ANNIVERSARY REVIEW: 50 years since the discovery of bromocriptine.

Ergotism is the long-term ergot poisoning by ingestion of rye or other grains infected with the fungus Claviceps purpurea and more recently by excessive intake of ergot drugs. It has either neuropsychiatric or vascular manifestations. In the Middle Ages, the gangrenous poisoning was known as St. Anthony's fire, after the order of the Monks of St. Anthony who were particularly skilled at treating the condition. In 1917, Prof. Arthur Stoll returned home to Switzerland from Germany, to lead the development of a new pharmaceutical department at Sandoz Chemical Company. Stoll, using the special methods of extraction learned from his work with his mentor Willstetter, started his industrial research work with ergot. He succeeded in isolating, from the ergot of rye, ergotamine as an active principle of an old popular remedy for excessive post-partum bleeding. The success of this discovery occurred in 1918 and was translated into a pharmaceutical product in 1921 under the trade name Gynergen. In subsequent work, Stoll and his team were leaders in identifying the structure of the many other alkaloids and amines produced by Claviceps purpurea This was the cultural background and scientific foundation on which bromocriptine was discovered.

A fatal intoxication case involving ropinirole.

Ropinirole, a specific non-ergoline dopamine D2-receptor agonist, belongs to the drugs applied in treatment of Parkinson's disease (PD) and restless legs syndrome (RLS) and acts as a D2, D3, and D4 dopamine receptor agonist with highest affinity for D3. Therapeutic ropinirole plasma levels in adults are defined between 0.4 and 6 ng/mL. This case report documents a fatal intoxication involving ropinirole. Information about lethal ropinirole concentrations is hitherto lacking in the literature and the assessed ropinirole levels of this case may present a step towards defining potentially lethal concentrations. A 37-year-old man without medical history was found dead in a converted van used as place of residence and an autopsy was performed. The pathological findings did not reveal an apparent cause of death but the toxicological analysis revealed the presence of ropinirole, paracetamol, and alcohol in the peripheral blood sample. Quantitative analysis revealed that ropinirole was present at a peripheral blood concentration of 64 ng/mL. The ropinirole concentrations determined in vitreous humor, urine and bile were respectively, 11 ng/mL, 2670 ng/mL and 826 ng/mL. Paracetamol was detected at a blood level of <2 µg/mL. Based on the autopsy findings and toxicological results, the cause of death was primarily attributed to intoxication with ropinirole in combination with alcohol.

Cardiotoxicity after massive amantadine overdose.

INTRODUCTION: Amantadine hydrochloride is an antiviral medication used as therapy for parkinsonism and as a cognitive enhancer. We report 2 cases of massive, acute ingestion of amantadine hydrochloride confirmed with serial serum levels. CASE REPORTS: A 47-year-old woman presented to the emergency department (ED) 30 minutes after ingesting 10 g of amantadine (150 mg/kg) by her report. Initial ECG revealed a sinus rhythm with rate of 93 bpm, and a QRS of 84 msec. While in the ED, the patient sustained a pulseless cardiac arrest and the monitor revealed ventricular tachycardia. She was successfully defibrillated. Postdefibrillation ECG showed a sinus rhythm (rate = 82 bpm), QRS of 236 msec, and QTc of 567 msec. The serum potassium was 1.0 mEq/L (1.0 mmol/L). The patient was given 300 ml (300 cc) 3% sodium chloride IV over 10 minutes. Ten minutes after completion of the hypertonic saline infusion, the patient's ECG abnormalities resolved and the QRS was 88 msec. Her potassium was repleted over the next 11 hours postpresentation, and she also received an IV bolus of 4 g of magnesium sulfate immediately after the cardiac arrest. No further hypotension, dysrhythmia, conduction delay, or ectopy was noted during the patient's hospital stay. The second case involved a 33-year-old female patient who presented 1 hour after ingesting 100 tablets of amantadine hydrochloride (100 mg/tab). Initial ECG revealed sinus tachycardia with a QRS of 113 msec, an R wave in lead aVR of 4-5 mm and a QTc of 526 msec. Her serum potassium was 3.0 mEq/L (3.0 mmol/L), her serum calcium was 9.4 mg/dl (2.35 mmol/L), and serum magnesium was 2.1 mg/dl (0.86 mmol/L) on labs drawn at initial presentation. The patient was intubated for airway protection, and her potassium was repleted and corrected over the next 9 hours. Her ECG abnormalities improved 8 hours after initial presentation and normalized at approximately 14 hours postingestion. The patient was discharged home 11 days after her ingestion. CONCLUSION: Acute amantadine toxicity manifests with life-threatening cardiotoxicity. Concurrent, often profound, hypokalemia may complicate the administration of sodium bicarbonate in the management of cardiac dysrhythmias.

Fatal intoxication using amantadine and pramipexole in a uremic patient.

We report a fatal intoxication in a 59-year-old woman who had uremia undergoing hemodialysis, and then took amantadine and pramipexole for Parkinsonian tremor. Toxic manifestation includes myoclonus, ataxia, confusion and sudden death. This report highlights the fact that using amantadine and pramipexole may be fatal in patients with uremia even undergoing hemodialysis.

Acute overdose with controlled-release levodopa-carbidopa.

INTRODUCTION: Reports of acute levodopa-carbidopa overdose are rare and no case of an acute overdose with a controlled-release formulation has been described. We describe such a case in which serial concentrations of catecholamines were measured. CASE REPORT: A 55-year-old man ingested 89 tablets of Sinemet 50/200 (17.8 g of levodopa, 4.45 g of carbidopa). Clinical effects and plasma concentrations of dopamine, noradrenaline and adrenalin were assessed over 66 hours. On admission 2.5 hours after the ingestion, his physical examination was normal except for mydriasis and urine retention. Five hours post-ingestion he had psychomotor agitation, delirium with logorrhea, joviality, visual hallucinations, regular sinus tachycardia and xerostomia. The clinical course included two episodes hypotension and four of transient tachycardia. Treatment was symptomatic and supportive. Clinical toxicity reappeared 48 hours after the intoxication. The patient was discharged at the end of the fourth day with amnesia for the event. DISCUSSION: Dopamine showed an initial plasma concentration peak 14 hours after the toxic ingestion, followed by a second peak 38 hours after the ingestion. The initial peak of noradrenaline occurred 20 hours post-ingestion with a second lower peak at 38 hours. There were no elevations in adrenalin concentrations. CONCLUSION: There appeared to be no correlation between the intensity of the clinical signs and the blood concentrations of dopamine and noradrenaline, although the resolution of the clinical signs did correspond to these catecholamines return to normal values. Patients who ingest controlled-release formulations need to be observed until after the second catecholamine peak.

A fatal overdose of the ergot derivative cabergoline.

A 79-year-old woman, with Parkinson's disease treated with cabergoline, was admitted to a hospital due to jaundice and weakness. She was found confused, absent minded, and died after 2 weeks. Autopsy showed an extrahepatic bile duct adenocarcinoma with spread to the gall bladder, the liver, and regional lymphnodes. While cleaning the hospital bed after her death, the nurses found several tablets hidden in the bed. Biological samples obtained at the autopsy were screened for common drugs and narcotics. Several drugs such as buprenorphine, codeine, paracetamol, and propranolol were detected in the blood at therapeutic levels. A method to determine cabergoline in whole blood and other forensic matrices was developed, and further investigations determined cabergoline concentrations in whole blood and liver tissue of 94 and 3100 microg/kg, respectively. The blood concentration was 100 times above the therapeutic level reported on cabergoline in plasma and in combination with her symptoms, suggest she took a fatal overdose of cabergoline.

Fatal benztropine toxicity.

Benztropine is an anticholinergic agent used in the treatment of Parkinson's disease and drug induced extrapyramidal disorders. We report a case of fatal benztropine toxicity. This drug is regarded as relatively safe and reports of isolated toxicity are scarce. In ascribing a particular death to fatal drug toxicity the forensic pathologist must take into account the circumstances surrounding the death, the presence and significance of any co-existent natural disease and the potential contribution of any other detected therapeutic or illicit agents. This interpretation will occur in the knowledge that certain drugs will not be detected and that with respect to quantification of postmortem drug levels, the notion of postmortem redistribution should always be considered.

Abuso y dependencia de fármacos antiparinsonianos / Anti-parkinson drugs: abuse and dependence

Objetivo: analizar los factores de riesgo asociados al abuso y dependencia de benzodiacepinas. Material y métodos: revisión de los estudios publicados en los que se analizan distintos factores de riesgo asociado al abuso y dependencia de benzodiacepinas. Resultados: son varios los factores que influyen para que un paciente abuse y/o se haga dependiente de las benzodiacepinas. En cada paciente es preciso evaluar la relación beneficio/riesgo antes de prescribir este grupo de fármacos. Conclusiones: las benzodiacepinas continúan siendo los fármacos de elección de distintos procesos como la ansiedad y el insomnio. Sin embargo no debe minimizarse el potencial de riesgo de abuso y dependencia de estos fármacos. Desde el punto de vista de las políticas de salud, la regulación efectiva del uso de los medicamentos depende básicamente de si la medicación prescrita tiene un beneficio terapéutico que sobrepase los riesgos de salud que pueda presentar (AU)

Orphenadrine poisoning in a child: clinical and analytical data.

Orphenadrine is an anticholinergic drug used mainly in the treatment of Parkinson's disease. It has a peripheral and central effect and a known cardiotoxic effect when taken in large doses. We report the successful outcome of the treatment of a 2 1/2-year-old girl who accidentally ingested 400 mg of orphenadrine hydrochloride (Disipal). One hour after ingestion she presented neurological symptoms: confusion, ataxic walking, and periods of severe agitation. Generalized tonic-clonic seizures appeared resistant to the administration of multiple antiepileptics. They ceased after a supplementary dose of intravenous diazepam, endotracheal intubation, and mechanical ventilation. An episode of ventricular tachycardia responded well to i. v. lidocaine. Physostigmine was administered in three successive doses. The initial orphenadrine plasma level (3,55 microg/ml) was in the toxic range, associated with high mortality. The calculated elimination half-life was 10.2 h and the molecule and/or its metabolites were found up to 90 h after ingestion.

[Fatalities caused by anticholinergic antiparkinsonian drugs. Analysis of findings in a 11-year national material]. / Dødsfall forårsaket av antikolinerge antiparkinsonmedikamenter. Analysefunn i et nasjonalt 11-årsmateriale.

All autopsy samples received at the National Institute of Forensic Toxicology during the years 1986-1996 which contained anticholinergic antiparkinsonian drugs were reviewed. Of a total of 69 cases, orphenadrine was present in 57 (83%), biperiden in 8 (12%), procyclidine in 3 (4%), and trihexyphenidyl/benzhexol in 1 (1%) of the subjects. The measured concentrations were assessed in light of previously published data. Of 21 cases where causality between drug ingestion and death was classified as either highly probable (18/21) or possible (3/21), all subjects tested positive for orphenadrine. In the autopsy samples from these patients, orphenadrine concentrations in the 4.5-600 mumol/l range (mean 62.5 mumol/l, SD 126.5 mumol/l) were determined. Because of a low national autopsy rate, there is reason to believe that the actual numbers of drug-related deaths in this period may have been significantly higher. It is concluded that orphenadrine is responsible for a disproportionally high number of overdose deaths.

[Clinical pharmacology of anticholinergic antiparkinson agents. A review with emphasis on acute toxicity]. / Antikolinerge antiparkinsonmedikamenters kliniske farmakologi. En oversikt med vekt på akutt toksisitet.

Today, anticholinergic antiparkinsonian drugs are primarily used to ameliorate extrapyramidal side-effects induced by neuroleptic agents. Orphenadrine dominates quantitatively among these drugs in Norway, presumably because it is assumed to carry a lower risk of abuse. There are numerous reports of deaths following orphenadrine overdoses. Orphenadrine has complex pharmacokinetic properties and a narrow therapeutic index. After an overdose, it confers toxic effects of rapid onset to several organ systems. No specific and effective therapy for orphenadrine intoxication has been established. For the two other drugs in this class which are marketed in Norway, biperiden and benztropine, toxicity is mainly connected to their anticholinergic properties. Notably, no reports of lethalities after overdoses of biperiden seem to be available. A small number of accounts of deaths following benztropine intoxication have been published. Neither of these two agents, and benztropine in particular, has been subjected to comprehensive pharmacokinetic evaluations. The relatively extensive use of orphenadrine should be discouraged.

Glia protect fetal midbrain dopamine neurons in culture from L-DOPA toxicity through multiple mechanisms.

Mesencephalic glia produce soluble factors that protect dopamine neurons from L-DOPA toxicity. The chemical composition of these soluble factors is unknown. We investigated the protective effect against L-DOPA neurotoxicity in midbrain dopamine neurons of fractions of different molecular size of glia conditioned medium and candidate neuroprotective agents produced by glia including neurotrophic factors and antioxidants. Protective effects were evaluated according to the number of tyrosine hydroxylase immunoreactive cells, high affinity dopamine uptake and levels of quinones. Both fractions of glia conditioned medium, smaller and larger than 10kD, protected against L-DOPA, but the fraction of smaller molecular size, that contains small free radical scanvenger molecules, was more effective than the fraction of larger molecular size, that contains large neurotrophic peptides. Among the neurotrophic factors GDNF and BDNF totally prevented L-DOPA neurotoxicity, while NGF and bFGF were less effective. However, only NGF significantly reduced the elevation of quinones induced by L-DOPA. Ascorbic acid, at the concentration found in glia conditioned medium, provided partial protective effect against L-DOPA toxicity. Glutathione, had neurotrophic effects on untreated midbrain dopamine neurons and prevented the effect of L-DOPA. In conclusion, the protective effect against L-DOPA neurotoxicity by glia conditioned medium is mediated by several compounds including neurotrophic factors and small antioxidants.