[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.

[Liver injury under tuberculostatic treatment]. / Leberschädigung unter Tuberkulostatika-Behandlung.

We report the case of a patient with nausea, loss of appetite and increase of the aminotransferase levels to eight times the upper normal limit occurring two weeks after she was started on isoniazide, rifampicine and pyrazinamide for treatment of tuberculosis. Isoniazide is the most likely cause of liver injury occurring during combined antituberculosis therapy, whereas pyrazinamide or rifampicine are only rarely responsible. The case presented is used to review and compare the different recommendations concerning the monitoring of patients receiving antituberculous therapy and the clinical management of patients developing liver injury.

[Cholestatic liver diseases]. / Cholestatische Leberkrankheiten.

Cholestatic liver disease is primarily caused by impaired bile production on the level of hepatocytes and cholangiocytes. Clinically cholestasis can be divided into intrahepatic and extrahepatic forms based on the presence or absence of dilated bile ducts (sonography). Intrahepatic cholestasis is most frequently caused by end stage liver cirrhosis followed by primary cholangiopathies and canalicular transport defects in hepatocytes. The causes of the most important cholangiopathies, such as Primary Biliary Cirrhosis (PBC) and Primary Sclerosing Cholangitis (PSC) are so far not known. Therefore, drug therapy of cholestatic liver disease focuses on the improvement of symptoms such as fatigue, pruritus, abdominal discomfort, jaundice, xanthoma, hypercholesterolemia, portal hypertension, blood count abnormalities, osteoporosis/osteomalacia, and the prevention of complications such as bile-duct strictures in PSC and development of cholangiocarcinoma. The first choice drug in the treatment of cholestatic liver disease of various causes is urosodeoxycholic acid (UDCA), that has been shown to decrease bile acid toxicity in general and prolong the transplant free survival of patients with PBC. If cholestasis persists cirrhosis of the liver is the major complication and liver transplantation may be the definitive treatment in advanced cases of cholestatic liver disease.

[The clinicopharmacological case (5). serotonin reuptake inhibitor and 5-HT3-receptor antagonists: are there clinically relevant interactions?]. / Der klinisch-pharmakologische Fall (5). Serotoninwiederaufnahmehemmer und 5-HT3-Rezeptor-Antagonisten: Gibt es klinisch relevante Interaktionen?

We describe a patient with chronic depression who was treated with the selective serotonin-reuptake-inhibitor sertraline. Following surgery, the patient developed severe nausea and vomiting, necessitating an efficient antiemetic treatment, possibly including the 5-HT3-receptor antagonist ondansetrone. Because both drugs, sertraline and ondansetrone, interact with the serotonin system at the synapsis, a possible interaction was discussed. Since the effect of the selective serotonin-reuptake inhibitors mainly depends on 5-HT1 and 5-HT2-receptors, a pharmacodynamic interaction between an 5-HT3-antagonist and a serotonin-reuptake-inhibitor at the synapsis leading to the relapse of depression seems to be very unlikely. There exist also no conclusive data suggesting a clinically relevant pharmacokinetic interaction between the two drugs. A treatment with ondansetrone was considered to be safe in this patient.

[Clinical-toxicological case (1). Dosage of N-acetylcysteine in acute paracetamol poisoning]. / Der klinisch-toxikologische Fall (1). Dosierung von N-Acetylcystein bei akuter Vergiftung mit Paracetamol.

There are currently three protocols used for the administration of N-acetylcysteine in the treatment of acute paracetamol poisoning. In the USA only the oral protocol is approved, while in Europe an intravenous protocol is used. If treatment is started within 10 h. after paracetamol ingestion, all three protocols appear to be equally effective. If treatment is started 10 to 24 h. after the ingestion, the oral protocol and the Smilkstein protocol appear to be superior to the Prescott protocol. N-acetylcysteine is effective also when started more than 15 h after the ingestion. Patients who present with liver failure after paracetamol poisoning should be treated with a prolonged course of N-acetylcysteine.

[Serious plant poisonings in Switzerland 1966-1994. Case analysis from the Swiss Toxicology Information Center]. / Wichtige Pflanzenvergiftungen in der Schweiz 1966-1994. Eine Fallanalyse aus dem Schweizerischen Toxikologischen Informationszentrum (STIZ).

AIM: To analyze the types, frequency and severity of plant poisonings in Switzerland over 29 years. METHODS: Retrospective analysis of severe poisonings with toxic plants reported to the Swiss Toxicological Information Center (STIC). Assessment of the causality, severity of symptoms and the types of plants involved. RESULTS: During the period under review the STIC registered 24 950 cases of contact with or ingestion of toxic plant material. In 99.4% of all cases the clinical course was either unknown, asymptomatic or associated with only minor symptoms (no hospitalization). Severe plant poisonings occurred in 152 cases. Detailed analysis was possible in 135 cases (23 children, 112 adults) including 5 lethal cases (all adults). The 24 plants involved produced the following severe symptoms: Atropa belladonna (42 cases): anticholinergic syndrome (42), acute psychosis (33), convulsions (2), coma (2). Heracleum mantegazzianum (18): severe photodermatitis (18). Datura stramonium (17): anticholinergic syndrome (17), psychosis (12), coma (2). Dieffenbachia (11): severe stomatitis (8), corneal lesions (3). Colchicum autumnala (10): diarrhea (10), liver necrosis (9), fatal multiorgan failure (2). Veratrum album (8): bradycardia ( < or = 40/min) (6), shock (5). Aconitum napellus (4): tachyarrhythmia (2), AV-block II/III (2). Aesculus hippocastanum (3): allergy (3), anaphylactic shock (2). Hyoscyamus niger (3): anticholinergic syndrome (3). Ricinus communis (3): diarrhea (3), toxic megacolon (1). Oenanthe crocata (2): convulsions (1), lethal coma (1). Taxus baccata (2): tachyarrhythmia (1), fatal asystole (1). Further single cases with severe poisonings were observed with Arum maculatum, Asarum europaeum, Chrysanthemum vulgare, Cyclamen persicum, Datura suaveolens, Glycyrrhiza glabra, Laburnum anagyroides, Lycopodium, Narcissus pseudonarcissus (lethal aspiration), Nerium oleander, Senecio vulgaris and Vicia faba. CONCLUSIONS: Potential and real intoxications with plant materials occurred in 7.2% of all cases registered at the STIC. However, among all plant cases only 0.6% were severe intoxications requiring hospitalization. Although severe plant intoxications are rare events, a small number of specific plants appear to be mainly responsible for continued serious plant poisoning in Switzerland. The present study has identified the plants with the highest toxicological risks and provides a data base for more rational prevention, diagnosis and treatment of plant poisoning cases in the future.

[Acute overdose of Zolpidem (Stilnox)]. / Akute Uberdosierungen mit Zolpidem (Stilnox).

Zolpidem (Stilnox), an imidazopyridine derivative, is a strong sedative with minor myorelaxant and anticonvulsant properties which exhibits high-affinity binding at a benzodiazepine-receptor subtype. Although the structure of zolpidem differs from the benzodiazepines, the acute toxicity of zolpidem has generally been compared to triazolam (Halcion) and midazolam (Dormicum). 5 years after introduction of zolpidem to the Swiss market we have therefore retrospectively analyzed 91 well documented cases of acute zolpidem intoxication reported to the Swiss Toxicological Information Center. Furthermore, 54 single-drug poisonings with zolpidem were compared with 53 triazolam and 55 midazolam intoxications observed over the same time period. 0.01-0.02 g of zolpidem is the recommended therapeutic dose. But only mild symptoms were observed in acute single-drug poisonings with zolpidem up to 0.6 g. Patients mainly suffered from somnolence. Only one anorectic patient became comatose after ingestion of 0.6 g zolpidem. The acute toxicity of zolpidem was markedly less pronounced than that of the short-acting benzodiazepines triazolam and midazolam. With forty-fold the therapeutic dose no severe symptoms occurred in patients with zolpidem single-drug poisonings, while coma was encountered in 4 cases with triazolam (11% of patients) and 4 cases with midazolam (10%). While only the patient mentioned above was reported to be comatose after overdosing with zolpidem, 6 (11%) and 8 (15%) comatose patients were observed in triazolam and midazolam single-drug poisonings, respectively. On the other hand, in combined intoxications with other CNS active drugs or ethanol a zolpidem dose as low as 0.1-0.15 s induced coma in some patients, even if the amount of the additionally ingested drugs in itself would not have caused a comatose state. Flumazenil (Anexate) was an effective antidote in mono- and combined intoxications involving zolpidem. In conclusion, our results indicate that zolpidem single-drug poisonings are generally benign and require no specific therapeutic measures. In combined intoxications, however, patients may develop coma at relatively low zolpidem doses and should therefore be monitored for approximately 24 hours. If necessary, disturbances of consciousness can be successfully treated with flumazenil.

[Clinicopharmacological case report (3). Drug-induced angioedema]. / Der klinisch-pharmakologische Fall (3). Medikamentös bedingtes Angioödem.

We report the case of a patient with an angioedema during therapy with enalapril and tramadol. The most likely cause of the adverse effect if the ACE-inhibitor enalapril. A rechallenge with the ACE-inhibitor is dangerous and should not be performed. Because of its potential risks, further treatment with ACE-inhibitors should be avoided in all patients with ACE-inhibitor-induced angioedema. Possible therapeutic alternatives include diuretics, beta-blocking agents, calcium antagonists and also angiotensin II receptor antagonists.

[A clinical-pharmacological case (1). Action of cisapride (Prepulsid) on bladder function]. / Der klinisch-pharmakologische Fall (1). Wirkung von Cisaprid (Prepulsid) auf die Harnblasenfunktion.

We report the case of a 75 old man with chronic constipation due to traumatic spinal cord injury 25 years ago. Following prostatectomy the patient developed retention of urine and urinary incontinence, which improved significantly during a therapy with cisapride (3 x 10 mg/day). While the administration of cisapride is associated with increased detrusor activity and possibly urinary incontinence in neurologically normal persons, patients with urinary retention due to spinal cord injury may benefit from a therapy with this indirect parasympathomimetic agent.

[Acute poisoning in childhood]. / Akute Vergiftungen im Kindesalter.

Accidental ingestions of noxious substances are frequent events during childhood, especially in children one to three years of age. In contrast, severe symptoms and a serious outcome of these intoxications have been observed rather rarely; therefore, it is very important to avoid unnecessary and potentially harmful therapeutic measures. An extensive body of information has been collected nationally and internationally, allowing an accurate risk assessment in a constantly increasing number of cases. If there is need for treatment at all, the early application of activated charcoal (dose: 1 g/kg body weight) will efficiently inhibit absorption of noxious substances in most instances. Whereas the first dose of activated charcoal is administered to block absorption, repeated administration (0.5 g/kg body weight, every 2 to 4 hours) has been shown to shorten half-life and enhance the nonrenal clearance of chemically different substances even after absorption. Only few substances like heavy metals, lithium, or alcohols are not adsorbed by activated charcoal. Whole bowel irrigation may be a valuable alternative in cases where activated charcoal has been shown to be ineffective. Poisoning with ferrum formulations is an instructive example of this type of intoxication. Gastric lavage and pharmacologically induced emesis are no longer considered a routine treatment in poisoning but rather a special therapeutic option for very special situations. In all cases of severe poisoning, maintenance of vital functions, applying the principles of emergency medicine, has to have first priority.(ABSTRACT TRUNCATED AT 250 WORDS)

[Drug interactions as a cause of drug side effects]. / Interaktionen von Medikamenten als Ursache von unerwünschten Arzneimittelwirkungen.

Adverse drug interactions are a frequent clinical problem. Mechanistically, they can be classified as pharmaceutic, pharmacokinetic and pharmacodynamic interactions. Mostly, however, several different mechanisms are involved in the pathogenesis of adverse drug interactions, which makes their predictability as well as their prevention strongly dependent on the early and adequate recognition of high-risk patients. Such high-risk situations include drug-related (e.g. galenic form, stability, enantiomers), patient-related (e.g. pharmacokinetics, age, genetic disposition) and various exogenous (e.g. polypragmasy, alcohol abuse, food) factors. Especially the recent progress in the molecular characterization of hepatic biotransformation reactions has markedly increased our understanding of many potentially toxic drug interactions. In addition, several alternative compounds with distinct potentials for interactions with other drugs are now available in various therapeutic drug classes. In the future it will be important to further increase our pathophysiologic and pharmacogenetic knowledge, in order to further improve the predictability, prevention, early recognition and therapy of adverse drug interactions.

Cellular mechanisms of intrahepatic cholestasis.

Most forms of intrahepatic cholestasis are caused by a failure of hepatocytes to secrete osmotically active bile constituents into the minute channels of bile canaliculi. This overall vectorial bile secretory process is dependent upon a variety of polarised active transport functions at the basolateral (sinusoidal and lateral) and canalicular plasma membrane domains, as well as upon the coordinated vectorial movement of intracellular vesicles. Although considerable progress has been made in recent years in the identification, characterisation and exact localisation of a number of polarised hepatocellular transport systems, the primary mechanisms and targets leading to defective bile secretion and cholestasis are still not completely understood. For example, not all reported experimental data are compatible with the concept that estrogen-induced cholestasis represents a predominant sinusoidal disease process. In addition, the pathophysiological significance of disturbed transcytotic pathways and/or disrupted intracellular calcium homeostasis are not yet clear. For many forms of cholestasis, it remains uncertain as to whether leaky tight junctions represent a primary cause rather than a secondary phenomenon of the cholestatic state. However, the ongoing progress in the understanding of the normal mechanisms involved in the establishment, maintenance and regulation of ion homeostasis and polar transport functions in hepatocytes will, undoubtedly, improve our knowledge of the pathogenesis of intrahepatic cholestasis and, it is hoped, lead to better therapeutic strategies in the near future.

Taurocholate transport by liver plasma membrane vesicles is not altered in cirrhotic rats.

Recently, we have shown that taurocholate transport is impaired in hepatocytes isolated from CCl4 cirrhotic rats. Na+,K+-ATPase activity depends on the lipid composition of the surrounding membrane. Therefore, we performed this study in order to detect differences in plasma membrane composition and membrane functions between livers of CCl4 cirrhotic (n = 17) and of control rats (n = 15). After biochemical characterization of the animals we isolated basolateral and canalicular membrane vesicles and determined membrane enzyme activities, transport functions and lipid composition. We found no differences in the isolation characteristics of the plasma membranes between the two groups. The lipid composition of the membrane fractions was not altered, except for a lower cholesterol content in the canalicular membranes of the cirrhotic group (200 +/- 15 vs. 246 +/- 18 micrograms/mg protein, P less than 0.05). Taurocholate transport into basolateral membrane vesicles and marker enzyme activities of the membrane fractions were also equal in control and cirrhotic animals. We conclude that the plasma membrane composition and membrane enzyme/transport activities have returned to normal in CCl4 cirrhotic rats 14 days after cessation of exposure to CCl4. Thus, a disturbed transport system is not the cause for the observed decreased taurocholate transport into hepatocytes from cirrhotic rats. Even a cirrhotic liver has a high potential for recovery after acute CCl4 intoxication.