[High-dose magnesium sulfate in the treatment of aconite poisoning]. / Hochdosiertes Magnesiumsulfat bei Aconitumintoxikation.

This article reports the case of a 62-year-old male patient who ingested the roots of Monkshood (Aconitum napellus) and white hellebore (Veratrum album) dissolved in alcohol with a suicidal intention and suffered cardiotoxic and neurotoxic symptoms. After contacting the Poison Information Centre ventricular arrhythmia was treated with high-dose magnesium sulphate as the only antiarrhythmic agent and subsequently a stable sinus rhythm could be established after approximately 3 h. Aconitum napellus is considered the most poisonous plant in Europe and it is found in gardens, the Alps and the Highlands. Poisoning is mainly caused by the alkaloid aconite that leads to persistent opening and activation of voltage-dependent sodium channels resulting in severe cardiac and neurological toxicity. As no specific antidote is known so far, poisoning is associated with a high mortality. The therapy with high-dose magnesium sulphate is based on in vitro and animal experiments as well as limited clinical case reports.

Pharmacokinetics of obidoxime in patients poisoned with organophosphorus compounds.

OBJECTIVES: Reactivation of inhibited acetylcholinesterase (AChE) with oximes is a causal therapy of intoxication with organophosphorus compounds (OPs). Maximal oxime effects are expected when effective doses are administered as soon as possible and as long as reactivation can be anticipated. An obidoxime plasma level in the range of 10-20 microM was estimated as appropriate. The achievement of this target was assessed in 34 severely OP-poisoned patients. METHODS: After admission to the intensive care unit (ICU) the obidoxime regimen (250 mg i.v. as bolus, followed by 750 mg/24h) was started and maintained as long as reactivation was possible. Plasma concentrations of obidoxime were determined by HPLC. RESULTS: A total amount of 2269+/-1726 mg obidoxime was infused over 65 h+/-55 h resulting in a steady state plasma concentration of 14.5+/-7.3 microM. Obidoxime was eliminated with t(1/2(1)) 2.2 and t(1/2(2)) 14 h. The volumes of distribution amounted to 0.32+/-0.1L/kg (V((1))) and 0.28+/-0.12 (V((2)))L/kg. Postmortem examination of tissue in one patient showed obidoxime accumulation in cartilage, kidney and liver and pointed to brain concentrations similar to plasma concentration. CONCLUSIONS: Using the suggested obidoxime regimen, the targeted plasma concentration could be achieved. Obidoxime was eliminated biphasically and was well tolerated. This result allows the recommendation of using this definite regimen for adults also in case of mass casualties.

[Lead intoxication in a group of workers in Germany]. / Gruppenvergiftung mit Blei am Arbeitsplatz.

HISTORY AND ADMISSION FINDINGS: Seventeen East-European workers with a suspected lead-intoxication presented themselves to the Department of Toxicology. All of them had worked on the renovation of pylons of a high-tension line. The old paint, known to contain lead was removed with needle descalers. The patients had blood lead concentrations between 325 and 1124 microg/l, but no specific symptoms. The workers neglected the protective measures at their working-place. INVESTIGATIONS: 12 of 17 workers had lead-concentrations above 400 microg/l (Reference < 90 microg/l). 10 of 17 patients showed an increased level of free protoporphyrins and all workers showed a decreased activity of delta-aminolaevulinacid-dehydratase (ALAD). TREATMENT AND COURSE: Patients with lead-concentration above 700 microg/l were treated with the chelating agent meso-2,3-dimercaptosuccinic acid (DMSA) 3 x 200 mg/d for nine days. The patients with lead concentrations between 400 and 700 microg/l were treated which DMSA 3 x 100 mg/d. After the DMSA-treatment the lead-concentrations had dropped (p < 0.001). During the DMSA-therapy one patient had to be treated in the hospital because of a generalised allergic exanthema. CONCLUSION: We report seventeen patients with high lead concentration in their blood due to occupational exposure. The high blood lead levels showed that the workers had not been protected adequately. This examplifies that occupational lead exposure still occurs, also in Germany. By patients with unspecific symptoms connected with lead exposure a biomonitoring for lead is necessary.

Monitoring of neuromuscular transmission in organophosphate pesticide-poisoned patients.

Thirty-four adult patients with severe organophosphorus compounds (OP) poisoning requiring artificial ventilation were enrolled in a clinical study and received atropine and obidoxime (250 mg i.v., followed by 750 mg/24 h) as antidotal treatment. Here, we re-analyzed the cholinesterase status (red blood cell acetylcholinesterase (RBC-AChE) activity, reactivatability of RBC-AChE, and plasma butyrylcholinesterase (Pl-BChE) activity) in relation to the neuromuscular transmission (NMT) data. When RBC-AChE activity ranged between 100% and 30% NMT was unimpaired after tetanic stimulation with frequencies up to 50 Hz. A further decrease in RBC-AChE activity was accompanied by a marked disturbance of NMT, being strongly impaired at AChE activities <5% of normal. Higher stimulation frequencies (>30 Hz) facilitated the discrimination of the types of impairment. The neuromuscular transmission was the best quantified by using the ratio of the ninth to the first amplitude, while the standard method was less discriminative. At RBC-AChE levels higher than 40% of normal weaning from the ventilator may be considered. Completely aged RBC-AChE as indicated by loss of reactivatability loses its guidance function. Then, steadily increasing Pl-BChE activity suggests lack of circulating poison. One-week later, neuromuscular transmission may be largely normal and patients could be weaned from the respirator if other complications are not withstanding.

[Amanita poisoning--comparison of silibinin with a combination of silibinin and penicillin]. / Knollenblätterpilzvergiftung. Silibinin und Kombination von Silibinin und Penicillin im Vergleich.

BACKGROUND AND AIMS: Current treatment of amatoxin poisoning includes the administration of silibinin and penicillin in combination or silibinin alone. The aim of this study was to compare both therapeutic regimes. PATIENTS AND METHODS: Of 604 patients with the suspected diagnosis of amatoxin poisoning 367 were retrospectively analysed: 118 patients had received silibinin alone and 249 patients silibinin in combination with penicillin. Logistic regression analyses were applied to investigate the efficacy of both therapeutic regimens by comparing death and liver transplantation rates. A potentially independent effect on outcome of age, sex, year of treatment, latency period of symptoms and start of silibinin therapy was taken into account. RESULTS: In the group who had received the combination of silibinin and penicillin 8.8% died or underwent liver transplantation compared to 5.1% in the group of those who had received silibinin alone. The risk of death or organ transplantation was thus reduced by nearly 40% in the latter group (adjusted odds ratio: 0.58; 95% CI: 0.21-1.57; p=0.28). A longer latency period (< or =12h vs. >12h) was associated with a significant reduction of this risk (adjusted OR.: 6.10; 95% CI:1.77-21.3; p=0.004). A later start of silibinin therapy (>24h vs. < or = 24h) was associated with a tendency toward an increased frequency of death or organ transplantation (adjusted OR.: 3.0; 95% CI: 0.96-9.20; p=0.059). CONCLUSIONS: A lower death and transplantation rate was observed in the silibinin treatment group than in group treated with silibinin combined with penicillin. However, this difference was not statistically significant. The high risk ratio relating to the time-dependent effect of silibinin suggests its efficaciousness in the treatment of amatoxin poisoning. The latency period was assessed as an independent prognostic factor.

Treatment of health complaints attributed to amalgam.

The aim of the present study was to compare the reduction of subjective complaints by 3 treatment strategies in 90 "amalgam patients" whose complaints could not be explained by a medical or psychological disorder. The individuals were randomly assigned either to removal of dental amalgam only (removal group), or removal in combination with a "biological detoxification" therapy with high doses of vitamins and trace elements (removal-plus group), or participation in a health promotion program without removal of dental amalgam (no-removal group). Between baseline and month 12, the sum score of main complaints decreased by 3.5 (SD=2.2) points on average in the removal group as well as in the removal-plus group, and by 2.5 (SD=2.4) points in the no-removal group (p=0.152). Both removal groups showed a significant decrease in steady-state levels of inorganic mercury compared with the no-removal group. Thus, all 3 interventions were associated with clinically relevant improvements.

Blood and urine mercury levels in adult amalgam patients of a randomized controlled trial: interaction of Hg species in erythrocytes.

UNLABELLED: Parts of the population are permanently exposed to low levels of Hg degrees and Hg(II) from dental amalgam. It was the aim (1) to investigate the internal exposure to amalgam-related mercury from the kinetics of inorganic Hg in plasma and erythrocytes after amalgam removal, and (2) to estimate the amalgam-related absorbed dose. Dietary coexposure was monitored by determination of blood organic-Hg. Postremoval steady-state Hg concentrations were measured for 18 months. Eighty-two patients had been randomized into three groups: (A) removal of the fillings; (B) removal and non-specific detoxification, and (C) a health promotion program without removal. After amalgam removal, inorganic Hg dropped rapidly in plasma and red cells, stabilizing at 27% of preremoval levels after 60 days. Concentrations of organic Hg in plasma remained unchanged, indicating no change in dietary uptake of organic Hg. The concentration of organic Hg in red cells of group A was in the early postremoval phase lower and in the late postremoval phase higher than the preremoval control (p<0.01 for low-high difference). A protracted increase in organic Hg was also found in red cells of group B after 60 days. Thus, the effect of removal on organic Hg levels in the combined group A+B was compared with the values of group C in a linear mixed effects (LME) model which showed a significant increase with time in group A+B (p=0.028). In all groups, time profiles of urinary concentration and excretion of total-Hg were very similar to those of inorganic-Hg levels in plasma. From extrapolations of blood and urine data it was estimated that the amalgam-related inhalation and ingestion of Hg species were within the limits proposed by WHO, ATSDR and EPA. The integrated daily Hg dose absorbed from amalgam was estimated up to 3 microg for an average number of fillings and at 7.4 for a high amalgam load. CONCLUSIONS: This is the first study on adult amalgam patients which continuously monitored the postremoval decline of inorganic Hg and the coexposure from dietary organic Hg in a randomized-controlled-trial design. The integrated daily dose of 7.4 microg absorbed from a high amalgam load is well below the tolerable dose of 30 microg (WHO, 1990). The unexpected postremoval increase in erythrocyte organic Hg, which is associated with the depletion of cellular inorganic Hg, might result from binding of organic Hg to cellular sites previously occupied by inorganic Hg.

Lessons to be learnt from organophosphorus pesticide poisoning for the treatment of nerve agent poisoning.

The increasing threat of nerve agent use for terrorist purposes against civilian and military population calls for effective therapeutic preparedness. At present, administration of atropine and an oxime are recommended, although effectiveness of this treatment is not proved in clinical trials. Here, monitoring of intoxications with organophosphorus (OP) pesticides may be of help, as their actions are closely related to those of nerve agents and intoxication and therapy follow the same principles. To this end, the clinical course of poisoning and the effectiveness of antidotal therapy were investigated in patients requiring artificial ventilation being treated with atropine and obidoxime. However, poisoning with OP pesticides shows extremely heterogeneous pictures of cholinergic crisis frequently associated with clinical complications. To achieve valuable information for the therapy of nerve agent poisoning, cases resembling situations in nerve agent poisoning had to be extracted: (a) intoxication with OPs forming reactivatable OP-AChE-complexes with short persistence of the OP in the body resembling inhalational sarin intoxication; (b) intoxication with OPs resulting rapidly in an aged OP-AChE-complex resembling inhalational soman intoxication; (c) intoxications with OPs forming a reactivatable AChE-OP complex with prolonged persistence of the OP in the body resembling percutaneous VX intoxication. From these cases it was concluded that sufficient reactivation of nerve agent inhibited non-aged AChE should be possible, if the poison load was not too high and the effective oximes were administered early and with an appropriate duration. When RBC-AChE activity was higher than some 30%, neuromuscular transmission was relatively normal. Relatively low atropine doses (several milligrams) should be sufficient to cope with muscarinic symptoms during oxime therapy.

[Poisoning by the autumn crocus plant]. / Verwechslungsgefahr im Frühjahr: Bärlauch und Herbstzeitlose. Warnen Sie lhre Patienten vor dem tödlichen Salat!

Confirmed cases of poisoning resulting from the ingestion of Colchicum autumnale in mistake for Allium ursinum were analysed retrospectively. The study included 32 patients between 27 and 90 years. The severity of the intoxication was graded on the basis of the poisoning severity score (PSS). All the patients developed diarrhea and/or vomiting after a latency period of between 2 and 24 h. All those patients with a latency of > 9 h suffered only mild poisoning. If the leaves were boiled before being eaten, 64% of the patients suffered moderate, severe or fatal poisoning; when the leaves were eaten raw, only 33%. It is presumed that heating may promote the liberation of colchicines from the plant. Eight of the nine patients with severe or fatal poisoning were older than 65 years. A possible cause of the more serious course in the elderly may be a decrease in renal clearance. In addition, a diminished sense of smell may allow the absence of the typical garlic smell and taste of Allium ursinum to go unrecognised.

[The development of a toxic megacolon due to Amanita phalloides poisoning. A rare complication]. / Die Entwicklung eines toxischen Megakolons bei Knollenblätterpilzvergiftungen - Eine ungewöhnliche Komplikation -

HISTORY: A 71-year-old previously healthy man consumed a mushroom meal containing Amanita phalloides, which he had confused with Agaricus campestris. Approximately 8 hours later, typical gastrointestinal symptoms began with copious loss of fluids. Treatment with penicillin G was initiated followed by a continuous silibinin infusion before the patient was transferred to our toxicological department. Other than a transient tachycardia and diffuse pain on abdominal palpation clinical examination was without abnormal findings. INVESTIGATIONS: Laboratory findings showed severe hepatic damage with 100-fold increased transaminases, elevation of serum creatinine, hyperbilirubinemia and a serious disturbance of coagulation. Infection with HIV, hepatitis- and CMV as well as pathogenic enteric bacteria and antibiotic-associated pseudo-membranous colitis were excluded. 11 days after the mushroom meal x-ray of abdomen showed a 6 cm dilatation of the small intestine and an 8 cm dilatation of the colon. DIAGNOSIS AND TREATMENT: Although clinical condition and laboratory findings nearly fulfilled transplantation criteria, hepatic injury resolved during intensive care therapy. Intractable diarrhea, dilatation of the intestine on x-ray as well as other findings met criteria of toxic megacolon. Therapy with antibiotics and systemic steroids was ineffective, so the patient needed decompression by a catheter, which was placed by colonoscopy. 30 days after the serious amanita poisoning complicated by development of toxic megacolon, the patient's condition resolved without sequelae and he was discharged. CONCLUSIONS: In addition the well known complications of amanita-poisoning, such as hepatic failure, encephalopathy and multi-organ failure, involvement of other organs like bone marrow, pancreas, kidney and gastrointestinal tract (except for the initial cholera-like gastroenteritis) are not well documented in the literature. Uncommon complications like toxic megacolon require an empirical approach.

Stable tracer investigations in humans for assessing the biokinetics of ruthenium and zirconium radionuclides.

The interest in the biokinetics of ruthenium and zirconium in humans is justified by the potential radiological risk represented by their radionuclides. Only a few data related to the biokinetics of ruthenium and zirconium in humans are available and, accordingly, the biokinetic models currently recommended by the ICRP for these elements are mainly based on data from animal experiments. The use of stable isotopes as tracers, coupled with a proper analytical technique (nuclear activation analysis with protons) for their determination in biological samples, represents an ethically acceptable methodology for biokinetic investigations, being free from any radiation risk for the volunteer subjects. In this work, the results obtained in eight biokinetic investigations for ruthenium, conducted on a total of three healthy volunteers, and six for zirconium, performed on a total of three subjects, are presented and compared to the predictions of the ICRP models.

Assessment of intestinal absorption of trace metals in humans by means of stable isotopes.

This study is aimed to demonstrate the feasibility of stable isotopes for the assessment of reliable data on fractional intestinal absorption of trace metals in healthy humans. Among the various methods available, the double isotope technique, i.e. one isotope given orally together with the test substance to be investigated and another isotope injected intravenously to correct for retention and endogenous excretion of the particular trace metal, provides quantitative figures of intestinal absorption at reasonable expenses with regard to costs for materials and number of samples to be evaluated. The trace metals exemplarily included in this study, i.e. iron, cobalt and molybdenum show diverging relations between absorbed fractions and amounts administered which are indicative for different regulatory mechanisms of their body content. Food ligands influence the fractional absorption significantly so that the uptake from a composite meal cannot be derived from results on uptake from particular foodstuffs. Therefore, validated data on the behaviour of intestinal absorption will significantly contribute to a better understanding of human trace metal metabolism.

Internal biokinetic behaviour of molybdenum in humans studied with stable isotopes as tracers.

Although molybdenum is considered to be an essential trace metal for humans, the knowledge about its metabolism is rather limited. The present study was aimed at the assessment of biokinetics following intravenous injection of trace amounts of 95Mo or 96Mo into five healthy volunteers. In a total of 11 investigations, the plasma clearance up to eight hours and the urinary excretion for at least three days after the injection were evaluated. The tracer concentrations were determined by proton nuclear activation analysis in blood plasma and by thermal ionization mass spectrometry in urine samples respectively. In all subjects, the plasma clearance is much faster than expected from the literature. The data obtained for the plasma clearance of the tracer can reasonably be fitted by a two exponential equation. The half times of the fast component range between 4 and 70 minutes and for the slow component between 3 and 30 hours. The urinary excretion of the injected tracer seems also to be faster than expected and the fractions lost are higher for larger doses administered. For the smallest dose given, 34% of the injected tracer were excreted within one day whereas for the four times larger dose about 60% were lost. These findings on urinary excretion are in agreement with recently published results.

[Metformin-induced lactic acidosis]. / Metformin-induzierte Laktatazidose.

HISTORY AND ADMISSION FINDINGS: A 62-year-old woman had been found unconscious on her bed. She had to be resuscitated several times in the ambulance on the way to hospital. On admission her pupils were dilated and fixed, the cardiovascular system was unstable. Her rectal temperature was 28 degrees C. She was a diabetic being treated with metformin and glimepiride and was in incipient renal failure (serum creatinine 1.5 mg/dl). She was also in heart failure due to coronary heart disease and was in a debilitated state. INVESTIGATIONS: She had marked lactic acidosis (lactate 45.3 mmol/l; pH 6.6). Toxicological screening tests were negative. TREATMENT AND COURSE: In the absence of a history she was at first treated symptomatically. Conventional management of the lactic acidosis neither corrected the acidosis nor stabilized the circulatory system. Continuous veno-venous haemodialysis with bicarbonate-buffered solutions succeeded in reducing the need for catecholamines. Neurological examination was supplemented by recording acoustic and sensory evoked potentials. Suspected metformin-induced lactic acidosis was confirmed by appropriate tests. Three weeks after admission she was well enough to be transferred to a normal medical ward and ultimately discharged without further complications. CONCLUSION: Metformin should only be prescribed if the contraindications, in particular renal failure are carefully monitored. Severe lactic acidosis should be treated early with continuous veno-venous haemodialysis with bicarbonate-buffered substituting fluids. The good neurological results in this case are probably largely due to the marked hypothermia.

Intoxication with huperzine A, a potent anticholinesterase found in the fir club moss.

BACKGROUND: Herbs from Lycopodium are generally reputed to be nontoxic and are occasionally used for preparing a salubrious tea. In Europe, the common Lycopodium clavatum can be easily confused with Lycopodium selago, the fir club moss. CASE REPORT: We report 2 patients who drank a tea, erroneously prepared from dried herbs of Lycopodium selago, which resulted in sweating, vomiting, diarrhea, dizziness, cramps, and slurred speech. These symptoms were suggestive of a cholinergic mechanism. To elucidate the active principle, aqueous extracts of Lycopodium selago were checked for their suspected anticholinesterase activity using human erythrocytes as an enzyme source in a modified Ellman assay. The extracts did exhibit significant anticholinesterase activity. The anticholinesterase(s) were most effectively extracted with dichloromethane and isolated by high-performance liquid chromatography. The major compound with anticholinesterase activity co-chromatographed with authentic huperzine A, but had a 2-3-fold higher inhibitory potency than the racemic standard. The amount of huperzine A found in the Lycopodium selago sample used for the tea preparation was calculated to be sufficient for a relevant acetylcholinesterase inhibition. CONCLUSION: The signs and symptoms of Lycopodium selago poisoning are consistent with the anticholinesterase activity of huperzine A and should favorably respond to atropine therapy. This report demonstrates once more that laymen should not be encouraged to gather their remedies from "Mother Nature" without advanced botanical knowledge.

Modern strategies in therapy of organophosphate poisoning.

Considering the various microscopic reactions as well as toxicokinetic and pharmacokinetic principles in therapy of organophosphate poisoning, the administration of obidoxime by an initial bolus dose followed by continuous infusion appears rational. Using this protocol, six patients each with parathion or oxydemeton methyl poisoning were treated. In parathion poisoning, reactivation was possible up to 7 days. At paraoxon concentrations > 0.1 microM obidoxime only partially reactivated acetylcholinesterase (AChE) of erythrocytes in vivo although reactivation could be assessed in vitro, which roughly fitted theoretical calculations. AChE-inhibitory material was detected up to 5 days. Cholinergic signs soon subsided when AChE was above 20% of normal, and atropine plasma levels could be kept below 7 ng/ml. In one patient brain damage persisted. Oxydemeton methyl poisoning responded to obidoxime therapy only when the oxime was instituted shortly after poisoning. Out of six patients one died. No intermediate syndrome and no signs of permanent hepatic dysfunction were found in the 12 patients.

Cholinesterase status, pharmacokinetics and laboratory findings during obidoxime therapy in organophosphate poisoned patients.

1 The effectiveness of oxime therapy in organophosphate poisoning is still a matter of debate. It appears, however, that the often cited ineffectiveness of oximes may be due to inappropriate dosing. By virtue of in vitro findings and theoretical considerations we concluded in the preceding paper that oximes should preferably be administered by continuous infusion following an initial bolus dose for as long as reactivation of inhibited acetylcholinesterase (AChE) can be expected. This conclusion has called for a clinical trial to evaluate such oxime therapy on the basis of objective parameters. 2 Before transfer to the intensive care unit (ICU), 5 patients received primary care by an emergency physician. In the ICU, atropine sulphate was administered i.v. upon demand according to the endpoints: no bronchorrhoea, dry mucous membranes, no axillary sweating, heart rate of about 100/min. Obidoxime (Toxogonin) was given as an i.v. bolus (250 mg) followed by continuous infusion of 750 mg/24 h. 3 Intoxication and therapy were monitored by determining erythrocyte AChE (eryAChE) activity, reactivatability of the patient's eryAChE ex vivo, plasma cholinesterase activity, the presence of AChE inhibiting compounds, as well as the concentrations of obidoxime and atropine in plasma. 4 Obidoxime was effective in life-threatening parathion poisoning, in particular when the dose absorbed was comparably low. In mega-dose poisoning, net reactivation was not achieved until several days after ingestion, when the concentration of active poison in plasma had declined. Reactivatability in vivo lasted for a longer period than expected from in vitro experiments. 5 Obidoxime was quite ineffective in oxydemetonmethyl poisoning, when the time elapsed between ingestion and oxime therapy was longer than 1 day. When obidoxime was administered shortly after ingestion (1 h) reactivation was nearly complete. 6 Obidoxime levels of 10-20 microM were achieved by our regimen, and atropine could rapidly be reduced to approx. 20 microM, as attained by continuous infusion of 1 mg atropine sulphate/h. Maintenance of the desired plasma levels was not critical even when renal function deteriorated. 7 Signs of transiently impaired liver function were observed in patients who showed transient multiorgan failure. In the present stage of knowledge, we feel it advisable to keep the plasma concentration of obidoxime at 10-20 microM, although the full reactivating potential of obidoxime will not then be exploited. Still, the reactivation rate, with an apparent half-time of some 3 min, is twice that estimated for a tenfold higher pralidoxime concentration.