salt of GHB or sodium oxybate is approved and registered in some countries as a therapeutic substance (Xyrem(®)) for the treatment of narcolepsy-associated cataplexy. This study was designed to measure the GHB endogenous levels in blood and breast milk of 20 breastfeeding women. In addition, blood and breast milk samples of a 32-year-old narcoleptic nursing mother, who was on sodium oxybate treatment, were simultaneously collected at 0.5, 1, 3, 4 and 5h following a 4.5g GHB dose and analyzed, in order to establish the safety interval of time to breastfeed. A GC-MS method for the detection and quantification of GHB in blood and breast milk was developed and fully validated. The geometric mean of endogenous GHB levels in blood and breast milk detected at time 0 were 0.57mg/L; 95% Reference Interval (RI): 0.21-1.52mg/L and 0.36mg/L; 95% RI: 0.13-1.03mg/L, respectively. The geometric mean of the concentration of GHB in milk was 37% less (95% RI: from 14 to 53%) compared to that found in the blood. The analysis of blood and breast milk samples collected from the 32 years-old female showed the following results: GHB blood concentration 0.5h after medication intake was 80.10mg/L, reaching the peak 1h after the drug administration (108.34mg/L) and it steadily decreased to reach a level of 1.75mg/L, 5h after the medication intake. The GHB concentration found in breast milk followed the same pattern as for the blood, with the highest concentration being 23.19mg/L, 1h after sodium oxybate administration and the lowest 0.99mg/L, 5h after the medications intake. The comparison between blood and breast milk GHB levels in the 32-year-old woman, showed significant lower GHB levels in milk at 0.5, 1 and 3h, ranging from 71 to 80% less. It is interesting to note that only at 4 and 5h the difference between blood and breast milk GHB levels fell within the 95% RI (14-53%) of endogenous levels. Taking into consideration the absence of reference values for endogenous GHB in milk, we suggest the following reference interval: 0.13-1.03mg/L. We would recommend, following these preliminary data, that nursing mothers under sodium oxybate treatment should breastfeed at least 5h after the last GHB administration. However, further studies are necessary in order to confirm these findings.

Smart drugs and synthetic androgens for cognitive and physical enhancement: revolving doors of cosmetic neurology.

Cognitive enhancement can be defined as the use of drugs and/or other means with the aim to improve the cognitive functions of healthy subjects in particular memory, attention, creativity and intelligence in the absence of any medical indication. Currently, it represents one of the most debated topics in the neuroscience community. Human beings always wanted to use substances to improve their cognitive functions, from the use of hallucinogens in ancient civilizations in an attempt to allow them to better communicate with their gods, to the widespread use of caffeine under various forms (energy drinks, tablets, etc.), to the more recent development of drugs such as stimulants and glutamate activators. In the last ten years, increasing attention has been given to the use of cognitive enhancers, but up to now there is still only a limited amount of information concerning the use, effect and functioning of cognitive enhancement in daily life on healthy subjects. The first aim of this paper was to review current trends in the misuse of smart drugs (also known as Nootropics) presently available on the market focusing in detail on methylphenidate, trying to evaluate the potential risk in healthy individuals, especially teenagers and young adults. Moreover, the authors have explored the issue of cognitive enhancement compared to the use of Anabolic Androgenic Steroids (AAS) in sports. Finally, a brief overview of the ethical considerations surrounding human enhancement has been examined.

Cost analysis of brachial plexus injuries: variability of compensation by insurance companies before and after surgery.

Traumatic paralysis of the brachial plexus is an extremely disabling pathology. The type of trauma most frequently suffered by this group of patients is due to motorcycle injuries. It therefore affects a population of young patients. In the majority of cases, these patients receive compensation for permanent damage from insurance companies. Surgery of the brachial plexus enables various forms of functional recovery, depending on the number of roots of the brachial plexus involved in the injury. The aim of this study is to compare the functional deficit and the extent of the related compensation before and after surgical intervention, and to evaluate the saving in economic terms (understood as the cost of compensation paid by insurance companies) obtainable through surgical intervention. The authors analysed the functional recovery obtained through surgery in 134 patients divided into 4 groups on the basis of the number of injured roots. The levels of compensation payable to the patient before surgical intervention, and 3 years after, were then compared. The results showed that the saving obtainable through surgical treatment of brachial plexus injuries may exceed 65% of the economic value of the compensation that would have been attributable to the same patients if they had not undergone surgical treatment.

Stability of endogenous GHB in vitreous humor vs peripheral blood in dead bodies

For the first time, the stability of GHB was tested in post-mortem peripheral blood and vitreous humor samples, collected from 22 dead bodies at two different times: at the external body examination at the place of death and then during autopsy. An ad hoc method for the detection and quantification of GHB in vitreous humor by gas chromatography coupled to mass spectrometry (GC-MS) was developed and validated, with a good linearity between 0.1 and 50μg/mL (r2=0.991) and a precision and accuracy always better than 10% and an analytical recovery higher than 90%. The geometric mean of GHB concentration in the 22 peripheral blood samples at t0 was: 3.6μg/mL (95% CI: 2.3-5.9μg/mL) and at t1 it was 7.4μg/mL (95% CI: 5.0-10.9μg/mL); that of GHB in the 22 vitreous humor at t0 was: 2.5μg/mL (95% CI: 1.5-4.1μg/mL) and at t1 it was 3.0μg/mL (95% CI: 1.9-4.8μg/mL). There was no significant difference between the GHB concentrations in vitreous humor and peripheral blood at t0 in all the samples (p>0.10). Conversely at t1, the increase of GHB in the peripheral blood was significantly increased by a 102% (range: 86-120%) (p<0.001 vs t0), while in the vitreous humor only a slight increase by 19% was observed (range: 16-21%) (p>0.05 vs t0). Finally at t1, GHB values in the two matrices were statistically different, being that of peripheral blood higher (p<0.01). This study demonstrated the usefulness of vitreous humor as a more stable alternative matrix in comparison to peripheral blood for the post-mortem determination of endogenous GHB.

Neurotoxicity Induced by Mephedrone: An up-to-date Review

Mephedrone is a β-ketoamphetamine belonging to the family of synthetic cathinones, an emerging class of designer drugs known for their hallucinogenic and psychostimulant properties as well as for their abuse potential. The aim of this review was to examine the emerging scientific literature on the possible mephedrone-induced neurotoxicity, yet not well defined due to the limited number of experimental studies, mainly carried on animal models. Relevant scientific articles were identified from international literature databases (Medline, Scopus, etc.) using the keywords: “Mephedrone”, “4-MMC,” “neurotoxicity,” “neuropharmacology”, “patents”, “monoamine transporters” and “neurochemical effects”. Of the 498 sources initially found, only 36 papers were suitable for the review. Neurotoxic effect of mephedrone on 5-HT and DA systems remains controversial. Although some studies in animal models reported no damage to DA nerve endings in the striatum and no significant changes in brain monoamine levels, some others suggested a rapid reduction in 5-HT and DA transporter function. Persistent serotonergic deficits were observed after binge like treatment in a warm environment and in both serotonergic and dopaminergic nerve endings at high ambient temperature. Oxidative stress cytotoxicity and an increase in frontal cortex lipid peroxidation were also reported. In vitro cytotoxic properties were also observed, suggesting that mephedrone may act as a reductant agent and can also determine changes in mitochondrial respiration. However, due to the differences in the design of the experiments, including temperature and animal model used, the results are difficult to compare. Further studies on toxicology and pharmacology of mephedrone are therefore necessary to establish an appropriate treatment for substance abuse and eventual consequences for public health.

Determination of oxycodone and its major metabolites noroxycodone and oxymorphone by ultra-high-performance liquid chromatography tandem mass spectrometry in plasma and urine: application to real cases

Abstract Background: Oxycodone is a narcotic drug widely used to alleviate moderate and severe acute and chronic pain. Variability in analgesic efficacy could be explained by inter-subject variations in plasma concentrations of parent drug and its active metabolite, oxymorphone. To evaluate patient compliance and to set up therapeutic drug monitoring (TDM), an ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) assay was developed and validated for the parent drug and its major metabolites noroxycodone and oxymorphone. Methods: Extraction of analytes from plasma and urine samples was obtained by simple liquid-liquid extraction. The chromatographic separation was achieved with a reversed phase column using a linear gradient elution with two solvents: acetic acid 1% in water and methanol. The separated analytes were detected with a triple quadrupole mass spectrometer operated in multiple reaction monitoring (MRM) mode via positive electrospray ionization (ESI). Results: Separation of analytes was obtained in less than 5 min. Linear calibration curves for all the analytes under investigation in urine and plasma samples showed determination coefficients (r2) equal or higher than 0.990. Mean absolute analytical recoveries were always above 86%. Intra- and inter-assay precision (measured as coefficient of variation, CV%) and accuracy (measured as % error) values were always better than 13%. Limit of detection at 0.06 and 0.15 ng/mL and limit of quantification at 0.2 and 0.5 ng/mL for plasma and urine samples, respectively, were adequate for the purpose of the present study. Conclusions: Rapid extraction, identification and quantification of oxycodone and its metabolites both in urine and plasma by UHPLC-MS/MS assay was tested for its feasibility in clinical samples and provided excellent results for rapid and effective drug testing in patients under oxycodone treatment.

Can the intrapartum ultrasonography reduce the legal liability in distocic labor and delivery

Abstract The authors emphasize the importance of performing an intrapartum ultrasonography in order to prevent maternal and neonatal complications but also physician legal liability. The main advantages of using this technique are: improvement of fetal head’s malposition diagnosis; prevention of maternal and fetal complications of childbirth due to the use of forceps or vacuum extractor (VE); a more accurate planning of cesarean section; a proof of professional correctness.

The issue of delivery room infections in the Italian law. A brief comparative study with English and French jurisprudence

Abstract Delivery room infections are frequent, and many of them could be avoided through higher standards of care. The authors examine this issue by comparing it to English and French reality. Unlike England, in Italy and France the relationship established between health facility, physician and patient is outlined in a contract. In England, the judges’ decisions converge toward a better and higher protection of the patient–the actor–and facilitate the probative task. In case of infections, including those occurring in the delivery room, three issues are evaluated: the hospital’s negligent conduct, damages if any and causal nexus. Therefore, the hospital must demonstrate to have taken the appropriate asepsis measures according to current scientific knowledge concerning not only treatment, but also diagnosis, previous activities, surgery and post-surgery. In order to avoid a negative sentence, both physicians and hospital have to demonstrate their correct behavior and that the infection was caused by an unforeseeable event. The authors examine the most significant rulings by the Courts and the Supreme Court. They show that hospitals can avoid being accused of negligence and recklessness only if they can demonstrate to have implemented all the preventive measures provided for in the guidelines or protocols.