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Biomedical subjects

C E Clarke

Publications and source records attributed to C E Clarke.

81 records · Page 5Linked to original sources
PubMed1987

Levodopa-induced dyskinesia and response fluctuations in primates rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

Six non-human primates received doses of MPTP sufficient to produce a severe parkinsonian syndrome. Levodopa therapy reversed parkinsonian features in all animals, but resulted in dose-dependent choreoathetoid movements of the lower limbs of 3, together with akathisia and dystonia in 2. 'End-of-dose deterioration' was common to all animals, although 'on-off' periods were only seen in 3. Preliminary observations using a clinical rating scale and automatic activity counters demonstrate that both the motor response to levodopa and the complications of therapy are readily quantifiable. We suggest that this is a useful experimental model for testing new strategies in the management of idiopathic Parkinson's disease, particularly with regard to the prevention of drug-induced involuntary movements.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1987

MPTP-induced parkinsonism in the monkey: neurochemical pathology, complications of treatment and pathophysiological mechanisms.

MPTP induces parkinsonism in monkeys by destruction of the substantia nigra, pars compacta. It can also damage ventral tegmental dopamine neurones and the noradrenergic locus coeruleus, both of which may be affected in Parkinson's disease. Motor symptoms in MPTP-treated monkeys respond readily to levodopa or dopamine agonist therapy. Administration of levodopa over 4-8 weeks leads to the emergence of "peak-dose" dyskinesia. Such abnormal movements are not seen following challenge doses of levodopa in animals not on long-term therapy. Radioligand studies reveal a 40-180% increase in D2 receptor binding in the striatum of parkinsonian monkeys. 2-deoxyglucose studies of regional brain metabolism indicate that MPTP-induced parkinsonism is characterised by abnormally increased activity of medial pallidal neurones which project to the thalamus and pedunculopontine nucleus and reduced activity of subthalamic nucleus neurones.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1987

Subacute myelopathy caused by spinal venous infarction.

A 44 year old female presented with a subacute myelopathy in association with pelvic venous thrombosis. It is inferred from the temporal relationship of these events that the patient suffered a subacute spinal venous infarction. This is discussed along with the aetiology, anatomical distribution and management of the condition.

Adult↗
PubMedDate not supplied

A randomized, double-blind, placebo-controlled, ascending-dose tolerability and safety study of remacemide as adjuvant therapy in Parkinson's disease with response fluctuations.

The objective of this study was to establish the maximum tolerated dose of the low affinity non-competitive N-methyl-D-aspartate receptor antagonist remacemide in patients who have Parkinson's disease with response fluctuations or dyskinesias, or both. A total of 33 patients were randomly assigned in a 3-to-1 ratio to receive remacemide or placebo. Remacemide was administered orally at 150 mg twice daily, increasing incrementally by 100 mg (50 mg twice daily) at 2-week intervals to a final daily regimen of 400 mg twice daily or until a maximum tolerated dose was identified. The maximum total treatment period was 12 weeks. Of the 23 patients randomly selected to receive remacemide, four completed the study at the maximum permitted dose, compared with four of the 10 patients given placebo. The median maximum tolerated dose of remacemide was 450 mg/d. There was no clinically relevant change in percentage of "on" time between baseline and maximum tolerated dose in either group. At the maximum tolerated dose of remacemide for each patient, the mean Unified Parkinson's Disease Rating Scale (UPDRS) motor examination score (part III) decreased from 33 (SD = 18) to 26 (SD = 13) compared with a decrease from 28 (SD = 12) to 27 (SD = 8) in the placebo group. There was a decrease in the mean UPDRS "complications of therapy" score (part IV) in the remacemide group from 8 (SD = 4) to 6 (SD = 4), and the placebo group remained unchanged at 6 (SD = 4). The most common adverse events associated with remacemide were nausea, vomiting, dizziness, headache, abnormal vision, and hypokinesia. Remacemide was well tolerated at a dose level of 400 mg/d. There was a trend suggesting that remacemide was effective in improving symptoms at patients' individual maximum tolerated doses. These improvements occurred without exacerbating levodopa-induced dyskinesias.

Acetamides↗
PubMedDate not supplied

Uncertainties in the pharmacotherapy of Parkinson's disease and how to solve them.

The causative relationship between levodopa and the long-term motor complications of therapy, along with the possibility that levodopa may be toxic to dopaminergic neurones in vivo, has led to a move away from its use in early Parkinson's disease. Alternatives such as amantadine and the anticholinergics suffer from poor efficacy in comparison and a high side effect profile. Selegiline is probably less effective than levodopa and the issue of its safety versus neuroprotective properties remains unresolved. Long-term trials with the old and newer dopamine agonists as monotherapy have shown that as a class they can delay the development of dyskinesia and probably response fluctuations. However, major uncertainties remain about their use as monotherapy in all patients instead of levodopa. No data on their effect on quality of life and health care costs are available. Most of the trials were heavily biased towards younger patients with Parkinson's disease, so little data in the elderly are available. In later disease when patients have already developed motor complications on levodopa, the choice rests between adjuvant therapy with a dopamine agonist, a catechol-O-methyltransferase inhibitor (COMT; e.g. entacapone), and a monoamine oxidase B inhibitor (MAO B; e.g. selegiline). Trials with the former two classes have confirmed that they can reduce 'off' time, reduce levodopa dose, and improve motor impairments and disabilities with acceptable increases in adverse events including dyskinesia. Trials with selegiline as adjuvant therapy were less rigorous but it can allow a reduction in levodopa dose and motor impairments. No studies have compared these three classes of drug as adjuvant therapy so there is no evidence on which to base rational decisions in this type of patient. A large pragmatic trial which includes older patients is needed to clarify which treatment is best for different stages of the disease.

Aged↗
PubMedDate not supplied

Quality of life and care in Parkinson's disease.

Seventy-two parkinsonian patients attending a subregional movement disorder clinic completed a novel questionnaire designed to examine their quality of life and care. Significant problems with housing, travel, holidays and hobbies were identified. Financial difficulties due to premature retirement and the complex benefit system were found. Many carers were ill but, even when hospitalised, patients were cared for in the community by friends and relatives. Few patients had been referred for paramedical therapies, in spite of considerable disability in some cases. Aids and adaptations were commonly in use without advice from an occupational therapist. The specialised clinic and Parkinson's disease nurse advisor were welcomed by many patients. Most were satisfied with their hospital care and general practitioner, but follow-up arrangements with general practitioners were variable. It is suggested that further research concentrates on the roles of physiotherapy, speech therapy, nurse advisors and social workers in the management of Parkinson's disease, and on the value of increased carer support, including respite care.

Aged↗