A comprehensive analysis of attempted and fatal suicide cases involving frequently used psychotropic medications.

OBJECTIVES: Self-poisoning is the most common suicide method in non-lethal suicide attempts and the third most frequent in fatal suicides. Psychoactive drugs are often used for intentional self-poisoning. While poisons centre data typically focus on survived suicide attempts and underrepresent fatal self-poisoning, medical examiner reports give insight into suicide deaths. To close this gap, we combined and compared data sets from both sources, assessing the mortality of psychotropic drugs used for self-poisoning. METHODS: Anonymized cases of self-poisoning with suicidal intention from 2000 to 2010 were extracted from the national poisons centre case database and compared with cases of suicide documented in the project "Suicides, a national survey". All cases with single substance exposure to a psychoactive drug (antidepressants, mood stabilizers, antipsychotics, sedatives) were included in the analyses. Opioids, over-the-counter- and illicit- drugs were excluded from the analysis. A mortality index was calculated by the ratio of the number of suicides and the sum of all (lethal and non-lethal) suicide attempts. RESULTS: Tricyclics had a higher mortality rate than other antidepressants. Among the sedatives, zolpidem was found to have a higher mortality index compared to benzodiazepines. Clozapine and levomepromazine were found to be the most lethal antipsychotics. Non-lethal suicide cases with single substance exposure (n = 4697) diminished as age increased, while the rate of suicide cases (n = 165) was higher in elderly subjects (>65 years of age, p < 0.001). CONCLUSION: In summary, our findings confirm previous study results on the relative toxicity of distinct classes of psychotropic drugs. In this comprehensive analysis of a national cohort lorazepam had a lower mortality rate compared to other sedatives.

Seizures after single-agent overdose with pharmaceutical drugs: analysis of cases reported to a poison center.

CONTEXT: Seizures during intoxications with pharmaceuticals are a well-known complication. However, only a few studies report on drugs commonly involved and calculate the seizure potential of these drugs. OBJECTIVES: To identify the pharmaceutical drugs most commonly associated with seizures after single-agent overdose, the seizure potential of these pharmaceuticals, the age-distribution of the cases with seizures and the ingested doses. METHODS: A retrospective review of acute single-agent exposures to pharmaceuticals reported to the Swiss Toxicological Information Centre (STIC) between January 1997 and December 2010 was conducted. Exposures which resulted in at least one seizure were identified. The seizure potential of a pharmaceutical was calculated by dividing the number of cases with seizures by the number of all cases recorded with that pharmaceutical. Data were analyzed using descriptive statistics. RESULTS: We identified 15,441 single-agent exposures. Seizures occurred in 313 cases. The most prevalent pharmaceuticals were mefenamic acid (51 of the 313 cases), citalopram (34), trimipramine (27), venlafaxine (23), tramadol (15), diphenhydramine (14), amitriptyline (12), carbamazepine (11), maprotiline (10), and quetiapine (10). Antidepressants were involved in 136 cases. Drugs with a high seizure potential were bupropion (31.6%, seizures in 6 of 19 cases, 95% CI: 15.4-50.0%), maprotiline (17.5%, 10/57, 95% CI: 9.8-29.4%), venlafaxine (13.7%, 23/168, 95% CI: 9.3-19.7%), citalopram (13.1%, 34/259, 95% CI: 9.5-17.8%), and mefenamic acid (10.9%, 51/470, 95% CI: 8.4-14.0%). In adolescents (15-19y/o) 23.9% (95% CI: 17.6-31.7%) of the cases involving mefenamic acid resulted in seizures, but only 5.7% (95% CI: 3.3-9.7%) in adults (≥ 20y/o; p < 0.001). For citalopram these numbers were 22.0% (95% CI: 12.8-35.2%) and 10.9% (95% CI: 7.1-16.4%), respectively (p = 0.058). The probability of seizures with mefenamic acid, citalopram, trimipramine, and venlafaxine increased as the ingested dose increased. CONCLUSIONS: Antidepressants were frequently associated with seizures in overdose, but other pharmaceuticals, as mefenamic acid, were also associated with seizures in a considerable number of cases. Bupropion was the pharmaceutical with the highest seizure potential even if overdose with bupropion was uncommon in our sample. Adolescents might be more susceptible to seizures after mefenamic acid overdose than adults. "Part of this work is already published as a conference abstract for the XXXIV International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) 27-30 May 2014, Brussels, Belgium." Abstract 8, Clin Toxicol 2014;52(4):298.

Acute calcineurin inhibitor overdose: analysis of cases reported to a national poison center between 1995 and 2011.

Transplant recipients and other patients requiring immunosuppression with calcineurin inhibitors or their household contacts may be exposed to overdose. This study investigated the circumstances, pharmacokinetics and outcomes of overdose with cyclosporine and tacrolimus reported to the Swiss Toxicological Information Centre between 1995 and 2011. Of 145,396 reports by healthcare professionals, 28 (0.02%) concerned enteral or parenteral overdose with these calcineurin inhibitors. Thirteen (46%) were iatrogenic errors, 12 (43%) were with suicidal intent and 3 (11%) were accidental. Iatrogenic overdoses usually involved noncapsule drug formulations. Acute enteral overdoses caused symptoms in a dose-dependent fashion but were generally well tolerated; the mean multiple of patient's usual dose was 20.8 ± 28.8 for symptomatic versus 4.4 ± 3.4 for asymptomatic cases (p = 0.037). The most common symptoms were nausea, headache, somnolence, confusion, hypertension and renal impairment. In contrast, acute intravenous overdoses were often poorly tolerated and resulted in one fatality due to cerebral edema after a cyclosporine overdose. Enteral decontamination measures were performed in six cases involving oral ingestion and appeared to reduce drug absorption, as shown by pharmacokinetic calculations. In the one case where it was used, pharmacoenhancement appeared to accelerate tacrolimus clearance after intravenous overdose.

Countering health threats by chemicals with a potential terrorist background--creating a rapid alert system for Europe.

BACKGROUND: The acronym "ASHT" stands for "Alerting System and Development of a Health Surveillance System for the Deliberate Release of Chemicals by Terrorists". Imagine this scenario: 15 patients with respiratory symptoms following a concert in Rome and 12 patients coughing after lunch in a cafeteria in the Czech Republic; are these events related? Today these events would never be connected as there is no mechanism to allow EU Member States to share this type of information effectively. The main objective of the ASHT project was to improve data sharing between EU Member States. In part, this was achieved by an internet accessible EU-wide alerting system with the aim to detect the deliberate (i.e. criminal or terrorist) or accidental release of chemicals. Nevertheless more information from police, fire brigades and health professionals is needed. METHODS: Description of the design, development, functionality and testing of the relational database system called "RAS-CHEM" (Rapid Alert System for Chemicals). RESULTS: A database structure appropriate for the description of "events" with sophisticated retrieval functions was developed. For evaluation purposes 37 events were entered into the database including 29 scenarios and 8 historical mass intoxications. The alert level was "background information" for 21 events, "suspected mass intoxication" for 6 cases and "confirmed mass intoxication" for 10 events. CONCLUSION: The RAS-CHEM database works and will be integrated into the Health Emergency Operations Facility (HEOF) with other European Rapid Alert Systems. Poisons centres receive a large number of enquiries and could be important sentinels in this field of toxicovigilance.

[A retrospective study of animal poisoning reports to the Swiss Toxicological Information Centre (1997 - 2006)]. / Von Hanf bis Schokolade: Tiervergiftungen im Wandel der Zeit Eine retrospektive Aufarbeitung der Kasuistik des Schweizerischen Toxikologischen Informationszentrums (1997 - 2006).

The purpose of this retrospective study was to analyse the etiology, frequency and outcome of toxicological cases recorded by the consultation service of the Swiss Toxicological Information Centre (STIC) hotline over a 10-year period, from 1997 to 2006. A detailed analysis of this database indicates that common human drugs not intended for use in animals, as well as pesticides and toxic plants represent the most prominent hazards involved in the reported cases of animal poisonings. The comparison with a previous survey from the years 1976 - 1985 revealed new toxic risks due to the accidental uptake of cannabis products, castor seeds or chocolate by dogs. In addition, there is a striking increase of serious poisonings with pyrethroids in cats. The follow-up reports delivered by veterinarians also reflect novel pharmacological and technological trends in the management of poisonings.

[Carbofuran poisoning in mallard ducks]. / Carbofuran-Vergiftung bei wildlebenden Stockenten.

Carbofurane, a pesticide from the group of carbamates, has been employed against soil nematodes on a small meadow at the lake of Lugano, Switzerland. On the next morning, the first cases of death involving a total of 19 mallard ducks (Anas platyrhynchos) have been reported. By inhibiting the enzymatic breakdown of the neurotransmitter acetycholine, carbamates lead to excessive activation of the parasympathicus. In addition, paralysis of skeletal muscles is caused by continued stimulation of neuromuscular junctions. Death may occur by asphyxia. In the present case report, the diagnosis of poisoning could be confirmed by the chemical detection of carbofuran in the stomach, blood, muscle and kidney tissue of the affected mallard ducks.

[Acute drug poisoning]. / Akute Intoxikationen mit Drogen.

The range of illicit substances of abuse is broad. Compounds of major importance are cannabinoids, opiates, cocaine, amphetamines, ecstasy, hallucinogens, phencyclidine, gammahydroxybutyrate, volatile nitrites, solvents, and nitrous oxide. The corresponding toxidromes vary considerably according to their mechanisms of action. Substances with a low general acute toxicity such as ecstasy may cause rare cases of severe or fatal complications. The therapy is rarely specific but symptomatic in most instances. Monitoring is important, and there is a need for a high index of suspicion for severe complications.

[Fatal brain edema after ingestion of ecstasy and benzylpiperazine]. / Tödliches Hirnödem nach Einnahme von Ecstasy und Benzylpiperazin.

HISTORY AND ADMISSION FINDINGS: A 23-year-old woman was hospitalized with headache, malaise and somnolence 11 hours after ingestion of A2 (benzylpiperazine), 7 hours after ingestion of ecstasy (MDMA), and large volume of fluids. On admission she had bradycardia (heart rate 48/min), hypertension (blood pressure 154/95 mm Hg), and reduced consciousness with diminished tendon reflexes and non-reacting pupils (Glasgow Coma Score 6). INVESTIGATIONS: Serum sodium was markedly decreased (115 mmol/l [normal 135-145]) with low plasma osmolality (246 mosm/kg [normal 280-300]). Other laboratory findings were within normal limits. TREATMENT AND COURSE: The patient had severe hypervolaemic hypotonic hyponatraemia. 40 minutes after admission she seized twice and was intubated. Brain CT scan showed massive cerebral oedema with beginning tonsillar herniation. Serum sodium concentration returned to normal within 38 hours, but the patient deteriorated neurologically with increasing tonsillar herniation detected in a second brain CT scan. The patient died 57 hours after admission. CONCLUSION: 13 cases of MDMA-associated severe hyponatraemia are reported. Intake of fluids after MDMA ingestion may lead to potentially fatal hypervolaemic hypotonic hyponatraemia with cerebral oedema. Symptoms appear about 8 hours (range 4-18) after MDMA ingestion. Even low doses of MDMA and fluids may lead to a serious outcome. The only risk factor is female gender. Measurement of serum sodium and brain CT scan is recommended in all patients with altered mental status after MDMA consumption.

[Sudden coma in a 20-year-old man]. / Plötzliches Koma bei einem 20-jährigen Mann.

A 20-year-old male patient was brought to the emergency department by Emergency Medical Services after having been found unconscious. Upon arrival the patient was comatose with a GCS of 3, his vital signs were stable (with blood pressure 100/54 mmHg, heart rate 48 per minute, respiration rate 12 per minute and oxygen saturation 98% on room air). Both pupils were 3 mm, symmetric, and only minimally responsive. Approximately 2 hours after arrival the patient awoke and admitted having taken three ampoules of GHB (gamma hydroxybutyrate). GHB is a synthetic analog of gamma-amino butyric acid (GABA), a centrally inhibitory neurotransmitter. While GHB produces euphoria in low doses, small overdosing can result in severe poisoning with coma. The combination with other CNS depressants such as alcohol, opioids, and other narcotics is particularly dangerous. Physicians should be alerted to the clinical effects of GHB since abuse has become more widespread in Switzerland within the last months. In patients with unexplained coma the differential diagnosis of GHB-intoxication should be taken into consideration.

Dose-dependent toxicity of diphenhydramine overdose.

BACKGROUND: Diphenhydramine (DPHM) overdose is a frequent cause of acute poisoning. Although its clinical features are well known, information about the dose-dependent toxicity of DPHM is still scarce. The objective of this study was to investigate the dose-dependent toxicity of DPHM in patients with acute DPHM poisoning. METHODS: We have analyzed retrospectively all well-documented cases with DPHM monointoxications reported by physicians to the Swiss Toxicological Information Centre (STIC) between January 1984 and April 1996. In addition, a prospective study focusing on ingested DPHM doses and severity of symptoms was performed between May 1996 and December 1998. RESULTS: The retrospective and prospective studies included 232 and 50 patients with DPHM monointoxications, respectively. In both studies, mild symptoms (somnolence, anticholinergic signs, tachycardia, nausea/vomiting) occurred in 55-64%, moderate symptoms (isolated and spontaneously resolving agitation, confusion, hallucinations and ECG disturbances) in 22-27% and severe symptoms (delirium/psychosis, seizures, coma) in 14-18% of patients. Moderate symptoms occurred above ingested doses of 0.3 g DPHM. For severe symptoms the critical dose limit was 1.0 g DPHM. Although the frequency of delirium/psychosis remained constant or even decreased, coma and seizures were significantly (p<0.05) more frequent in the >1.5-g compared with the 1.0- to 1.5-g-dose group. CONCLUSIONS: These data demonstrate a clear dose-dependent acute toxicity of DPHM. They indicate that only patients with DPHM ingestions above 1.0 g are at risk for the development of severe symptoms and, therefore, should be hospitalized. Thus, the results contribute to the data basis required for a cost effective management of patients with DPHM overdose.

Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man.

AIMS: Saquinavir is a potent HIV protease inhibitor whose effectiveness is limited in vivo by its low bioavailability. Since saquinavir is metabolized by CYP3A4, the effect of grapefruit juice, an inhibitor of CYP3A4, was investigated on its bioavailability. METHODS: After an overnight fast, eight healthy volunteers were treated with either 400 ml grapefruit juice or water before intravenous (12 mg) or oral saquinavir (600 mg) was administered. Serial blood samples were obtained over the following 24 h and standardized meals were served 5 and 10 h after the administration of saquinavir. The plasma concentrations of saquinavir were determined by high-performance liquid chromatography and pharmacokinetic parameters were calculated by routine methods. RESULTS: The AUC was not affected by grapefruit juice after intravenous administration, but it increased significantly from 76+/-96 (water, mean (s.d.) to 114+/-70 (microg l[-1] h) (grapefruit juice) after oral saquinavir. Similarly, the oral bioavailability of saquinavir increased by a factor of 2 with grapefruit juice (from 0.7% to 1.4%). In contrast, clearance, volume of distribution and elimination half-life of saquinavir were not affected by grapefruit juice. After oral, but not after intravenous administration, the plasma concentration-time curve showed a second peak after lunch irrespective of pretreatment, suggesting enhancement of absorption by food. CONCLUSIONS: The studies demonstrate that grapefruit juice increases the bioavailability of saquinavir without affecting its clearance, suggesting that inhibition of intestinal CYP3A4 may contribute. Since the antiretroviral effect of saquinavir is dose-dependent, inhibition of CYP3A4 may represent a way to enhance its effectiveness without increasing the dose.

[Bile duct cysts in adults]. / Gallengangzysten beim Erwachsenen.

INTRODUCTION: Bile duct cysts are rare, congenital dilations of the intrahepatic and/or extrahepatic biliary tract. Most of them present during childhood. The classical triad right upper quadrant pain, jaundice and abdominal mass is present only in a few instances. We report here the bile duct cysts which were diagnosed at our institution from 1989 to 1996. METHODS: 3245 consecutive endoscopic retrograde cholangiopancreatograms (ERCP) were evaluated retrospectively. Diagnosis was made when localized cystic dilations of the intrahepatic and/or extrahepatic biliary tract were present. Diffuse dilations of the intrahepatic and extrahepatic biliary tract were excluded. RESULTS: Bile duct cysts were found in 20 patients (17 females, 3 males) among 3245 ERCPs. Their mean age was 56 +/- 20 (median 64, range 10 to 83) years. The cyst types (according to the Alonso-Lej classification with the Todani modification) were type I in 11 (55%), type II, III and IV in two instances each (10%), and type V (or Caroli's disease) in 3 patients (15%). Leading symptoms were cholestasis in 14 patients, 10 of whom had abdominal pain, jaundice in 4 patients, and single cases of pancreatitis, cholangitis, and abdominal mass. In 2 patients the diagnosis was made incidentally. 10 patients had bile duct stones. We performed endoscopic sphincterotomy in 15 patients with concretions or persistent symptoms, 3 patients had cyst resection. One of these, with a type I cyst, already had a disseminated cholangiocarcinoma. 10 of 17 patients without cyst resection are currently symptom-free after complete removal of all gallstones. One male patient with cholecystolithiasis, who is not operable due to advanced liver disease, has recurrent cholangitis, 4 patients have died from causes unrelated to the bile duct cysts, and 2 patients are lost to follow up. CONCLUSION: Bile duct cysts in adults are rare. There is a preponderance in the female gender, and the most common type is the extrahepatic (choledochal) cyst. The leading symptoms are cholestasis and right upper quadrant pain. There is an increased risk of cholangiocarcinoma. In young patients the cysts should be entirely removed to prevent malignancy. Older persons are usually symptomless after complete removal of gallstones.

[Follow-up and therapy of acute colchicine poisoning]. / Verlauf und Therapie der akuten Colchicinintoxikation.

Colchicine poisoning is a rare event. Its outcome is, compared to other drug intoxications, often serious or even fatal. Intaxications with colchicine may occur by ingestion of tablets as well as by consumption of meadow saffron leaves (Colchicum autumnale) that are often mistakenly collected instead of the leaves of ramson herb (Allium ursinum). Colchicine poisoning typically shows three phases: initially gastrointestinal symptoms predominate, in the second phase multiorgan failure may occur possibly leading to death. In case the patient survives, the third phase of recovery follows during which the patients often present with hair loss. The fatal dose of acute colchicine poisoning is estimated at about 0.9 mg/kg. Since hemodialysis and hemoperfusion are not effective measures because of the high volume of distribution, an aggressive primary decontamination with gastric lavage and activated charcoal is required as early as possible. A promising new aspect in the treatment of heavy colchicine overdose is the immunotherapy with colchicine-specific fab-fragments. At present this treatment is still in an experimental stage and has been applied so far to one patient with beneficial effects. Unfortunately colchicine-specific antibodies are not yet commercially available.

[Pericarditis in chronic inflammatory bowel disease: underlying disease or side effects of therapy? Clinical problem solving]. / Perikarditis bei chronisch entzündlicher Darmerkrankung: Grundkrankheit oder Nebenwirkung der Therapie? Ein "clinical problem solving".

Pericarditis and myocarditis are rare extraintestinal manifestations of chronic inflammatory bowel disease (ulcerative colitis and Crohn's disease). Pericarditis as a side effect induced by sulfasalazine or 5-aminosalicylic acid, drugs used in the therapy of these diseases, was first described only 7 years ago. In older case reports the relationship between the use of these drugs and pericarditis is unclear. We analyze the reported cases of 68 patients (38 men, 24 women) with ulcerative colitis (n = 45) or Crohn's disease (n = 15) who had one or more episodes of pericarditis or myopericarditis. Pericarditis was not associated with high activity of bowel disease in all cases. In most cases therapy with corticosteroids led to uneventful recovery. In drug induced pericarditis omission of the 5-ASA therapy was sufficient in a few cases. There was one fatal case (with myocarditis). The decision whether pericarditis is a symptom of the underlying disease or a side effect of the drug used for the treatment of the disease is not always easy. We present an analysis (clinical problem solving) of a pertinent observation in a patient with Crohn's disease and pericarditis, showing the dilemma of pericarditis in chronic inflammatory bowel disease and its therapy.

[The absence of autoantibodies does not rule out autoimmune hepatitis]. / Das Fehlen von Autoantikörpern schliesst eine Autoimmunhepatitis nicht aus.

UNLABELLED: The diagnosis of autoimmune hepatitis is mainly based on the finding of characteristic autoantibodies. Untreated patients have a poor prognosis because of rapid development of cirrhosis. Immunosuppressive treatment most often leads to remission. We report on 2 female patients aged 44 and 53 with autoimmune hepatitis. Initially no significant titers of autoantibodies against nuclear, cytosolic or microsomal components of the hepatocyte could be demonstrated. Seropositivity for autoantibodies was demonstrated 6 and 8 weeks later in the course. Immunosuppressive therapy with steroids resulted in rapid decrease of transaminases with persistent remission of autoimmune hepatitis. CONCLUSION: seropositivity for characteristic autoantibodies is not an absolute criterion for the diagnosis of autoimmune hepatitis. Patients with hepatitis of unknown origin should therefore be given a steroid treatment trial.

[Clinico-pharmacological case (2). Bradycardia and ventricular tachycardia of the torsades de pointes type as a side effect of vasopressin: 3 case reports]. / Der klinisch-pharmakologische Fall (2).Bradykardie und ventrikuläre Tachykardia vom Typ Torsade de pointes als Nebenwirkung von Vasopressin: drei Fallberichte.

We present three patients with ornipressin-induced bradycardia, one of which developed also ventricular tachycardia of the torsade de pointes type. All three patients were treated with this vasopressin derivative because of bleeding esophageal varices due to portal hypertension in liver cirrhosis. Bradycardia ceased after discontinuing ornipressin therapy. One patient was treated successfully with atropine, one with isoprenalin and magnesium (he had to be defibrillated); the third patient recovered after cessation of ornipressin administration. Bradycardia is a known but rarely reported side effect of vasopressin and its derivatives. Animal studies suggest that this effect is due to its cardiodepressive action and also to a vagus-mediated reflex following vasopressin-induced increase in blood pressure. When injected directly into the ventricles of the brain, vesopressin leads to a decrease of the heart rate without affecting blood pressure; however, it remains unclear whether this mechanism is responsible for bradycardia after intravenous administration. Careful monitoring is essential during the treatment with vasopressin and its derivatives.

[Virus titre and histological inflammation activity in chronic hepatitis C]. / Virustiter und histologische Entzündungsaktivität bei chronischer Hepatitis C.

We determine the correlation between viremia in serum specimens, transaminase activity (ALT and AST) and histological grading in 37 patients with chronic hepatitis C. In addition we compared two PCR methods for hepatitis C virus (HCV)-RNA in serum specimens. For the histological grading we used a modified Knodell score. For detection and quantification we measured the viremia (HCV-RNA titer) with a standardized "nested primer" PCR (end-point dilution method) and the commercially available Amplicor HCV Monitor. The mean HCV-RNA and AST level was significantly higher in patients with a histologically active inflammation. In the individual patient we could not conclude from the titer of HCV-RNA on the histologic grading because of the wide range of the results. We did not find a significant difference in ALT in patients having varying histological gradings. HCV-RNA titer and transaminases (ALT and AST) did not correlate significantly. The HCV-RNA titer was significantly marked in older patients (above 40 years) and patients having sporadic hepatitis than in younger patients and patients with chronic hepatitis after drug abuse. The "nested primer" PCR (end-point dilution method) was more sensitive for detection of HCV-RNA in serum specimens than Amplicor HCV Monitor. The lack of HCV-RNA with Amplicor HCV Monitor in 12 of 37 patients (32%) did not rule out viremia. We conclude that in patients with a chronic hepatitis C marked viremia points to a histologically active inflammation. In the individual patient we could not conclude from the titer of HCV-RNA on the histological grading. Because of the lower sensitivity of Amplicor HCV Monitor it is necessary to confirm negative results with a "nested primer" PCR.