Amniotic fluid embolism pathophysiology suggests the new diagnostic armamentarium: β-tryptase and complement fractions C3-C4 are the indispensable working tools

Amniotic fluid embolism (AFE) is an uncommon obstetric condition involving pregnant women during labor or in the initial stages after delivery. Its incidence is estimated to be around 5.5 cases per 100,000 deliveries. Therefore, this paper investigated the pathophysiological mechanism, which underlies AFE, in order to evaluate the role of immune response in the development of this still enigmatic clinical entity. The following databases (from 1956 to September 2014) Medline, Cochrane Central, Scopus, Web of Science and Science Direct were used, searching the following key words: AFE, pathophysiology, immune/inflammatory response, complement and anaphylaxis. The main key word "AFE" was searched singularly and associated individually to each of the other keywords. Of the 146 sources found, only 19 were considered appropriate for the purpose of this paper. The clinical course is characterized by a rapid onset of symptoms, which include: acute hypotension and/or cardiac arrest, acute hypoxia (with dyspnoea, cyanosis and/or respiratory arrest), coagulopathies (disseminated intravascular coagulation and/or severe hemorrhage), coma and seizures. The pathology still determines a significant morbidity and mortality and potential permanent neurological sequelae for surviving patients. At this moment, numerous aspects involving the pathophysiology and clinical development are still not understood and several hypotheses have been formulated, in particular the possible role of anaphylaxis and complement. Moreover, the detection of serum tryptase and complement components and the evaluation of fetal antigens can explain several aspects of immune response

From clinical application to cognitive enhancement: the example of methylphenidate

Methylphenidate (MPD) is a central nervous system (CNS) stimulant, which belongs to the phenethylamine group and is mainly used in the treatment of attention deficit hyperactive disorder (ADHD). However, a growing number of young individuals misuse or abuse MPD to sustain attention, enhance intellectual capacity and increase memory. Recently, the use of MPD as a cognitive enhancement substance has received much attention and raised concerns in the literature and academic circles worldwide. The prescribing frequency of the drug has increased sharply asconsequence of the more accurate diagnosis of the ADHD and the popularity of the drug itself due to its beneficial short-term effect. However, careful monitoring is required, because of possible abuse. In this review different aspects concerning the use of MPD have been approached. Data showing its abuse among college students are given, when the drug is prescribed short term beneficial effects and side effects are provided; moreover studies on animal-models suggesting long lasting negative effects on healthy brains are discussed. Finally, emphasis is given to the available formulationsand pharmacology

Does defensive medicine change the behaviors of vascular surgeons? a qualitative review

Although in literature few successful claims have been shown in comparison with other medical specialties such as gynaecology and orthopaedics, vascular surgery is included among high-risk specialties. The high-risk of receiving medical claims may lead vascular surgeons to practice defensive medicine, as is normal in several other areas of clinical practice. No studies are available to our knowledge of the incidence of defensive medicine in the field of vascular surgery. Taking into consideration the scarce amount of information, the authors provide a critical discussion regarding the application of defensive medicine behaviour among vascular surgeon

Development and validation of a GC-MS method for the detection and quantification of clotiapine in blood and urine specimens and application to a postmortem case

INTRODUCTION: Clotiapine is an atypical antipsychotic of the dibenzothiazepine class introduced in a few European countries since 1970, efficient in treatment-resistant schizophrenic patients. There is little published data on the therapeutic and toxic concentrations of this drug. AIMS: The aim of the present study is the development and validation of a method that allows the detection and quantification of clotiapine in blood and urine specimens by gas chromatography-mass spectrometry (GC-MS). METHODS: Validation was performed working on spiked postmortem blood and urine samples. Samples were extracted with liquid-liquid extraction (LLE) technique at pH 8.5 with n-hexane/dichloromethane (85/15 v/v) and analysis was followed by GC-MS. Methadone-d9 was used as internal standard. RESULTS: The limit of detection (LOD) was 1.2 and 1.3 ng/mL for urine and blood, respectively, while the lower limit of quantification (LLOQ) was 3.9 and 4.3 ng/mL, respectively. Linearity, precision, selectivity, accuracy, and recovery were also determined. The method was applied to a postmortem case. The blood and urine clotiapine concentrations were 1.32 and 0.49 μg/mL, respectively. CONCLUSIONS: A reliable GC-MS method for the detection and quantification of clotiapine in blood and urine samples has been developed and fully validated and then applied to a postmortem case

Neurotoxicity induced by mephedrone: an up-to-date review

BACKGROUND: 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. OBJECTIVE: 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. MATERIALS AND METHODS: 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". RESULTS: Of the 498 sources initially found, only 36 papers were suitable for the review. Neurotoxic effect of mephedrone on 5-hydroxytryptamine (5-HT) and dopamine (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. CONCLUSIONS: 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

The static evolution of the new Italian code of medical ethics

Eight years since the last revision, in May 2014 the Italian code of medical ethics has been updated. Here, the Authors examine the reform in the light of the increasing difficulties of the medical profession arising from the severity of the Italian law Courts. The most significant aspects of this new code are firstly, the patient's freedom of self-determination and secondly, risk prevention through the disclosure of errors and adverse events. However, in both areas the reform seems to be less effective if we compare the ethical codes of France, the United Kingdom and the United States. In particular, the non-taking into consideration of the said code quality standards and scientific evidence which should guide doctors in their clinical practice is to say the least questionable. Since these are the most significant changes in the new code, it seems inevitable to conclude that the 2014 edition is essentially in line with previous versions. Now more than ever it is necessary that medical ethics acknowledges that medicine, society and medical jurisprudence have changed and doctors must be given new rules in order to protect both patients' rights and dignity of the profession. The physician's right to refuse to perform treatment at odds with his own clinical beliefs cannot be the only mean to safeguard the dignity of the profession. A clear boundary must also be established between medicine and professionalism as well as the criteria in determining the scientific evidences that physicians must follow. This has not been done in the Italian code of ethics, despite all the controversy caused by the Stamina case

Clinical applications of sodium oxybate (GHB): from narcolepsy to alcohol withdrawal syndrome

Gamma-hydroxybutyrate (GHB) is a short chain fatty acid endogenously produced within the central nervous system (CNS) and acts as a precursor and metabolite of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Although, it is an illegal recreational drug of abuse, its sodium salt (sodium oxybate) has been utilized as a medication for a number of medical conditions. The first aim of this review was to focus on current applications of sodium oxybate for the treatment of narcolepsy, with a particular emphasis on the key symptoms of this disorder: cataplexy and excessive daytime sleepiness (EDS). Secondly, the effectiveness of sodium oxybate therapy for the treatment of alcohol withdrawal syndrome (AWS) and the maintenance of alcohol abstinence has been assessed. Nowadays, sodium oxybate is the first-line treatment for narcolepsy and it is highly effective in meliorating sleep architecture, decreasing EDS and the frequency of cataplexy attacks in narcoleptic patients. Sodium oxybate currently finds also application in the treatment of AWS and the maintenance of alcohol abstinence in alcoholics. Most of the studies evaluating the efficacy of GHB in the treatment of AWS use a dosage of 50 mg/kg divided in three or four administrations per day. Human studies showed that GHB (dose of 50 mg/kg, divided in three administrations per day) is capable to increase the number of abstinent days, reduce alcohol craving and decrease the number of drinks per day. However, there is limited randomized evidence and, thus, GHB cannot be reliably compared to clomethiazole or benzodiazepines. Some randomized data suggest that GHB is better than naltrexone and disulfiram regarding abstinence maintenance and prevention of craving in the medium term i.e. 3-12 months. It is recommended that GHB should be used only under strict medical supervision, since concerns about the abuse/misuse of the drug and the addiction potential have been arisen

Lipid peroxidation and apoptotic response in rat brain areas induced by long-term administration of nandrolone: the mutual crosstalk between ROS and NF-kB

The aim of this study was to evaluate the played by oxidative stress in the apoptotic response in different brain areas of rats chronically treated with supra-physiological doses of nandrolone decanoate (ND). Immunohistochemical study and Western blot analysis were performed to evaluate cells' apoptosis and to measure the effects of expression of specific mediators, such as NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), Bcl-2 (B-cell lymphoma 2), SMAC/DIABLO (second mitochondria-derived activator of caspases/direct IAP-binding protein with low PI) and VMAT2 (vesicular monoamine transporter 2) on apoptosis. The results of the present study indicate that a long-term administration of ND promotes oxidative injury in rat brain specific areas. A link between oxidative stress and NF-κB signalling pathways is supported by our results. In addition to high levels of oxidative stress, we consistently observed a strong immunopositivity to NF-κB. It has been argued that one of the pathways leading to the activation of NF-κB could be under reactive oxygen species (ROS)-mediated control. In fact, growing evidence suggests that although in limited doses, endogenous ROS may play an activating role in NF-κB signalling, while above a certain threshold, they may negatively impact upon this signalling. However, a mutual crosstalk between ROS and NF-κB exists and recent studies have shown that ROS activity is subject to negative feedback regulation by NF-κB, and that this negative regulation of ROS is the means through which NF-κB counters programmed cells

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

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

Methylone and MDMA Pharmacokinetics Following Controlled Administration in Humans

The aim of this study is to define, for the first time, human methylone and HMMC plasma pharmacokinetics following controlled administration of 50–200 mg methylone to 12 male volunteers. A new LC-MS/MS method was validated to quantify methylone, MDMA, and their metabolites in plasma. The study was a randomized, cross-over, double-blinded and placebo-controlled study, with a total of 468 plasma samples collected. First, 10 µL of MDMA-d5, MDA-d5 and methylone-d3 internal standards were added to 100 µL of plasma. Two mL of chloroform and ethyl acetate 9:1 (v/v) were then added, mixed well and centrifuged. The supernatant was fortified with 0.1 mL acidified methanol and evaporated under nitrogen. Samples were reconstituted with a mobile phase and injected into the LC-MS/MS instrument. The method was fully validated according to OSAC guidelines (USA). Methylone plasma concentrations increased in a dose-proportional manner, as demonstrated by the increasing maximum concentration (Cmax) and area under the curve of concentrations (AUC). Methylone Cmax values were reported as 153, 304, 355 and 604 ng/mL, AUC0–24 values were reported as 1042.8, 2441.2, 3524.4 and 5067.9 h·ng/mL and T1/2 values as 5.8, 6.4, 6.9 and 6.4 h following the 50, 100, 150 and 200 mg doses, respectively. Methylone exhibited rapid kinetics with a Tmax of 1.5 h for the 50 mg dose and 2 h approximately after all the other doses. HMMC exhibited faster kinetics compared to methylone, with a Cmax value that was 10–14-fold lower and an AUC0–24 value that was 21–29-fold lower. Methylone pharmacokinetics was linear across 50–200 mg oral doses in humans, unlike the previously described non-linear oral MDMA pharmacokinetics. An LC-MS/MS method for the quantification of methylone, MDMA and their metabolites in human plasma was achieved. Methylone exhibited linear pharmacokinetics in humans with oral doses of 50–200 mg