Dirk Deleu

Subcutaneous apomorphine: An evidence-based review of its use in Parkinson's disease

Apomorphine, a short-acting dopamine D1 and D2 receptor agonist, was the first dopamine receptor agonist used to treat Parkinson’s disease. Subcutaneous apomorphine is currently used for the management of sudden, unexpected and refractory levodopa-induced ‘off’ states in fluctuating Parkinson’s disease either as intermittent rescue injections or continuous infusions. Other indications include the challenge test for determining the dopaminergic responsiveness and finding the appropriate dose of the drug in intermittent subcutaneous administration.Except for a rapid on- and offset of the antiparkinsonian response with subcutaneous apomorphine, the magnitude and pattern of the motor response to single dose of subcutaneously administered apomorphine is qualitatively comparable to that of oral levodopa. Seventy-five percent of patients achieve a clinically significant improvement with a dose of apomorphine 4mg.The efficacy of intermittent subcutaneous apomorphine injections as an add-on to levodopa therapy in advanced Parkinson’s disease was explored in one short-term, randomised, double-blind, placebo-controlled trial, one short-term and six long-term, open-label, uncontrolled studies, including a total of 195 patients. These studies provide evidence that this mode of administration was successful in aborting ‘off’ periods and improving Parkinson’s disease motor scores, but tended to increase dyskinesias. No levodopa-sparing effect was observed.Eleven long-term, open-label, uncontrolled studies, including a total of 233 patients evaluated the efficacy of continuous subcutaneous apomorphine infusions in monotherapy or as an add-on to levodopa therapy in advanced Parkinson’s disease. These studies proved that subcutaneous apomorphine infusions are successful in aborting ‘off’ periods, reducing dyskinesias and improving Parkinson’s disease motor scores with the added benefit of a substantial levodopa-sparing effect.The apomorphine challenge test has at least 80% overall predictive ability to clinically diagnose Parkinson’s disease across the different stages of the disease and parkinsonian syndromes. Similarly, those data also indicate that the apomorphine challenge test has a >80% ability to predict dopaminergic responsiveness across all stages of Parkinson’s disease.Adverse events are usually mild and consist predominantly of cutaneous reactions and neuropsychiatric adverse effects. The incidence of adverse effects is higher in patients receiving continuous infusion than in those receiving intermittent pulsatile administration.Based on the results of these studies it is recommended that subcutaneous apomorphine either as intermittent injections or continuous infusions should be offered to any suitable Parkinson’s disease patient who has difficulties in his/her management with conventional therapy. Low-dose levodopa therapy in combination with waking-day hours subcutaneous apomorphine infusion would probably be the most efficient treatment. Continuous subcutaneous apomorphine infusions should be evaluated before more invasive measures or neurosurgical interventions are contemplated.

Familial Progressive Sensorimotor Neuropathy with Agenesis of the Corpus callosum (Andermann Syndrome): A Clinical, Neuroradiological and Histopathological Study

Three siblings from consanguineous parents, originating from Tanzania, presented with symptoms of complete or partial agenesis of the corpus callosum. Two males had in addition a sensorimotor neuropathy, moderate mental retardation and skeletal dysmorphism (Andermann syndrome). A study of sural nerve biopsies revealed thickening of the perineurium and reduction in the number of large myelinated fibres with axonal degeneration. Muscle biopsies showed neurogenic atrophy. The Andermann syndrome is autosomal recessive and almost exclusively confined to the region of Charlevoix and Saguenay-Lac-St-Jean (Quebec, Canada). Moreover in families with the Andermann syndrome, no siblings with only agenesis of the corpus callosum have been described.

Quantitative Microdialysis for Studying the in Vivo L-DOPA Kinetics in Blood and Skeletal Muscle of the Dog

In this study the microdialysis technique, using α-methyldopa as internal standard (IS), is introduced for the in vivo determination of L-DOPA, dopamine (DA), and their metabolites dihydroxyphenylacetic acid (DOPAC) and 3-O-methyldopa (3-OMD) in blood plasma and skeletal muscle extracellular fluid (ECF), in anaesthetised beagle dogs, after i.v. administration of L-DOPA. In a first calibration experiment, the in vivo relative losses (RL) of the compounds and the IS were determined. These were lower in skeletal muscle than in blood plasma. K was defined as the ratio of the RL of the IS to the RL of the compound of interest and was shown to be constant for a certain compound within one tissue. However, except for DA, a significant difference was seen in K values between blood plasma and skeletal muscle. In a second step, the method was validated in blood plasma. The AUC0→3values for the non-protein bound L-DOPA did not differ significantly between the dialysis (141.3 ± 16.0 nmol.h/ml) and traditional whole blood sampling (145.3 ± 18.7 nmol.h/ml), confirming that microdialysis combined with accurate calibration is a reliable technique for studying the kinetics of drugs in vivo in different tissues.

Simultaneous monitoring of levodopa, dopamine and their metabolites in skeletal muscle and subcutaneous tissue in different pharmacological conditions using microdialysis☆

Microdialysis, in combination with ion-pair reversed-phase liquid chromatography and electrochemical detection is described for the simultaneous determination of levodopa, dopamine, 3-O-methyldopa and 3,4-dihydroxyphenylacetic acid in the extracellular space of skeletal muscle and subcutaneous tissue in vivo in beagle dog. The relative recoveries in vitro for levodopa, dopamine, 3-O-methyldopa and 3,4-dihydroxyphenylacetic acid with a 16 mm probe at a flow rate of 5 microliters min-1 were 29.1, 25.1, 34.7 and 30.1%, respectively. This technique was then applied for three types of pharmacological experiments. In the first experiment L-dopa was administered without carbidopa pretreatment, in the second one, L-dopa was administered following carbidopa pretreatment, and in the last experiment, following pretreatment with both carbidopa and the catechol-O-methyltransferase inhibitor, OR-611. After the administration of levodopa without carbidopa pretreatment, all four compounds could be detected in dialysates from skeletal muscle, whereas dopamine and 3,4-dihydroxyphenylacetic acid were not found in dialysates from subcutaneous tissue. After the administration of levodopa following carbidopa pretreatment and following pretreatment with both carbidopa and OR-611 all compounds could be measured except for dopamine. This method enables the pharmacokinetics and metabolism of levodopa to be studied in subcutaneous tissue and skeletal muscle simultaneously.

Toluene induced postural tremor

We read with interest the article by Miyagi et al 1 and comment on the medical treatment of toluene induced tremor. Microdialysis experiments in rats have shown that inhalation of toluene increases extracellular γ-aminobutyric acid (GABA) concentrations within the cerebellar cortex2 which probably explains why GABA agonists including benzodiazepines (for example, clonazepam) are not very effective in toluene induced tremor and ataxia. Rat experiments also showed a 50% reduction in …

Continuous intravenous monitoring of levodopa and 3-O-methyldopa by microdialysis and high-performance liquid chromatography with electrochemical detection

Microdialysis, in association with ion-pair reversed-phase high-performance liquid chromatography with electrochemical detection, was applied in vitro for the determination and quantification of levodopa and 3-O-methyldopa in blank spiked plasma and blood. The method presented gave accurate results; the calibration graphs for plasma were linear over the range of the expected values for both compounds. When using a dialysis probe with a membrane length of 1.6 cm at a 5 microliters min-1 perfusion speed, the recovery rate in plasma for levodopa was 30.1% and 68.5% for 3-O-methyldopa. However, less reproducible results were obtained for plasma levodopa levels in the range of 0.5 microliter ml-1 and lower. The microdialysis technique was subsequently successfully applied for the continuous intravenous monitoring of levodopa and 3-O-methyldopa in a levodopa-treated dogs.

In-vivo microdialysis sampling in pharmacokinetic studies

Abstract Microdialysis sampling is a powerful technique for studying in-vivo pharmacokinetics and the metabolism of drugs. Introduction of a dialysis membrane into a blood-vessel or tissue allows the collection of small molecules from the extracellular space. Several calibration methods are discussed as well as the analytical challenges involved with this technique. The application to blood and muscle are demonstrated for studies of the in-vivo pharmacokinetics and biotransformation Of L-DOPA in dog.

Extrapontine Myelinolysis-Induced Parkinsonism in a Patient with Adrenal Crisis

Background. Extrapontine myelinolysis (EPM) has been well described in the presence of rapid correction of hyponatremia. It is seldom reported with adrenal insufficiency. We report a unique case where a patient developed EPM as a result of adrenal insufficiency where the brain MRI revealed symmetrical lesion in the basal ganglia with pallidal sparing. Case Report. A 30-year-old gentleman with panhypopituitarism developed adrenal crisis, hyponatremia, and hyponatremic encephalopathy. Seven days after the rapid correction of hyponatremia, he developed parkinsonism and neuropsychiatric symptoms. MRI showed extrapontine myelinolysis without central pontine myelinolysis. Conclusion. Extrapontine myelinolysis without central pontine myelinolysis is rare and should raise a concern of associated adrenal insufficiency in the right clinical setting. Rapid correction of hyponatremia particularly in steroid-deficient states should be avoided as it can predispose to extrapontine myelinolysis. Magnetic resonance imaging is very helpful in supporting the diagnosis of EPM.

COMA as presenting manifestation of Wernicke's encephalopathy

A patient in whom coma was the presenting manifestation of Wernickes encephalopathy is reported. Clinical reports on coma in Wernickes encephalopathy are scarce, but postmortem studies have demonstrated that this form of presentation is often not recognized. The diagnosis of Wernickes encephalopathy should be suspected in any patient presenting with coma of unclear etiology.

Dissociated ipsilateral horizontal gaze palsy in one‐and‐a‐half syndrome A clinicopathologic study

We report a patient with a one-and-a-half syndrome due to an isolated small infarction in the left rostral part of the paramedian pontine reticular formation and the ipsilateral medial longitudinal fasciculus. Oculocephalic movements toward the left were preserved (dissociated ipsilateral horizontal conjugate gaze palsy).