Continuous plasma resin perfusion for detoxification of methotrexate.

UNLABELLED: Acute renal failure is a rare but very severe side-effect of methotrexate (MTX) treatment requiring extracorporeal detoxification. A new detoxification regime, consisting of a haemodiafiltration (HDF) and continuous plasma resin perfusion (PRP) over anion exchange resin column with high affinity for MTX, was used for treatment of MTX-induced acute renal failure in a 2-year-old boy with medulloblastoma. More than 99% of MTX was removed from plasma by perfusion over the resin column resulting in a marked decrease of MTX plasma half-life. No haematological complications occurred. CONCLUSION: The use of PRP alone or in combination with HDF is a new and effective treatment strategy for extracorporeal detoxification of MTX.

[Successful therapy of salicylate poisoning using glycine and activated charcoal]. / Erfolgreiche Therapie akuter Salizylatintoxikationen mit Glycin und Aktivkohle.

Acute intoxications with salicylates are common. In a dosage of 150-300 mg/kg they are severe, and above 500 mg/kg potentially fatal. To commit suicide 4 patients ingested 375-460 mg/kg acetylsalicylic acid; 3-8 hours after ingestion salicylate blood levels of up to 760 mg/l were observed. The patients were treated for a period of 16 hours with oral charcoal and glycine (1 g/kg initially, followed every 4 hours by 0.5 g/kg, and 8 g initially, followed by 4 g, respectively). To increase urinary pH (7-9) they received i.v. NaHCO3. Blood levels of salicylic acid including its metabolites dropped initially with a virtual half-life of 2-4 hours. 18 hours after hospital admission every patient was in good general condition; none of them required hemodialysis. The urinary excretion of total salicylate reached only 6-14% of the dose within the first 12 hours of therapy, clearly indicating the importance of combined therapy with glycine and charcoal in achieving a good clinical outcome.

[Acute poisoning with thioridazine]. / Akute Intoxikationen mit Thioridazin.

OBJECTIVE: As previous single case reports have indicated that acute poisoning with thioridazine can be potentially dangerous, an investigation was undertaken to find out whether the risk of severe poisoning in adults and children can be judged from the amount of the drug that has been taken. PATIENTS AND METHODS: In a case-control study 202 medical notes of 202 patients were analysed (141 adults, aged 16-82 years; 61 children, aged 0.3-15 years) in which thioridazine was the only potentially harmful substance taken, the precise amount swallowed was known and the drug was the certain or probable cause of the signs. 30 children were excluded from the study, because their body weight was not known. RESULTS: Mild thioridazine poisoning was characterized by somnolence, tremor, ataxia and dysarthria. The severity of the poisoning and the degree of disorder of consciousness correlated significantly with the amount of thioridazine taken. Severe intoxication with coma and ventricular arrhythmias was observed at a dose of 2 g and more. While the disorder of consciousness completely regressed in the first 24 hours, in a few of the patients the cardiac arrhythmias persisted for up to 28 hours after the drug intake. Charcoal administration seemed to influence the course favourably. CONCLUSION: Prolonged, intensive care supervision and treatment are essential if more than 2 g thioridazine have been swallowed. In addition to standard treatment with gastric lavage charcoal should be given as early as possible to limit absorption.

[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.

[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.

Case report: 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.

[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)

Tissue distribution of succinylacetone in the rat in vivo: a possible basis for neurotoxicity in hereditary infantile tyrosinemia.

Neurologic dysfunction is a significant component of hereditary infantile tyrosinemia, an autosomal recessive disorder of man. The specific enzyme defect leads to endogenous production of the biochemical marker compound, succinylacetone (SA). Earlier study of the role which SA plays in generation of the renal Fanconi syndrome, also associated with this disorder, led to speculation that SA might also have neurotoxic effects. Thus, we have studied the distribution and impact on heme metabolism of SA in brain, liver and kidney from rats treated in vivo. Our results show far greater retention of SA in brain and kidney than in liver, by a ratio of approx. 3:1. Delta-aminolevulinate dehydratase (ALAD) was reduced to less than 10% of control activity in all three tissues after three daily injections; after a 7-day recovery, activity was regained at different rates in the three tissues. Total heme content of each tissue showed a steady decline beyond the treatment period, the most marked reduction being found in kidney. Porphyrin intermediates, heme oxygenase activity and cytochrome P-450 content evidenced varying responses to SA exposure which differed from tissue to tissue. Our results show that brain tissue sequesters SA and that heme biosynthesis in brain, as distinct from liver and kidney, is adversely affected. Such effects could result in impaired oxidative metabolism in brain, producing the CNS manifestations of tyrosinemia.

[Therapy of acute salicylate poisoning]. / Die Therapie der akuten Salizylatintoxikation.

Poisoning with salicylic acid and its derivatives is a quite common event, leading to possibly life-threatening complications. A case of fatal intoxication of a sixty-year old patient with acetylsalicylic acid is described and the therapeutic options are discussed. In acute poisoning it is mandatory to initiate simple and effective measures first. This gives time for discussing and planning the more laborious procedures. The initial treatment of salicylate poisoning is based on the prevention of further absorption by a sufficiently large quantity of orally administered activated charcoal (approximately 1 g/kg b.w.). Given repeatedly, activated charcoal may enhance non-renal clearance of salicylates. Intravenously administered sodium bicarbonate counteracts the metabolic acidosis. Moreover, bicarbonate therapy limits tissue distribution of the drug and enhances its renal excretion. The availability of glycine for salicylic acid metabolism may be limited in poisoning because glycine has been used for forming the conjugation product salicyluric acid. Glycine may be administered orally to overcome this bottleneck. Gastric lavage has been proven to be of limited efficacy. This efficacy is further diminished if gastric lavage is performed late after drug ingestion. When it is performed, however, activated charcoal should be administered before and after gastric lavage. Whenever the more simple treatment options fail, hemodialysis or hemoperfusion should be additionally considered since these procedures are effective in removing salicylates from the body.

[Incidence and clinical aspects of scombroid fish poisoning]. / Inzidenz und Klinik der Scombroid-Fischvergiftung.

An impressive case of scombroid-fish poisoning in a 34-year-old woman prompted us to investigate the incidence, clinical findings and follow-up of this disease, the syndrome of which resembles histamine intoxication. In 25 years (1966-1991) a total of 76 incidents after intake of tuna fish were reported to Swiss Toxicological Information Centre. 27 reports came from physicians, and of these 18 fulfilled the criteria of scombroid-fish poisoning. Thus, this intoxication occurs rarely in Switzerland. The symptoms in 31 well documented cases are described. Most patients had erythema (87%), half complained of headache and one third had gastrointestinal symptoms. The clinical course was benign in all patients, and the symptoms had disappeared after a mean period of 8 hours.

delta-Aminolevulinic acid dehydratase: effects of succinylacetone in rat liver and kidney in an in vivo model of the renal Fanconi syndrome.

Succinylacetone (SA) is a known inhibitor of the heme biosynthetic pathway in liver. We have demonstrated previously the SA enhancement of delta-aminolevulinic acid dehydratase (ALAD) in renal tubules, while this enzyme is known to be impaired by SA in the liver. The present studies, based on in vivo treatment of animals with SA, show equivalent degree of inhibition of specific ALAD activity in liver and kidney. Both tissues evidenced an ability to restore enzyme activity with time, the recovery occurring much more slowly in kidney than in liver. The discrepant in vitro and in vivo effect of SA on renal ALAD may be due to differences between a direct inhibitor-enzyme interaction and inhibitor actions in the living cell, respectively. Persistent tissue levels of SA, consistent with demonstrated SA in plasma and urine, might account for continuing inhibition, with the greatest tissue accumulation in kidney where the substance must be cleared for excretion.

Physiological basis for an animal model of the renal Fanconi syndrome: use of succinylacetone in the rat.

1. The biochemical basis for the human renal Fanconi syndrome, including glucosuria, phosphaturia and aminoaciduria, remains enigmatic. This is due, in part, to the lack of an appropriate animal model. Since there is an association between the human genetic disease hereditary tyrosinaemia, for which urinary excretion of the compound succinylacetone constitutes a biochemical marker, and a renal Fanconi syndrome, we have examined the relationship between succinylacetone and renal tubular function in the rat. 2. Intraperitoneal injection of succinylacetone for 3 consecutive days into adult male Sprague-Dawley rats resulted in succinylacetone plasma concentration of 3 mmol/l. This concentration was associated with glucosuria, aminoaciduria, polyuria, reduced renal phosphate reabsorption and normal creatinine clearance. In addition, urinary porphobilinogen and total porphyrin excretions were markedly reduced. In animals permitted to recover for 7 days after succinylacetone administration, these renal functional changes remitted partially or completely. Ultrastructural examination of the kidneys after the 3 days of treatment showed no fine structural changes. 3. We conclude that the physiological alterations produced in normal rat renal tubules by succinylacetone provide the basis for the study of the biochemical changes underlying the human renal Fanconi syndrome.

[Measures for the acceleration of toxin excretion via liver, bile and intestines]. / Massnahmen zur Beschleunigung der Toxinausscheidung über Leber, Galle und Darm.

It is possible to enhance elimination of already absorbed xenobiotics through the gastrointestinal tract by influencing distribution, by specifically inducing metabolism, by interrupting the enterohepatic circulation, and by increasing intestinal secretion, respectively. Case reports of clinical experiences, however, are not sufficient support for a rational and comprehensive concept of secondary decontamination (i.e. all measures to enhance elimination of substances that have been absorbed). This is especially true during and after either subacute or chronic exposure to harmful xenobiotics. Further scientific work in the laboratory is needed to provide the necessary background for controlled clinical studies. Highly lipophilic compounds with a long terminal half-life, as for example amiodarone or persistent environmental pollutants, will challenge such a concept.

[The STIZ and the epidemiology of poisoning in Switzerland (Swiss Toxicologic Information Center)]. / Das STIZ und die Epidemiologie der Vergiftungen in der Schweiz.

Despite the fact that the danger and the sequelae of poisoning are regularly referred to in the media, comprehensive reports about type and frequency of poisoning in Switzerland are not available in the literature. Thus morbidity of poisoning can only be judged by the calls and written replies of treating physicians. According to the retrospective evaluation of the data available to us (1966 to 1991), the number of poisoning leading to severe life-threatening symptoms is tending to decline. This apparent success of prevention and treatment of poisoned patients in our country should be corroborated by extensively investigating quantitative and qualitative aspects of poisoning. Moreover, overall mortality of poisoning is increasing, especially because of the deaths caused by abusing habit-forming drugs. On the other hand, the number of suicides using medicaments shows a tendency to decline. Detailed statistical data about the circumstances and xenobiotics involved in poisoning could efficiently help to develop measures to prevent a fatal outcome.

Renal heme metabolism in hereditary tyrosinemia: use of succinylacetone in rat renal tubules.

Succinylacetone (SA), a metabolic end-product found in urine from individuals with hereditary tyrosinemia and associated renal Fanconi syndrome and a known inhibitor of hepatic 5-aminolevulinic acid dehydratase (ALAD), has been used to study heme metabolism in isolated rat renal tubules. Heme biosynthetic porphyrin precursors are increased selectively in the presence of 4 mmol/1 SA. Total porphyrin content of the tubules are increased approximately 2-fold, while both ferrochelatase and heme oxygenase activities remain unaffected by SA. Nonetheless, total heme content is reduced, as was incorporation of radioactive label from amino[14C]levulinic acid. Cytochrome P-450 content remained unaffected. Impairment of iron uptake and/or transport within the cell or enhancement of heme catabolism via a non-heme oxygenase-dependent pathway could explain the observations.

The use of 2,4,5,2',4',5'-hexachlorobiphenyl (6-CB) as an unmetabolizable lipophilic model compound.

2,4,5,2',4'5'-Hexachlorobiphenyl (6-CB)--a polychlorinated biphenyl (PCB) congener resistant to metabolism in most species--has become a major residue in the biosphere including human adipose tissue. Its use as a model of unmetabolizable lipophilic compounds and as a tool in toxicokinetics in the last two decades is reviewed. This extremely water-insoluble compound is transported in plasma by albumin and lipoproteins. Binding to these plasma proteins appears to be important for uptake and release processes in different tissues. The redistribution kinetics of 6-CB as well as its pronounced adipose tissue storage and a very slow excretion with the faeces has been established in long-term animal studies. Excretion is strongly influenced by an increasing or diminishing adipose storage compartment size. Other minor pathways of elimination, e.g., via hair, become also important in the absence of metabolism and renal excretion. 6-CB has revealed the possibility of an almost quantitative transfer of the maternal body burden to the offspring via milk. The use of 6-CB in studies with tissue preparations in vitro is providing insight into transport mechanisms of uptake and release.

Expression of multiple proteins structurally related to gamma-glutamyl transpeptidase in non-neoplastic adult rat hepatocytes in vivo and in culture.

Freshly isolated hepatocytes from normal adult rat liver do not express measurable gamma-glutamyl transpeptidase (GGT) mRNA in contrast to the significant GGT mRNA levels expressed by normal adult rat kidney and hyperplastic bile ductular tissue from bile duct-ligated rats. However, the induction of GGT activity in rat hepatocytes by two-thirds hepatectomy was accompanied by the appearance of a high level of GGT mRNA. We are now able to demonstrate that normal adult rat hepatocytes express 5 protein bands which cross-react with 2 different anti-rat kidney GGT antisera. The apparent molecular weights were 26.9, 58.0, 63.9, 73.5, and 83.4 kDa, respectively. Expression of the 26.9- and 58.0-kDa proteins strikingly parallels the pattern of induction of GGT enzymatic activity. This suggests that these 2 proteins correspond to the active dimeric enzyme previously described in kidney and neoplastic hepatocellular tissue. In normal hepatocytes, the 73.5-kDa protein represents 50% of the total GGT-immunoreactive protein, in contrast to kidney, where this band contains less than 4% of the GGT protein. The kinetics of expression of the 73.5-kDa protein upon induction of GGT activity in hepatocytes, as well as in culture turnover studies, suggests that this protein is a precursor form of the active enzyme, such as the described 78/79-kDa single-chain glycoprotein propeptide of GGT. It appears that in normal hepatocytes, this precursor is not processed to the same extent as in kidney or in hyperplastic bile ductular tissue.

Pharmacokinetic investigation of oral and i.v. dihydroergotamine in healthy subjects.

A new radioimmunoassay (RIA) for the specific measurement of dihydroergotamine (DHE), sufficiently sensitive for the determination of low plasma concentrations, has been used to investigate the pharmacokinetics of unchanged DHE. In a randomized cross-over trial, eight healthy male volunteers received single doses of DHE 5 mg, 10 mg and 20 mg orally and 0.1 mg and 0.5 mg intravenously. It was possible to determine plasma concentrations and urinary excretion of DHE over the following 48 h. A long terminal plasma elimination phase of unchanged DHE (half-life 15 h) was found. A similar terminal elimination half-life was also calculated from urine data. The multi-exponential decline in plasma DHE with a long terminal half-life suggests that distribution into a deep compartment contributes to the long-lasting effect of the drug. Plasma protein binding was 93%. Despite extensive tissue distribution (Vz = 33 l/kg) and a high plasma clearance (CLP = 2 l/min), dose-independent linear pharmacokinetics was observed. The present assay was at least 20-times more specific than the polyvalent RIA used previously and appears suitable to explore the pharmacokinetics of unchanged DHE in patients on low-dose therapy. The long terminal elimination half-life of DHE only reported previously in studies using 3H-labelled drug, and considered to be due to metabolites, was also true for the parent compound. This, in addition to the sustained pharmacological activity of the 8'-hydroxy metabolite already shown, provides a further explanation for the long duration of action of DHE in animals and man.

Kinetics of distribution and elimination of DDE in rats.

1. Rats were given single i.v. doses of 14C-DDE, and total drug (14C) and unchanged DDE (g.l.c.) were measured for up to 14 days in blood, tissues, and excreta. The 14C recoveries amounted to 90.0 +/- 10.8 (SD) % dose. 2. DDE underwent redistribution from blood to liver, muscle, skin and, ultimately, adipose tissue. The tissue/blood concentration ratios were 6 for liver and muscle, 35 for skin, 400 for adipose tissue. Concentrations in blood and lean tissues declined biphasically with beta-half-lives of 8-12 days. The half-lives for adipose tissue and total body burden were larger by one order of magnitude. However, due to the increase of adipose tissue mass with time, the amount of DDE stored therein remained constant at almost 60% dose. 3. Except for liver, no substantial metabolite concentrations in tissues were found. In particular, lipophilic metabolites were clearly absent. Thus, tissue kinetics and storage are controlled by unchanged DDE. 4. Of a given dose of DDE, 31% was excreted in the faeces as polar metabolites within 14 days, and 3-4% dose as DDE. Urinary excretion was negligible. The beta-half-life of faecal excretion was equal to the one in blood and lean tissues. It is concluded that excretion is limited by the slow formation of polar metabolites of DDE.

Single-dose kinetics of tissue distribution, excretion and metabolism of amiodarone in rats.

In order to better understand the pharmacokinetic differences between acute and chronic regimens of the basic lipophilic antiarrhythmic, amiodarone (AM), a mass-balanced single-dose study ([14C]AM, 50 mg/kg, i.v.) was carried out until total elimination had been achieved (10 days). Total drug, AM and desethylamiodarone (DEA) were determined in plasma, eight tissues and excreta of rats with constant body weight. Three exponential terms were sufficient to describe the plasma concentration-time curve of unchanged AM with a long terminal half-life of 131 hr. An equally long terminal half-life of AM could also be observed in all tissues investigated. After 5 min, 42% of the radioactivity appeared in the liver, where it underwent redistribution to muscle, skin and, ultimately, adipose tissues. Whereas plasma and liver contained mainly unidentified metabolites and little DEA, unchanged AM predominated in all other tissues. According to the time-integrated parameters of distribution, AM has a potential to accumulate in adipose tissue under chronic administration. In contrast, DEA accumulation would be likely to occur in lean tissues, mainly in the lung. In 10 days, 94% of the injected radioactivity was excreted in feces and less than 2% in urine. Almost all of the excreted radioactivity consisted of unidentified metabolites, indicating that both AM and DEA are eliminated by metabolism.