Davide Lonati

Metformin accumulation: Lactic acidosis and high plasmatic metformin levels in a retrospective case series of 66 patients on chronic therapy

Abstract Objective. The relationship between metformin accumulation and lactate increase is still debated. This observational case series aims to evaluate the correlation of metformin plasma levels with the pH, lactate and creatinine levels, and with the mortality rate in selected patients with metformin accumulation confirmed through metformin plasma concentration detection at hospital admission. Material and methods. All cases of lactic acidosis (pH, ≤ 7.35; arterial lactate, ≥ 5 mmol/L) related to metformin accumulation (plasma level ≥ 4 mcg/mL) from 2007 to 2011 were retrospectively reviewed. Erroneous ingestion and voluntary overdoses were excluded. Epidemiological, medical history, clinical and laboratory data were evaluated in all cases. Results. Sixty-six patients were included. Thirty-one patients (47%) had contraindication to therapy with metformin. All patients showed severe lactic acidosis (pH, 6.91 ± 0.18; lactate, 14.36 ± 4.90 mmol/L) and acute renal failure (creatinine, 7.24 ± 3.29 mg/dL). The mean metformin plasma concentration was 40.68 ± 27.70 mcg/mL. Metformin plasma concentrations showed a correlation, statistically significant even if not strong, with creatinine (p = 0.002, R = 0.37), pH (p < 0.0001, R = − 0.43) and plasma lactate levels (p = 0.001, R = 0.41). Sixty-two (94%) underwent dialysis. Early mortality (before discharge from ICU) was 26% (17 cases). Lactate and metformin concentrations had mean levels not statistically different in surviving and deceased patients. Conclusions. Patients on chronic therapy with metformin may develop a mitochondrial-related toxicity that should be considered when patients present with lactic acidosis, renal failure, and frequently, a medical history of gastrointestinal manifestations during the days preceding the hospital admission. The correlation between metformin plasma concentrations and creatinine, pH, and lactate levels seems to be related to the mechanism of action (inhibition of complex I of the mitochondrial respiratory chain) and to the kinetic properties (high distribution volume and low protein binding) of the drug. The relevant early mortality seems not correlated with the levels of metformin or lactates: this could be due to the possible role of concurrent illness even if, such as for the relationships with lactate and creatinine, a more proper toxicological evaluation could be obtained by assessing metformin erythrocyte concentrations instead of the plasmatic ones.

Comparative cellular toxicity of titanium dioxide nanoparticles on human astrocyte and neuronal cells after acute and prolonged exposure.

Although in the last few decades, titanium dioxide nanoparticles (TiO₂NPs) have attracted extensive interest due to their use in wide range of applications, their influences on human health are still quite uncertain and less known. Evidence exists indicating TiO₂NPs ability to enter the brain, thus representing a realistic risk factor for both chronic and accidental exposure with the consequent needs for more detailed investigation on CNS. A rapid and effective in vitro test strategy has been applied to determine the effects of TiO₂NPs anatase isoform, on human glial (D384) and neuronal (SH-SY5Y) cell lines. Toxicity was assessed at different levels: mitochondrial function (by MTT), membrane integrity and cell morphology (by calcein AM/PI staining) after acute exposure (4-24-48 h) at doses from 1.5 to 250 μg/ml as well as growth and cell proliferation (by clonogenic test) after prolonged exposure (7-10 days) at sub-toxic concentrations (from 0.05 to 31 μg/ml). The cytotoxic effects of TiO₂NPs were compared with those caused by TiO₂ bulk counterpart treatment. Acute TiO₂NP exposure produced (i) dose- and time-dependent alterations of the mitochondrial function on D384 and SH-SY5Y cells starting at 31 and 15 μg/ml doses, respectively, after 24h exposure. SH-SY5Y were slightly more sensitive than D384 cells; and (ii) cell membrane damage occurring at 125 μg/ml after 24h exposure in both cerebral cells. Comparatively, the effects of TiO₂ bulk were less pronounced than those induced by nanoparticles in both cerebral cell lines. Prolonged exposure indicated that the proliferative capacity (colony size) was compromised at the extremely low TiO₂NP doses namely 1.5 μg/ml and 0.1 μg/ml for D384 and SH-SY5Y, respectively; cell sensitivity was still higher for SH-SY5Y compared to D384. Colony number decrease (15%) was also evidenced at ≥0.2 μg/ml TiO₂NP dose. Whereas, TiO₂ bulk treatment affected cell morphology only. TiO₂ internalization in SH-SY5Y and D384 cells was appreciated using light microscopy. These findings indicated, that (i) human cerebral SH-SY5Y and D384 cell lines exposed to TiO₂NPs were affected not only after acute but even after prolonged exposure at particularly low doses (≥ 0.1 μg/ml), (ii) these in vitro critical doses were comparable to literature brain Ti levels detected in lab animal intranasally administered with TiO₂NP and associated to neurotoxic effects. In summary, the applied cell-based screening platform seems to provide effective means to initial evaluation of TiO₂NP toxicity on CNS.

Acute neurotoxicity after yohimbine ingestion by a body builder

Yohimbine is an alkaloid obtained from the Corynanthe yohimbe tree and other biological sources. Yohimbine is currently approved in the United States for erectile dysfunction and has undergone resurgence in street use as an aphrodisiac and mild hallucinogen. In recent years yohimbine use has become common in body-building communities for its presumed lipolytic and sympathomimetic effects. We describe a 37-year-old bodybuilder in which severe acute neurotoxic effects occurred in 2 h after yohimbine ingestion. The patient presented with malaise, vomiting, loss of consciousness, and repeated seizures after ingestion of 5 g of yohimbine during a body-building competition in a gymnasium. His Glasgow Coma Score was 3, requiring orotracheal intubation. Two hours after admission, vital signs were blood pressure 259/107 mmHg and heart rate 140 beats/min. Treatment with furosemide, labetalol, clonidine, and urapidil and gastrointestinal decontamination were performed. Twelve hours later the patient was extubated with normal hemodynamic parameters and neurological examination. The yohimbine blood levels at 3, 6, 14, and 22 h after ingestion were 5,240; 2,250; 1,530; and 865 ng/mL, respectively, with a mean half-life of 2 h. Few data are available about yohimbine toxicity and the related blood levels. This is a case of a large ingestion of yohimbine in which severe hemodynamic and neurological manifestations occurred and elevated blood levels of yohimbine were detected.

Chelation in Suspected Prosthetic Hip-Associated Cobalt Toxicity

To the Editor: We read with interest the letter from Dr Devlin et al. concerning cobalt (Co) chelation in prosthetic hip-associated Co toxicity. Currently, chelation in prosthetic hip-associated Co toxicity has been described in only a few cases with chelating agents such as edetate calcium disodium, sodium 2,3-dimercaptopropane sulfonate, and dimercaprol. Currently, the role of different chelating agents, timing of administration, and chelating efficacy represent debated aspects in Co chelation. As reported by Dr Devlin, in the medical literature N-acetyl-cysteine (NAC) has been described as an effective chelator only in animal models of Co poisoning. We observed a case of cardiac toxicity resulting from Co and chromium (Cr) release from a metal on metal (MoM) hip replacement in which NAC had been used to treat high CoCr blood levels. In October 2012, a 75-year-old male patient was referred to our Poison Control Centre for persisting high Co-Cr blood levels from MoM hip prosthesis. In 2006, the patient underwent revision of left hip arthroplasty with insertion of a MoM Co-Cr alloy hip. In July 2011, a ceramic hip revision was performed because of the appearance of local hip pain, asthenia, and abrasion of the left metal head with local metallosis. Echocardiography revealed a dilatated left ventricle, with global hypokinesis (ejection fraction, 32%; normal value > 55%), pericardial effusion and increased pulmonary pressures (43 mm Hg; normal value 15-28). Renal function was normal. Co-Cr serum levels before MoM explantation were 352.6 mg/L (normal value < 0.9) and 67.85 mg/L (normal value < 0.5) respectively. Fourteen months after MOM explantation, high Co-Cr blood levels (46.5 and 77.1 mg/L) persisted and chelation with intravenous high-dose NAC (150 mg/kg/90 min bolus followed by 300 mg/kg/ d for 10 days) was performed. Co-Cr serum concentrations dropped by about 51% and 40% of the prechelation levels,

Serpents exotiques en Europe: Un cas de morsure par Mocassin du Mexique (Agkistrodon bilineatus)

INTRODUCTION In the last years exotic snakebite envenomations are increasingly reported. These cases are difficult to manage because of the limited experience of European physicians in the treatment of bites from such venomous snakes; moreover, specific antivenoms are unevenly stocked and they are difficult to find in case of a medical emergency. OBSERVATION A 39-year-old herpetologist was bitten in his right hand by a mexican moccasin (Agkistrodon bilineatus) at the workplace, and presented in the Emergency Department 19 hours later. At admission, clinical evaluation showed local necrosis, swelling involving the entire limb up to the trunk, and severe pain. The specific antidote, not stocked in Italy, was sought abroad; its finding and routeing up to spot delivery required 12 hours. The antivenom, given 32 hours after the bite with no adverse reactions, was only partially effective. The clinical course was characterized by extensive edema with rhabdomyolysis. The necrotic wound at the bite site required after several days surgical debridement, and eventually skin graft. At 3 months follow-up, motor impairment of his right hand fingers with functional disability was still present. COMMENTS The envenomation by Agkistrodon bilineatus has some clinical aspects in common with that by European viper species, although crotalid venom usually causes more severe manifestations. The antivenom supply from a foreign country may delay its administration. A specific legislation aimed to simplify antidotes importing procedures for professional snake handlers may improve antivenoms availability and allow their timely use, as soon as clinically indicated.Resume Introduction Durant ces dernieres annees, les cas rapportes d’envenimation par serpents exotiques ont augmente. Leur prise en charge est delicate a cause, d’une part, de la faible experience des medecins europeens face a ce type d’intoxication, d’autre part, des difficultes de localisation des antivenins specifiques. Observation Un herpetologiste de 49 ans est admis aux urgences 19 heures apres avoir ete mordu a la main droite par un Mocassin du Mexique (Agkistrodon bilineatus) de son reptilarium. A son arrivee, on observe une necrose locale, un œdeme du membre superieur s’etendant jusqu’au creux axillaire et une douleur d’aggravation progressive. Douze heures sont necessaires a la localisation et a la delivrance en urgence de l’antivenin specifique, obtenu a partir de l’etranger car non disponible en Italie. L’antidote, administre 32 heures apres la morsure, a une efficacite partielle et n’entraine pas d’effets secondaires. L’evolution clinique est caracterisee par un œdeme massif et par une rhabdomyolyse. La necrose locale provoque une perte de substance necessitant une greffe cutanee. A 3 mois persiste un deficit moteur partiel de la main. Commentaires L’envenimation par morsure de Agkistrodon bilineatus presente des analogies avec celle imputable aux viperes europeennes, bien que le venin des crotalides soit habituellement responsable de manifestations plus graves. Le temps necessaire a l’approvisionnement en urgence de l’antivenin a partir d’un pays etranger peut entrainer des retards dans l’administration. La creation d’une legislation ad hoc visant a simplifier, pour les eleveurs specialises et/ou les reptilariums, les procedures d’approvisionnement et de stockage des antivenins specifiques pourraient permettre un traitement en temps utile.

Toxicokinetics and toxicodynamics of elemental mercury following self-administration

Introduction. Intravenous injection of mercury has seldom been reported, especially in cases of attempted suicide, and is associated with variable clinical outcomes. Case report. A young woman came to our attention after self-injecting and ingesting mercury drawn from 37 thermometers. The patient suffered lung embolization complicated by adult respiratory distress syndrome (ARDS), toxic dermatitis, anemia, mild hepato-renal impairment, and died after 30 days. Mercury was monitored in biological fluids (blood, plasma, urine, and bronchoalveolar fluid) to study its toxicokinetics and to evaluate dose–effect relationships. Its urinary clearance significantly increased after a chelation challenge test with meso-2,3-dimercaptosuccinic acid (DMSA) (median values of 2.48 and 8.85 before and after the test, respectively, p < 0.05). Conclusions. Mercury poisoning by intravenous injection is a clinical emergency, potentially leading to death. When injected, the element has a very slow clearance, mainly renal. Our data do not allow any conclusion about the effectiveness of chelation therapy.

Analytically diagnosed intoxication by 2-methoxphenidine and flubromazepam mimicking an ischemic cerebral disease

Flubromazepam and methoxphenidine are nonmedical drugs that have been synthesized some decades ago [1,2]. Flubromazepam is a long-acting designer benzodiazepine [3] and a GABAA receptor agonist. Studies on animals demonstrated that it has a higher potential than diazepam, nitrazepam and bromazepam [1]. Methoxphenidine is a diarylethylamine that acts as an N-methyl-D-aspartate Receptors (NDMARs) antagonist and it may have a dopamine reuptake inhibitor action [4]. They recently reappeared for sale on the Internet as new psychoactive substances (NPS) for recreational purposes. We report a case of an analytically confirmed poisoning by methoxphenidine and flubromazepam in a patient who manifested atypical neurological signs that initially suggested a focal deficit. A man, 25 years old, arrived to the emergency department (ED) 20 h after an episode of syncope with secondary head trauma. He was presented with excitatory behavior, psychomotor agitation, confusion, dysarthria and aphasia, mild hypertension (150/100mmHg), slight tachycardia (85 bpm), body temperature of 36.5 C (97.7 F), and SpO2 of 99% on room air; arterial blood gas results were normal. The patient was unable to maintain the upright position and referred hyposthenia at lower limbs. Hypertension (180/100mmHg) and agitation worsened and the patient presented a weakness on the left side of the body; midazolam (until 15mg i.v. bolus) and propofol were successfully administered. Perfusional and angiographic cerebral CT-scan resulted normal. The immunoassay-based toxicological screening (amfetamines, opiates, cocaine, barbiturates, ethanol, methadone, cannabis and benzodiazepines) in urine tested positive for cannabis and benzodiazepines. The patient was discharged two days later with prescription of paroxetine. Considering clinical manifestations not coherent with laboratory results, blood and urine sampled before sedation therapy and two products bought on the web by the patient were sent to our laboratory. The presence of methoxphenidine and flubromazepam in the products was detected by GC-MS (gas chromatography-mass spectrometry). Methoxphenidine and flubromazepam concentrations in blood were measured by liquid chromatography-tandem mass spectrometry (LC-MS-MS) and were, respectively, 247 ng/ml and 411 ng/ml. Blood and urine screening (LC-MS-MS) for the most common prescription benzodiazepines was negative, suggesting that the urinary positivity derived from the presence of flubromazepam metabolites. Blood sample was also analyzed for tetrahydrocannabinol and its main metabolite (THCCOOH) to evaluate recent consumption of cannabis and the analysis was negative (LC-MS-MS; LOD 1ng/ml). A urine screening for NPS by LC-MS-MS (15 synthetic cathinones, 5 designer benzodiazepines, 2 tryptamines, 17 phenetylamines, 4 arylamines) and GC-MS (NPS reference spectra from electronic libraries) and a blood screening for 28 synthetic cannabinoids (LC-MS-MS) were negative, too. Clinical manifestations observed on ED admission were unusual and unexpected for the age of the patient, particularly for focal signs and such lateralization that are very uncommon in NPS intoxication. We suggest that methoxphenidine intoxication may mimic an ischemic neurological symptomatology. In our case, the presence of flubromazepam may have partly mitigated the agitation and hypertension induced by methoxphenidine. In fact, severe agitation, hypertension and confusion are described in metoxphenidine intoxications [5,6]. Analytical evaluation of NPS, even if not timely available in many cases, might be considered to confirm the involvement of these compounds in the etiology of altered mental status. Intoxications by NPS agents may present with atypical clinical symptoms such as severe focal neurological signs and the habit of users to mix substances that may act in different toxicological ways makes it difficult to determine a correct diagnosis.

Antivenom for European Vipera species envenoming

Abstract Background: European viper bite is relatively uncommon but can cause serious envenoming, particularly swelling and hemorrhage spreading from limb to trunk that can cause long term disability. Systemic features are relatively mild compared to many other venomous species. Moderate-to-severe envenoming requires antivenom, which is given many hundreds of times each year across the continent. Several Vipera spp antivenoms are produced in Europe, but there is little comparative information available for the antivenoms and none is licensed with the European Medicines Agency. We aimed to collect descriptive data on European viper antivenoms and assess their relative effectiveness. Methods: A systematic review of articles relating to antivenom in Europe was performed using the Medline medical database. The following keywords “Europ*” or the individual names of each European country and “antiven*” or “immun*” or “envenom*” and “snake” or “viper*” or “adder” were used. Articles published between 1 January 1996 and 11 March 2016 pertaining to clinical outcome, including case reports, were selected. Referenced articles in the indexed articles were explored for suitability and included if they met any of the criteria: specific antivenom used, route of antivenom administration, adverse reactions to antivenom therapy and length of hospital admission. All accepted abstracts from EAPCCT conferences since 2000 were searched and abstracts relating to Vipera spp envenoming were assessed for suitability. We extracted data on study type, safety and effectiveness. We sought information on antivenoms from manufacturers and individual patient data from authors of publications. Since individual patient data were only rarely available, we compared median length of stay between case series reporting each antivenom. We identified 40 papers and six published abstracts, and one unpublished paper that reported clinical cases and case series of envenomed patients treated with antivenom. No publication reported randomized controlled trials comparing any European Vipera antivenom with either placebo or another antivenom. 25 reports were of retrospective hospital- (n = 13) or poison center-based (n = 12) case series including five or more patients; a further 12 reports were either case reports or case series with less than five patients and one paper was a limited literature review. An additional nine papers reported prospective data; seven collected data remotely through poison service telephone communication with the attending physicians. Antivenoms available in Europe: Eight antivenoms are available for European Vipera spp envenoming; a material safety data sheet providing information on manufacture was available for seven. Six are raised against V. berus or V. ammodytes venom; the seventh is raised against a mixture of V. ammodytes, V. aspis and V. berus venom and the eighth is raised against V. ammodytes, Macrovipera lebetina and Montivipera xanthina venom. Six manufacturers recommended intramuscular administration while two recommended intravenous administration. No randomized control trials comparing the effectiveness of antivenoms were identified. Pre-clinical data: We found two papers presenting comparative preclinical data. Clinical data: Clinical studies were predominantly retrospective and contained clinical data on antivenom used in 2602 patients; where the antivenom was identified (n = 2174), 2061 (94.8%) received Zagreb, ViperFAV or ViperaTAb antivenoms. There were few published data on the other antivenoms. Repeated use of antivenom: Repeat doses were reported in 230/1491 of cases (15.4%) where this information was recorded. Outcome and length of hospital stay: Intravenous administration of antivenom was associated with shorter length of hospital stay (median length of hospital stay in studies of intravenous ViperFAV or ViperaTAb ranged from 1 to 4.8 days versus 2 to 18 days for intramuscular Bulbio or Zagreb antivenoms). Antivenom versus no antivenom: Some small studies demonstrated no difference in the length of hospital stay in patients with equivalent envenomation grading who either did or did not receive antivenom. Adverse events: Adverse reactions were reported in 37 of 2408 cases (1.5%) including seven cases of anaphylaxis. Conclusions: There are very limited pre-clinical comparative data and no randomised controlled trials assessing effectiveness of the antivenoms against different Vipera species. Most descriptive data suggest the efficacy of Zagreb, ViperFAV and ViperaTAb antivenoms by the intravenous route but not intramuscular route, although this is level D evidence. Reported adverse reactions were rare, suggesting that the modern intravenous antivenoms are of good quality. Better and more systematic data, including perhaps randomized controlled trials comparing different antivenoms, are required for the many hundreds of antivenom administrations that occur annually across Europe.

Neurotoxicity of European viperids in Italy: Pavia Poison Control Centre case series 2001-2011

Abstract Context. Some clinical aspects about neurotoxicity after snakebites by European viper species remain to be elucidated. Objective. This observational case series aims to analyze neurological manifestations due to viper envenomation in Italy in order to describe the characteristic of neurotoxicity and to evaluate the clinical response to the antidotic treatment, the outcome, and the influence of individual variability in determining the appearance of neurotoxic effects. Materials and methods. All cases of snakebite referred to Pavia Poison Centre (PPC) presenting peripheral neurotoxic effects from 2001 to 2011 were included. Cases were assessed for time from bite to PPC evaluation, Grade Severity Score (GSS), onset/duration of clinical manifestations, severity/time course of local, non-neurological and neurological effects, and antidotic treatment. Results. Twenty-four were included (age, 3–75 years) and represented on average of 2.2 cases/year (about 5% of total envenomed patients). The mean interval time of PPC evaluation from snakebite was 10.80 ± 19.93 hours. GSS at ED-admission was 0 (1 case), 1 (10 cases), and 2 (13 cases). All patients showed local signs: 41.6%, minor; 58.4%, extensive swelling and necrosis. The main systemic non-neurological effects were as follows: vomiting (86.7%), diarrhea (66.7%), abdominal discomfort (53.3%), and hypotension (20%). Neurotoxic effects were accommodation troubles and diplopia (100%), ptosis (91.7%), ophtalmoplegia (58.3%), dysphagia (20.8%), drowsiness (16.6%), cranial muscle weakness (12.5%), and dyspnea (4.2%). Neurotoxicity was the unique systemic manifestation in 9 cases; in 4 cases, they were associated with only mild local swelling. In 10 patients the onset of neurotoxic effects followed the resolution of systemic non-neurological effects. Antidote was intravenously administered in 19 (79.2%) patients. The mean duration of manifestations in untreated versus treated groups was 53.5 ± 62.91 versus 41.75 ± 21.18 hours (p = 0.68, local effects) and 9.77 ± 3.29 versus 8.25 ± 12.23 hours (p = 0.1, systemic non-neurological effects) and 43.4 ± 14.69 versus 26.58 ± 20.62 hours (p = 0.03, neurotoxic effects). Conclusions. Neurotoxicity may appear late (11 hours after the bite in 58.3% of cases), in contrast with the data reported in medical literature. Neurotoxic effects have been reversible in all cases and may be the unique systemic manifestation of envenomation. Neurotoxic effects are shorter in treated group. The antidotic treatment of patients considered as GSS 2 only for neurotoxic effects (with mild local effects) may not be necessary. Variable factors such as different amount of venom injected, concentration of PLA2 component, and individual susceptibility may explain the less percentage of patients presenting neurotoxic effects.

Recurrent tonic - clonic seizures and coma due to ingestion of Type I pyrethroids in a 19-month-old patient

Abstract Context. Pyrethroids are synthetic pyrethrin analogues that induce sodium-channel depolarization and hyperexcitation. Severe pyrethroid poisoning is manifested by a “Tremor Syndrome” (Type I cyano-agents) or a “Choreoathetosis/Salivation Syndrome” (Type II non cyano-agents). Very few reports of neurotoxic effects caused by Type I pyrethroids ingestion are available, and no human data concerning Type I pyrethroid blood levels in pediatric poisoning are reported in the medical literature. Case details. A 19-month-old female patient presented with irritability and inconsolable crying that rapidly worsened to tonic–clonic seizures and coma (GCS 6). On admission vital signs including BP 110/70 mmHg, HR 110 beats/min, and SpO2 98% on room air were normal. Orotracheal intubation, oxygen administration, and midazolam infusion (4 μg/kg/min) were performed. Intravenous thiopental sodium, up to 18 mg/kg/hour, was administered to control convulsions. An inquiry revealed that 9 h before presentation the patient had ingested an unknown amount of an insecticide containing 7% piperonyl-butoxide and a mixture of the Type I pyrethroids bifenthrin (5%) and esbiothrin (3%). Consequently, gastric lavage was performed, followed by administration of activated charcoal and cathartics. On the subsequent 48 h, the patient returned progressively alert; she was extubated on day 4 and discharged asymptomatically 12 days after hospitalization. After 9, 48, and 72 h of ingestion, the plasma levels were 500, 95, and 40 ng/mL for bifenthrin and 1,640, 640, and 165 ng/mL for piperonyl-butoxide respectively. Discussion. This pediatric case showed severe pyrethroid neurotoxicity associated with measurable plasma levels of bifenthrin and piperonyl-butoxide. In pediatric pyrethroid poisoning, coma and seizures may represent the main life-threatening features. First-aid therapy including airway maintenance and control of muscle fasciculation and seizures is of major importance. Benzodiazepines and high-dose thiopental sodium were effective treatments for convulsion.