Sten-Magnus Aquilonius

Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson disease

Objectives: To compare daytime intraduodenal levodopa/carbidopa infusion as monotherapy with individually optimized conventional combination therapies in patients with advanced Parkinson disease (PD) for motor fluctuations and quality of life (QoL). Methods: Twenty-four patients with motor fluctuations and dyskinesia were studied in a randomized crossover design to compare individualized conventional treatment and intraduodenal infusion of a levodopa/carbidopa gel for 3 + 3 weeks. Video scoring of motor function was assessed by blinded assessors on a global Treatment Response Scale from −3 to 0 to +3 (from severe “off” to “on” to “on” with severe dyskinesia). Patient self-assessment of motor performance and QoL was done using an electronic diary. Results: Median percentage of ratings in a functional “on” interval (−1 to +1) was increased from 81 to 100% by infusion therapy (p < 0.01). This improvement was accompanied by a decrease in “off” state (p < 0.01) and no increase in dyskinesia. Median Unified Parkinsons Disease Rating Scale score decreased from 53 to 35 in favor of infusion (p < 0.05). QoL was improved, using the two instruments: Parkinsons Disease Questionnaire-39 and 15D Quality of Life Instrument (p < 0.01). Adverse events were similar for both treatment strategies. Conclusions: Continuous intraduodenal infusion of the levodopa/carbidopa enteral gel as monotherapy is safe and clinically superior to a number of individually optimized combinations of conventional oral and subcutaneous medications in patients with motor fluctuations. Intraduodenal infusion of levodopa offers an important alternative in treating patients with advanced Parkinson disease.

Biochemical changes in Dementia disorders of Alzheimer type (AD/SDAT)

In postmortem investigations of patients with dementia of Alzheimer type (AD/SDAT) (n = 14) the brain weight was significantly reduced when compared to controls (n = 16). In four AD/SDAT-brain parts investigated the concentrations of 5-hydroxy-tryptamine and noradrenaline were significantly reduced while 3-methoxy-4-hydroxyphenylglycol was significantly increased. In the caudate nucleus of the AD/SDAT-brains the concentrations of dopamine and homovanillic acid were significantly reduced. The activity of monoamine oxidase B was increased suggesting a proliferation of extra neuronal tissue in the AD/SDAT-brains. The activity of choline acetyl transferase was reduced in the four brain parts investigated, showing a general reduction in the acetylcholine system in the AD/SDAT-brains. The ganglioside concentration was significantly reduced suggesting a reduced density of nerve endings in the demented brains. The AD/SDAT-group was according to rating scales severely demented. Patients with an early onset of the dementia disease were more severely intellectually reduced and had more pronounced biochemical disturbances than those with a late onset of the dementia.

Optimizing levodopa pharmacokinetics: intestinal infusion versus oral sustained-release tablets.

Continuous duodenal infusion of carbidopa/levodopa has been shown to control motor fluctuations in advanced Parkinsons disease (PD). The authors compared the pharmacokinetics of levodopa and 3-O-methyldopa in patients with advanced PD after administration of an oral sustained-release levodopa preparation and after continuous intestinal levodopa infusion with a new formulation as a gel suspension. A randomized crossover trial was carried out in 12 patients. Carbidopa/levodopa was administered as an oral sustained-release tablet and by nasoduodenal continuous infusion for 3-week periods for each treatment. Plasma levodopa concentrations and motor performance were evaluated every 30 minutes during 3 test days of each treatment period. The average intraindividual coefficient of variation for the plasma levodopa concentrations after oral therapy was 34% and was significantly lower (14%, p < 0.01) during continuous infusion. Hourly video evaluations showed a significant increase in ON time during infusion and a significant decrease in OFF time and dyskinesia. Continuous intraduodenal delivery of a new carbidopa/levodopa formulation offers a means for markedly improved control of motor fluctuations in late stages of PD.

Duodenal levodopa infusion in Parkinson's disease--long-term experience.

Motor fluctuations in parkinsonian patients can be reduced by intraduodenal infusion of levodopa. Between 1991 and 1998 continuous daytime administration of levodopa through a transabdominal port has been used in 28 very advanced patients over a total period of 1045 months. A stable suspension of levodopa and carbidopa (Duodopa®) has been developed. Patients were characterized by early onset, long history of disease and levodopa therapy. The reason for infusion was in all cases related to on–off fluctuations. All patients experienced a general improvement after the introduction of continuous treatment. There have been no severe complications. Six patients have taken the decision to curtail their treatment. The mean daily levodopa consumption has been slightly reduced on infusion as compared to oral therapy. Nine of the first group of patients participating in the new therapy have been regularly evaluated by means of rating scales and movement analyses. Short‐term results have already been published and a follow‐up showing continued positive effect after 4–7 years of continuous duodenal infusion is presented.

In vivo evaluation of striatal dopamine reuptake sites using 11C-nomifensine and positron emission tomography

Abstract In vitro nomifensine demonstrates high affinity and specificity for dopamine reuptake sites in the brain. In the present study 11C‐nomifensine was administered i.v. in trace amounts (10–50μg) to ketamine anaesthetized Rhesus monkeys (6–10 kg b.w.) and the time‐course of radioactivity within different brain regions was measured by positron emission tomography (PET). Six base‐line experiments lasting for 60–80 min were performed. The procedure was repeated after pretreatment with nomifensine (2–6 mg/kg i.v.), another reuptake inhibitor, mazindol (0,3 mg/kg i.v.), desipramine (0.5 mg/kg i.v) or spiperone (0.3 mg/kg i.v.) before the administration of a second 11C‐nomifensine dose. The highest radioactivity uptake was found in the dopamine innervated striatum and the lowest in a region containing the cerebellum, known to be almost devoid of dopaminergic neurons. The difference between striatal and cerebellar uptake of 11C‐nomifensine derived radioactivity was markedly reduced after nomifensine and mazindol but not after desipramine and spiperone. These results indicate that in vivo the striatal uptake of 11C‐nomifensine, as measured with PET, involves specific binding with the dopamine reuptake sites. In the first human applications of 11C‐nomifensine and PET in a healthy volunteer, the regional uptake of radioactivity was similar to that in base‐line experiments with Rhesus monkeys. In the healthy subject the striatal/cerebellar ratio was 1.6, 50 min after the injection of 11C‐nomifensine. In a hemi‐parkinsonian patient this ratio was 1.1 contralaterally and 1.3 ipsilaterally to the affected side. 11C‐nomifensine and PET seems to be an auspicious method to measure the striatal dopaminergic nerve terminals of man in vivo.

Manganese induced brain lesions inMacaca fascicularis as revealed by positron emission tomography and magnetic resonance imaging

A series of positron emission tomography scans was made on two monkeys during a 16-month period when they received manganese(IV)oxide by subcutaneous injection. The distribution of [11C]-nomifensine uptake, indicating dopamine terminals, was followed in both monkey brains. The brain distributions of [11C]-raclopride, demonstrating D2 dopamine receptors, and [11C]-l-dopa, as a marker of dopamine turnover, were followed in one monkey each. The monkeys developed signs of poisoning namely unsteady gait and hypoactivity. The [11C]-nomifensine uptake in the striatum was reduced with time and reached a 60% reduction after 16 months exposure. This supports the suggestion that dopaminergic nerve endings degenerate during manganese intoxication. The [11C]-l-dopa decarboxylation was not significantly altered indicating a sparing of [11C]-l-dopa decarboxylation during manganese poisoning. A transient decrease of [11C]-raclopride binding occurred but at the end of the study D2-receptor binding had returned to starting values. The magnetic resonance imaging (MRI) revealed that the manganese accumulated in the globus pallidus, putamen and caudate nucleus. There were also suggestions of gliosis/edema in the posterior limb of the internal capsule. MRI might be useful to follow manganese intoxication in humans as long as the scan is made within a few months of exposure to manganese, i. e. before a reversal of the manganese accumulation.

Gender differences in Parkinson's disease symptom profile

Gender symptom differences were studied in 948 subjects with Parkinsons disease (PD) using a questionnaire covering the most common symptoms associated with PD at debut (SP‐1) and at present (SP‐2). The symptoms most frequently reported by both genders were: tremor, fumblingness, writing problems, rigidity and fatigue. At SP‐1 females reported neck‐pain and low back pain more frequently than males. At SP‐2 subjects reported an increased number of symptoms. The following symptoms were more frequent among males than females: writing difficulties, fumblingness, gait problems, speech problems, increased flow of saliva, lack of initiative. Sleep problems were common in both sexes with inability to turn in bed and calf muscle cramps in a high percentage. A majority of female subjects find their symptoms (e.g. depression) constantly distressing. Although depression is not one of primary reported symptoms (36%) attention is called for, due to the problem with compliance to treatment regimes. About 30% do not report having tremor and rigidity. This study indicates the usefulness of a symptom profile instrument capable of capturing the many symptoms involved in PD. Such an instrument could be used to detect apparent mistakes in medication and thereby increase the function and quality of life for the individual.

Dopamine receptor properties in Parkinson's disease and Huntington's chorea evaluated by positron emission tomography using 11C-N-methyl-spiperone

ABSTRACT— Dopaminergic receptor properties in the striatum of patients with Parkinson s disease (PD) and Huntingtons chorea (HD) were studied by positron emission tomography (PET), using 11C‐N‐methyl‐spiperone as a dopamine D2 receptor ligand. The time‐dependent regional radioactive uptake in the caudate nucleus and the putamen was measured and fitted to a 3‐compartment pharmacokinetic model. The rate constant k3 for specific binding to the receptor compartment in the striatum was determined in relation to the binding in regions with a low density of specific binding sites, such as the cerebellum and the frontal cortex–k3, which is a measure of the receptor density, was reduced in one patient with HD but less affected in PD in comparison with healthy controls. The pattern of k3 values calculated from the 6 PD patients is discussed in relation to any side‐to‐side differences in dopamine receptor densities in hemiparkinsonism and to possible “hypersensitivity” of dopamine receptors in the early stage of the disease and down‐regulation in more advanced disease.

Unilateral MPTP lesion in a rhesus monkey: effects on the striatal dopaminergic system measured in vivo with PET using various novel tracers

We have produced in one monkey a unilateral lesion of the dopaminergic nigrostriatal pathway by slowly infusing 1-methyl-4-phenyl-1.2.3.6-tetrahydropyridine (MPTP) into the right internal carotid artery, resulting in contralateral hemiparkinsonism. This procedure was combined with a series of positron emission tomography scans before and after the lesion, using several dopaminergic tracers in parallel. We show that specific binding of [11C]nomifensine in the lesioned striatum disappears to a large extent (80-90%) as a result of the lesion, indicating a corresponding loss of striatal dopamine re-uptake binding sites and thus of the dopamine nerve terminal pool. The uptake of radioactivity in the striatum contralateral to the lesion remained unchanged. In parallel, an early increase in ipsilateral [11C]raclopride binding, indicating upregulation of dopamine D2 receptors, was seen following the presynaptic lesion. [11C]Deprenyl uptake, indicating monoamine oxidase type B enzyme concentration, did not change after the lesion.

Palmar and axillary hyperhidrosis treated with botulinum toxin: one-year clinical follow-up.

Focal hyperhidrosis is a common and sometimes handicapping condition for which the presently most effective treatment, sympathectomy, often leads to irreversible side‐effects. We aimed to study effectiveness and tolerability of an alternative treatment with botulinum toxin injections over a period of one year for this condition.