Anna Talarico

The Active Metabolite of Warfarin (3'-Hydroxywarfarin) and Correlation with INR, Warfarin and Drug Weekly Dosage in Patients under Oral Anticoagulant Therapy: A Pharmacogenetics Study.

Objectives Warfarin oral anticoagulant therapy (OAT) requires regular and frequent drug adjustment monitored by INR. Interindividual variability, drug and diet interferences, and genetics (VKORC1 and CYP2C9) make the maintenance/reaching of stable INR a not so easy task. HPLC assessment of warfarin/enantiomers was suggested as a valid monitoring-tool along with INR, but definite results are still lacking. We evaluated possible correlations between INR, warfarin/3’-hydroxywarfarin, and drug weekly dosage aimed at searching novel alternatives to OAT monitoring. VKORC1/CYP2C9 pharmacogenetics investigation was performed to account for the known influence on warfarin homeostasis. Methods 133 OAT patients were recruited and assessed for warfarin/3’-hydroxywarfarin serum levels (HPLC), INR, and VKORC1 and CYP2C9 genotypes. A subgroup of 52 patients were monitored in detail (5 consecutive controls; c0-c4) till the target INR was reached. Correlation analyses were performed in both groups Results In the whole OAT group both warfarin and 3’-hydroxywarfarin correlate with INR at comparable degree (r2 = 0.0388 and 0.0362 respectively). Conversely, warfarin weekly dosage better correlates with warfarin than with 3’-hydroxywarfarin (r2 = 0.0975 and r2 = 0.0381 respectively), but considering together warfarin plus 3’-hydroxywarfarin the correlation strongly increased (r2 = 0.1114; p<0.0001). Interestingly, 3’-hydroxywarfarin reached a strong correlation at c4 respect to warfarin (r2 = 0.2157 and r2 = 0.0549; p = 0.0005 and p = 0.0944 respectively) seeming less affected by drug adjustments in the subgroup of 52 patients who started OAT. The multivariate analyses aimed at estimating the true contribution of 3’-hydroxywarfarin on INR value ascribed it the unique significant value (p = 0.0021) in spite of warfarin who lost association. The pharmacogenetics studies confirmed that patients carrying the VKORC1 variant-allele required lower warfarin maintenance dosage and that the combination of VKORC1 and CYP2C9 yielded a warfarin responsive index (WRI) inversely related to the number variant alleles Conclusion Our results overall suggest that 3’-hydroxywarfarin monitoring could be of great advantage in INR monitoring respect to classical warfarin assessment showing significant contribution also in multivariate analysis. Therefore, additional active metabolites should be recognized and investigated as novel useful indicators.

Neurological, sensorimotor and cardiorespiratory alterations induced by methoxetamine, ketamine and phencyclidine in mice

ABSTRACT Novel psychoactive substances are intoxicating compounds developed to mimic the effects of well‐established drugs of abuse. They are not controlled by the United Nations drug convention and pose serious health concerns worldwide. Among them, the dissociative drug methoxetamine (MXE) is structurally similar to ketamine (KET) and phencyclidine (PCP) and was created to purposely mimic the psychotropic effects of its “parent” compounds. Recent animal studies show that MXE is able to stimulate the mesolimbic dopaminergic transmission and to induce KET‐like discriminative and rewarding effects. In light of the renewed interest in KET and PCP analogs, we decided to deepen the investigation of MXE‐induced effects by a battery of behavioral tests widely used in studies of “safety‐pharmacology” for the preclinical characterization of new molecules. To this purpose, the acute effects of MXE on neurological and sensorimotor functions in mice, including visual, acoustic and tactile responses, thermal and mechanical pain, motor activity and acoustic startle reactivity were evaluated in comparisons with KET and PCP to better appreciate its specificity of action. Cardiorespiratory parameters and blood pressure were also monitored in awake and freely moving animals. Acute systemic administrations of MXE, KET and PCP (0.01–30 mg/kg i.p.) differentially alter neurological and sensorimotor functions in mice depending in a dose‐dependent manner specific for each parameter examined. MXE and KET (1 and 30 mg/kg i.p.) and PCP (1 and 10 mg/kg i.p.) also affect significantly cardiorespiratory parameters, systolic and diastolic blood pressure in mice. HighlightsMethoxetamine (MXE) is a ketamine (KET) ‐ like novel psychoactive substance (NPS).Number of MXE‐induced acute toxicity are increasing at an alarming rate.MXE induces significant neurological, sensorimotor, cardiorespiratory alterations.MXE effects were qualitatively but not quantitatively similar to KET and phencyclidine.

Novel Synthetic Opioids: The Pathologist’s Point of View

Background: New Psychoactive Substances (NPS) constitute a broad range of hundreds of natural and synthetic drugs, including synthetic opioids, synthetic cannabinoids, synthetic cathinones, and other NPS classes, which were not controlled from 1961 to 1971 by the United Nations drug control conventions. Among these, synthetic opioids represent a major threat to public health. Methods: A literature search was carried out using public databases (such as PubMed, Google Scholar, and Scopus) to survey fentanyl-, fentanyl analogs-, and other synthetic opioid-related deaths. Keywords including “fentanyl”, “fentanyl analogs”, “death”, “overdose”, “intoxication”, “synthetic opioids”, “Novel Psychoactive Substances”, “MT-45”, “AH-7921”, and “U-47700” were used for the inquiry. Results: From our literature examination, we inferred the frequent implication of fentanyls and synthetic opioids in side effects, which primarily affected the central nervous system and the cardiovascular and pulmonary systems. The data showed a great variety of substances and lethal concentrations. Multidrug-related deaths appeared very common, in most reported cases. Conclusions: The investigation of the contribution of novel synthetic opioid intoxication to death should be based on a multidisciplinary approach aimed at framing each case and directing the investigation towards targeted toxicological analyses.

Mirtazapine fatal poisoning

Mirtazapine is a noradrenergic and specific serotoninergic antidepressant agent that stimulates norepinephrine and serotonin release while also blocking serotonin receptors (5-HT2 and 5-HT3). Although the drug is used extensively, at present we do not know of any fatal cases due to mirtazapine alone. On the contrary, the published literature describes several fatal poisoning cases related to the intake of mirtazapine together with other drugs. Here we describe a fatal case of mirtazapine self-poisoning, since the other drug detected (lorazepam), was within the therapeutic range. Analyses were performed by LC-MS/MS on body fluids and a hair sample and mirtazapine concentration measured in blood was very high: 9.3mg/L. N-Desmethylmirtazapine was also quantitated. We then compared our results with those of previously published cases. In conclusion, even though mirtazapine can be considered a relatively safe drug, taking a large amount alone or in combination with other drugs, could lead to death.

Clinical and analytical aspects of quetiapine ingestion: a case report

37th International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) 16–19 May 2017, Basel, Switzerland 1. Deltamethrin poisoning in two children following treatment of head lice with a veterinary product Galina N. Bashinskaya, Yury N. Ostapenko, Gulbanu S. Sadykova, Saltanat T. Tulegenova and Kuandyk A. Amrekulov Municipal Hospital No 1, Astana, Kazakhstan; Research and Applied Toxicology Center of Federal Medical and Biological Agency, Moscow, Russian Federation; Municipal Pediatric Hospital, Taraz, Kazakhstan Objective: Using chemicals, including veterinary drugs not intended for human therapy, can be a serious health risk. We present two cases of severe acute deltamethrin poisoning in children following intentional treatment with a veterinary product. Case report: The mother of two girls aged 6 (patient 1) and 12 years (patient 2) washed their hair with a veterinary ectoparasitic product for cattle and sheep containing 5% deltamethrin (Butox®) for pediculosis capitis (head lice). The product was left on for 15minutes and on washing off it got into the eyes and mouths of the children. Within a few minutes both developed vomiting and dizziness, and on admission to hospital they had mental confusion, anxiety, excitation, pallor, acrocyanosis, cold extremities and dilated pupils. Patient 1 also had uncontrolled vomiting. Both had arterial hypertension (arterial BP 140/90 mmHg) and tachycardia (140 bpm patient 1; 120 bpm patient 2). Within a few hours superficial coma, divergent squint, upper deviation of eyeballs, reduced muscle tension, muscle spasm in distal sections of extremities and absence of tendon reflexes were noted. Clinical and biochemical blood and urine analyses were normal, except for moderate changes of acid–base balance indices: рН 7.140, рСО2 60.5mmHg, рО2 29.3 mmHg, bicarbonate 20.6mmol/L, base excess −8.5mmol/L, oxygen saturation 38.1%, which later resolved to рН 7.396, рСО2 39.1 mmHg, рО2 104.7 mmHg, bicarbonate 24.0 mmol/L, base excess 0.9mmol/L, oxygen saturation 98.0%. Radiographs showed bilateral focal-confluent shadows along all pulmonary fields. They were intubated with artificial ventilation for 10–12 hours. Local therapists consulted both the Astana Toxicological Center in Kazakhstan and Moscow Poison Information Center specialists for advice on management. Therapy was symptomatic, which also included gastric lavage, administration of activated charcoal and forced diuresis. Consciousness improved and neurologic symptoms resolved on the second hospital day in patient 2. In patient 1 neurologic symptoms resolved after 4 days. Both children recovered without complications and were discharged from hospital on the 8th day. Conclusion: This case demonstrates the risks of using veterinary drugs not intended for human use, and the favorable prognosis in deltamethrin poisoning. It is also a good example of international collaboration of toxicological centers. 2. Polyneuropathy following fenitrothion poisoning

Intensive Care Unit admission in poisoned patients: a 14-year study

36th International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) 24–27 May, 2016, Madrid, Spain 1. Intramuscular and intravenous e-liquid injection: a new phenomenon? Eleri Thomas, J. Allister Vale, Michael Eddleston, Simon HL Thomas and John P Thompson NPIS Cardiff, University Hospital Llandough, Cardiff, UK; NPIS Birmingham, City Hospital, Birmingham, UK; NPIS Edinburgh, Scottish Poisons Information Bureau, Edinburgh, UK; NPIS Newcastle, Regional Drug and Therapeutics Centre, Newcastle upon Tyne, UK Objective: Electronic cigarette design and shape have altered noticeably since their introduction to the UK market. Current e-cigarettes exist as disposable and re-chargeable devices. Cartridges of liquid nicotine solution can be placed inside these devices, or alternatively, a nicotine containing solution (known as e-liquid) can be used to replenish e-cigarette reservoirs. The solution typically contains nicotine, propylene glycol or vegetable glycerine, flavouring and water.[1] Solutions may also contain unspecified ingredients such as methyl salicylate (oil of wintergreen) [2] and nitrosamine.[1] Previous National Poisons Information Service (NPIS) data suggest that these highly concentrated, toxic liquids can be misused by means of ingestion. Recently, the NPIS has received enquiries concerning the parenteral administration of e-cigarette refill liquid. We sought to determine if the pattern of enquiries made to the UK NPIS concerning exposure to e-liquids containing nicotine is changing. Methods: Telephone enquiries to the NPIS between 1 April 2014 and 31 October 2015 relating to exposures concerning injections of liquid nicotine solution were examined to determine incidence and clinical features. Results: Of 379 enquiries identified relating to e-cigarettes and e-cigarette refill liquid, five were in relation to liquid nicotine solution administrated by injection. Cases involved individuals aged 39 to 59 years. All exposures were acute. Four patients were male, 2 patients injected e-liquid intramuscularly, 1 intravenously and 2 subcutaneously. E-liquid was injected both intentionally (n1⁄4 2) and as a result of recreational abuse (n1⁄4 2). One patient, who was accidentally exposed to the solution, remained asymptomatic. Three patients developed mild features including a localised skin reaction, somnolence, fever and palpitations. This corresponded to a maximum poisons severity score (PSS) [3] of one. Chest pain and QT prolongation occurred in one case resulting in a maximum PSS score of two. Conclusion: Parenteral use of e-liquid, including recreational use, is occasionally encountered. Although local problems such as extravasation injury, skin necrosis and compartment syndrome may be expected after injection of this agent, as nicotine is extremely irritating to tissues, serious outcomes were not encountered in this small case series. References [1] Wollscheid KA, Kremzner ME. Electronic cigarettes: safety concerns and regulatory issues. Am J Health Syst Pharm.36th International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) 24-27 May, 2016, Madrid, Spain36th International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) 24–27 May, 2016, Madrid, Spain 1. Intramuscular and intravenous e-liquid injection: a new phenomenon? Eleri Thomas, J. Allister Vale, Michael Eddleston, Simon HL Thomas and John P Thompson NPIS Cardiff, University Hospital Llandough, Cardiff, UK; NPIS Birmingham, City Hospital, Birmingham, UK; NPIS Edinburgh, Scottish Poisons Information Bureau, Edinburgh, UK; NPIS Newcastle, Regional Drug and Therapeutics Centre, Newcastle upon Tyne, UK Objective: Electronic cigarette design and shape have altered noticeably since their introduction to the UK market. Current e-cigarettes exist as disposable and re-chargeable devices. Cartridges of liquid nicotine solution can be placed inside these devices, or alternatively, a nicotine containing solution (known as e-liquid) can be used to replenish e-cigarette reservoirs. The solution typically contains nicotine, propylene glycol or vegetable glycerine, flavouring and water.[1] Solutions may also contain unspecified ingredients such as methyl salicylate (oil of wintergreen) [2] and nitrosamine.[1] Previous National Poisons Information Service (NPIS) data suggest that these highly concentrated, toxic liquids can be misused by means of ingestion. Recently, the NPIS has received enquiries concerning the parenteral administration of e-cigarette refill liquid. We sought to determine if the pattern of enquiries made to the UK NPIS concerning exposure to e-liquids containing nicotine is changing. Methods: Telephone enquiries to the NPIS between 1 April 2014 and 31 October 2015 relating to exposures concerning injections of liquid nicotine solution were examined to determine incidence and clinical features. Results: Of 379 enquiries identified relating to e-cigarettes and e-cigarette refill liquid, five were in relation to liquid nicotine solution administrated by injection. Cases involved individuals aged 39 to 59 years. All exposures were acute. Four patients were male, 2 patients injected e-liquid intramuscularly, 1 intravenously and 2 subcutaneously. E-liquid was injected both intentionally (n1⁄4 2) and as a result of recreational abuse (n1⁄4 2). One patient, who was accidentally exposed to the solution, remained asymptomatic. Three patients developed mild features including a localised skin reaction, somnolence, fever and palpitations. This corresponded to a maximum poisons severity score (PSS) [3] of one. Chest pain and QT prolongation occurred in one case resulting in a maximum PSS score of two. Conclusion: Parenteral use of e-liquid, including recreational use, is occasionally encountered. Although local problems such as extravasation injury, skin necrosis and compartment syndrome may be expected after injection of this agent, as nicotine is extremely irritating to tissues, serious outcomes were not encountered in this small case series. References [1] Wollscheid KA, Kremzner ME. Electronic cigarettes: safety concerns and regulatory issues. Am J Health Syst Pharm.36th International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) 24-27 May, 2016, Madrid, Spain