Hugo Kupferschmidt

Interaction between grapefruit juice and midazolam in humans

To investigate the effects of grapefruit juice on the pharmacokinetics and dynamics of midazolam.

Transient cortical blindness and bioccipital brain lesions in two patients with acute intermittent porphyria.

The most common neurologic manifestations of acute intermittent porphyria are autonomic visceral neuropathy, peripheral motor neuropathy, and central nervous system dysfunctions, including seizures and neuropsychiatric disturbances [1]. In rare instances, however, patients with acute intermittent porphyria have presented with acute cortical blindness [2-5], for which deleterious vasospasm in both posterior cerebral arteries has been inferred [3, 6]. We describe two patients in whom cortical blindness was the first symptom of acute intermittent porphyria. Magnetic resonance imaging showed extensive lesions involving primarily white matter of both occipital lobes consistent with vasospasm-induced ischemic lesions. However, the pathogenesis of the suspected vasospasm in acute intermittent porphyria is unknown. Because the enzyme nitric oxide synthase is a hemoprotein [7] and nitric oxide is a major vascular dilator [8], we hypothesize that severe heme deficiency during acute attacks may cause unopposed cerebral vasoconstriction due to a decrease in cerebral nitric oxide production. Case Reports Patient 1 A 35-year-old woman was hospitalized because of sudden loss of vision. With the exception of a brother with partial porphobilinogen deaminase deficiency, she had no family history of porphyria, and she had no known exposure to porphyrinogenic drugs. At admission, she appeared to be blind, was unable to see or fixate on any target (although she reacted to large moving targets), and could not see colors. The remainder of the neurologic examination was normal. During the patients first day in the hospital, she had two tonic-clonic seizures and was treated with carbamazepine and phenytoin. Computed tomography and magnetic resonance imaging showed multifocal lesions primarily in both occipital lobes (Figure 1). During the next 14 days, her vision was completely restored, but she developed flaccid tetraplegia. Electroneuromyography showed a pure axonal motor neuropathy. Routine biochemical assessments of serum and cerebrospinal fluid were normal. Urinary excretions of (delta-aminolevulinic acid [788 mol/d; normal, less than 50 mol/d], porphobilinogen (1346 mol/d; normal, less than 8 mol/d), uroporphyrin (369 nmol/d; normal, less than 60 nmol/d) and coproporphyrin III (701 nmol/d; normal, less than 200 nmol/d) were markedly increased. A diagnosis of acute intermittent porphyria was made and was confirmed by decreased porphobilinogen deaminase activity in lysed erythrocytes (51 pmol/h per mg protein; normal range, 60 to 150 pmol/h per mg protein). Plasma lead level was not elevated. She was treated with intravenous glucose (500 g/d) and hematin (4 mg/kg body weight per day; three 6-day courses of daily infusions over a 7-week period), and the biochemical and clinical signs of acute intermittent porphyria improved during the following 2 months. However, 6 months after the initial presentation, magnetic resonance imaging showed residual ischemic lesions in the bioccipital white matter. One year after the initial presentation, the patient had completely recovered. Figure 1. T2-weighted axial magnetic resonance images in Patient 1. Patient 2 A 32-year-old woman with no family history of acute intermittent porphyria and with no known exposure to porphyrinogenic drugs had abdominal hysterectomy because of a myoma. No known porphyrinogenic drugs were used for anesthesia. After this surgery, she had severe persisting abdominal pain and developed arterial hypertension (170/100 mm Hg), tachycardia (110 beats/min) and three generalized tonic-clonic seizures, for which she received phenytoin. She suddenly became blind but was unaware of her blindness (Anton syndrome [9]) and could correctly guess the direction of moving lights (Riddoch phenomenon [10]). Axial T1-weighted magnetic resonance images were compatible with cortical swelling, and T2-weighted images showed several, probably ischemic, lesions in the white matter of both occipital lobes and the right frontal lobe (Figure 2). On the basis of increased urinary excretion of delta-aminolevulinic acid (526 mol/d) and porphobilinogen (698 mol/d), a diagnosis of acute intermittent porphyria was made. Plasma lead level was not measured. After the patient received treatment with intravenous glucose (300 g/d) and heme-arginate (3 mg/kg per day; two 6-day courses of daily infusions over a period of 3 weeks), visual disturbances improved, but peripheral motor neuropathy developed, progressing rapidly to flaccid tetraparesis. Urinary excretion of porphyrin precursors returned to normal after 3 weeks of therapy with intravenous heme-arginate and high-dose glucose. However, 4 weeks later, magnetic resonance imaging showed only minimal improvement. Vision returned to normal within 3 weeks, and the tetraparesis improved within 8 months to the point that the patient was able to resume an independent lifestyle. Figure 2. T2-weighted axial magnetic resonance images in Patient 2. right panel Discussion During the last 10 years, we have seen 18 patients with severe attacks of acute intermittent porphyria. Of these, the 2 patients described here were the only ones who presented with transient cortical blindness, repetitive tonic-clonic seizures, and a severe peripheral motor neuropathy. Furthermore, magnetic resonance imaging in both patients showed cerebral abnormalities consistent with bioccipital ischemic brain lesions. These observations support the concept that multifocal ischemia and cerebral microinfarctions, possibly resulting from porphyria-induced vasospasms, may be important causes of cerebral dysfunction during acute attacks of acute intermittent porphyria [3, 5, 6]. That bilateral spreading cerebral hypoperfusion [11] and occipital magnetic resonance imaging [12] are found in patients with migraine-associated visual disturbances supports the idea that the magnetic resonance imaging abnormalities seen in our two patients may have resulted from vasospasm-induced ischemia. However, the pathogenesis of the suspected cerebral vasoconstriction in acute intermittent porphyria is unknown. Interestingly, the recently characterized enzyme nitric oxide synthase is a cytochrome P-450 type hemoprotein [7] whose activity may be reduced in situations of decreased heme production such as acute intermittent porphyria. Because nitric oxide is an established and important vasodilator in the central nervous system [8], decreased cerebral nitric oxide production in patients with acute intermittent porphyria may be associated with unopposed cerebral vasoconstriction, potentially leading to lesions in brain areas that are particularly vulnerable to hypoxia. Dr. Bont: Neurologische Universitatsklinik, Kantonsspital, Petersgraben 4, CH-4031, Basel, Switzerland. Drs. Schnorf and Landis: Hopital Cantoral de Gueve, Service de Neurologie, Rue Hicheli du Crest 24, 1211, Geneve, 14, Switzerland. Dr. Walter: Medizinische Universitatskinik, Abt. Innere Medizin II, Hugstetter Stra e 55, D-79106, Freiburg, Germany. Dr. Peter: Spital Limmattal, 8952 Schlieren, Medizinische Abteilung, Switzerland.

Reversible QT Prolongation With Torsades De Pointes in a Patient With Pimozide Intoxication

Pimozide is a diphenylpiperidine neuroleptic with well characterized cardiovascular side effects including QT prolongation. So far, life-threatening cardiac arrhythmias, in particular torsades de pointes, have not been described in patients treated with pimozide. The authors describe a patient in whom torsades de pointes developed after the ingestion of 800 mg pimozide as a suicide attempt. After intravenous treatment with lidocaine and magnesium, the patient recovered completely and the QT interval had normalized 5 days after the intoxication. Potential mechanisms leading to torsades de pointes in patients treated with pimozide are discussed.

The clinical picture of olanzapine poisoning with special reference to fluctuating mental status.

Background: Olanzapine is an atypical antipsychotic drug that is increasingly used in intentional drug overdoses. Although acute olanzapine overdose is predominantly associated with anticholinergic symptoms and central nervous system depression, miosis and unpredictable fluctuations between somnolence/coma and agitation/aggression have been suggested as typical signs of olanzapine intoxication in single case reports. Aims: To confirm the suggestion that fluctuating central nervous system changes and miosis are characteristic signs of olanzapine intoxication. To estimate the dose‐response relationship as a guide for the provision of optimal management of olanzapine intoxicated patients. Methods: Retrospective analysis of all well‐documented cases of olanzapine intoxication reported to the Swiss Toxicological Information Centre between January 1997 and October 2001. Inclusion criteria for detailed analysis were patient age ≥ 16 yr, acute olanzapine monointoxication, ingested dose > 20 mg, and a causal relationship between olanzapine overdose and clinical effects. The Poisoning Severity Score of the European Association of Poison Centres and Clinical Toxicologists (EAPCCT) assessed the intoxication severity. Results: Out of a total of 131 cases of olanzapine overdose, 26 cases fulfilled the inclusion criteria. The ingested olanzapine doses ranged from 30 to 840 mg. The most frequent findings were somnolence (77%), agitation (42%), and miosis (31%). The Poisoning Severity Score was “minor” in 14 (54%), “moderate” in 11 (42%), and “severe” in 1 (4%) patients. Nine patients (35% of all patients) with moderate olanzapine poisoning (120–840 mg) showed unpredictable fluctuations between somnolence and agitation. Five of these patients also demonstrated marked miosis. All patients recovered within 48h. One patient with severe poisoning (560 mg) had coma and convulsions. Moderate (and severe) symptoms occurred only at ingested doses above 120 mg. There was a statistically significant association between increasing ingested olanzapine doses and poisoning severity. Conclusions: Although olanzapine is tolerated relatively well in acute overdose, unpredictable and transient fluctuations between central nervous system depression and agitation, frequently associated with miosis, appear to be characteristic findings in moderate to high olanzapine overdoses. They are transient in nature and require careful clinical monitoring but rarely require specific therapeutic interventions.

Mushroom poisoning: A study on circumstances of exposure and patterns of toxicity

BACKGROUND Picking wild mushrooms is a popular pastime in Switzerland. Correct identification of the species is difficult for laypersons. Ingestion of toxic mushrooms may result in serious toxicity, including death. The aim of the study is to analyze and describe the circumstances of exposure to mushrooms, and to define the clinical relevance of mushroom poisoning for humans in Central Europe. MATERIALS AND METHODS We performed a retrospective case study and analyzed all inquiries concerning human exposures to mushrooms (n = 5638, 1.2% of all inquiries) which were reported to the Swiss Toxicological Information Centre between January 1995 and December 2009. RESULTS The most frequent reason for contacting the poison center in cases of adult exposure was toxicity resulting from edible species. Pediatric exposure predominantly occurred from mushrooms found around the home. Severe symptoms have not only been observed after ingestion of non-amatoxin-containing toxic mushrooms, i.e. Boletus sp. and Cortinarius sp., but also after meals of edible species. The mortality of confirmed amatoxin poisonings was high (5/32) compared to other reports. CONCLUSIONS Inquiries regarding mushroom poisoning were a relatively infrequent reason for contacting the poison center. Nevertheless, accidental ingestion of toxic mushrooms can be responsible for severe or fatal poisonings. Although pediatric exposure to mushrooms found around the home has not led to serious toxicity in this study, prevention of exposure is warranted. Inspection of wild mushrooms by a certified mushroom expert or a mycologist seems to be a safe procedure which should be recommended.

Escitalopram causes fewer seizures in human overdose than citalopram.

Context. Seizures are a recognized complication of acute overdose with the racemic (1:1 ratio of R- and S-enantiomers) selective serotonin reuptake inhibitor antidepressant citalopram. Objective. We tested the hypothesis that escitalopram (the therapeutically active S‐enantiomer of citalopram) causes fewer seizures in overdose than citalopram at comparable doses of the S-enantiomer. Methods. Multicenter retrospective review of cases with citalopram and escitalopram overdose reported to German, Austrian, and Swiss Poisons Centers between 1997 and 2006. Results. 316 citalopram and 63 escitalopram cases were analyzed. Somnolence, nausea, vomiting, tachycardia, QT prolongation, and tremor occurred with similar frequency in both groups. There was a striking difference in the frequency of single and multiple seizures: 43 cases (13.5%) in the citalopram group and 1 case (1.6%) with a single seizure in the escitalopram group (p = 0.0065). Discussion and conclusions. At comparable ingested doses of the S-enantiomer, the symptom profile for citalopram and escitalopram intoxications is similar except for seizures that occur more frequently in citalopram than in escitalopram poisoning.

Acute plant poisoning: Analysis of clinical features and circumstances of exposure

Introduction. Human contact with potentially toxic plants, which may occur through abuse or by accident or attempted suicide, is frequent and sometimes results in clinically significant toxicity. Objective. The aim of the present study was to identify which plants may lead to severe poisoning, and to define the clinical relevance of plant toxicity for humans in Switzerland. Methods. We analyzed 42 193 cases of human plant exposure and 255 acute moderate, severe, and lethal poisonings, which were reported to the Swiss Toxicological Information Centre between January 1995 and December 2009. Results. Plant contact was rarely responsible for serious poisonings. Lethal intoxications were extremely rare and were caused by plants with cardiotoxic (Taxus baccata) or mitosis-inhibiting (Colchicum autumnale) properties. Conclusions. Most often, plant contact was accidental and patients remained asymptomatic or developed mild symptoms, which fully resolved within a short time.

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

Abstract 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.

Retrospective analysis of stimulant abuse cases reported to the Swiss Toxicological Information Centre during 1997-2009.

STUDY AIM To describe characteristics of stimulant abuse and toxicity. METHOD We conducted a retrospective analysis of cases of exposure to cocaine, amphetamines (amphetamine, methamphetamine, and 3,4-methylenedioxymethamphetamine [MDMA]) and methylphenidate reported to the Swiss Toxicological Information Centre between 1997 and 2009. RESULTS There were 667 reports for cocaine, 147 for amphetamine, 41 for methamphetamine, 433 for MDMA, and 122 for methylphenidate. Detailed outcome data were available in 546 (39%) of all reported cases. Exposure to amphetamine or MDMA commonly resulted in mild to moderate toxicity, but severe toxicity was seen in approximately 15% of reported cocaine and MDMA exposures with a known medical outcome. Frequently observed clinical signs and symptoms included tachycardia, arterial hypertension, nausea, agitation, and panic. Amphetamine and MDMA exposures were seen in a younger population and were mainly reported at weekends, while cocaine users were older and exposures occurred proportionally more frequently on weekdays. Parenteral drug use and co-use of heroin was more frequent in cocaine users than in those using other stimulants. There has been an increase in reports of non-medical use of methylphenidate in recent years, indicating a need for further studies of abuse of prescription stimulants. CONCLUSION Stimulant abuse is associated with major toxicity in approximately 15% of reported cases with a known medical outcome. Amphetamine and MDMA users differed from cocaine users in terms of user characteristics, time of use and medical complications. Non-medical use of prescription stimulants such as methylphenidate needs attention.

Low-dose exposure to Veratrum album in children causes mild effects - a case series

Introduction. White or false hellebore (Veratrum album) has a toxicological relevance because of the potential for misidentification of this plant as yellow gentian (Gentiana lutea). Case series. We report a retrospective case series of 11 children (8–12 years) with accidental intake of V. album at a youth camp where they had collected herbs for preparing fresh herb tea. Two children (18%) remained asymptomatic. Nine (82%) developed mild gastrointestinal symptoms, six (55%) presented neurological symptoms, and three (27%) showed bradycardia. All children recovered completely within 10 h of ingestion. The plant was identified at the emergency department; however, detection of veratridine and cevadine by means of high-performance liquid chromatography–Mass spectrometry from the blood of the child with the most severe symptoms was negative (limit 0.01 ng/mL). Discussion. Veratrum species contain more than 200 different alkaloids, which are the principal toxins and are responsible for most clinical symptoms. There are likely multiple mechanisms of toxicity and some of them are only partially understood. The opening of voltage-gated sodium channels is probably one of the most relevant pathophysiological mechanisms. Conclusions. Veratrum album intoxication in children demonstrated the same clinical course as observed in adults. Accidental ingestion of a low dose of the plant had a favorable outcome with supportive care.