myparkinsons.co.uk

Levadopa its Strength and Weakness

By;Eduardo Tolosa

Oral levodopa was developed in laboratories in the US owned by the
Atomic Energy Commission: Brookhaven National Laboratory, Long
Island, New York.

A neurologist from Crete – George Cotzias –
published a crucial paper in 1967 in the New England Journal of
Medicine about how he administered melanocyte-stimulating
hormone (MSH) to patients with Parkinson’s disease (PD).

1967

He thought the problem was that patients needed melanin as the substantia nigra was depigmented. However, when he gave MSH the patients actually got worse and their skin darkened.

Cotzias’ focus then moved to levodopa, a precursor to melanin. In
the same paper he described how he administered D,L-dopa to
16 patients .

It was the first time this compound had been given orally in such massive amounts. Eight patients improved dramatically with the large doses of D,L-dopa, but many experienced profound nausea.
Improvements were seen and lasted for several months.

Nevertheless,in this study, dyskinesias were already being described – the first time they had been described in the literature.

Furthermore, D,L-dopa was toxic to bone marrow, and the dosing led to granulocytopoenia. Cotzias was forced to cease administration.

Despite these problems, Cotzias had achieved notable successes, including
laying the foundations of levodopa dosing:

1. many doses
2. slow titration
3. increasing dosage as much as necessary
4. daily doses distributed throughout the day.

1969
In 1969, Cotzias, still in the employ of the Atomic Energy Commission,
switched from D,L-dopa to levodopa. Again, all patients who received
the compound improved dramatically and had sustained improvements
in all symptoms for up to two years.

Even tremor improved – many
neurologists are reluctant to say that levodopa is as effective for tremor
as for bradykinesia, but Cotzias’ study shows that it is; it just takes a
little longer.
As early as this 1969 paper, Cotzias mentioned the emergence of
certain clinically significant symptoms in six patients: the ‘off’
phenomenon.

He noted that 14 patients also had involuntary
movements.

Furthermore, he described the antagonistic effect on
levodopa by pyridoxine (vitamin B6) and a high-protein diet.

Therefore,at this time Cotzias was already describing both the main benefits and the main weaknesses of levodopa as we know them today

.
In addition to levodopa, Cotzias laid the foundations for subsequent
work on oral dopamine agonists. He was the first to attribute the
effect of apomorphine to its dopamine-like structure.

2009
Levodopa and Parkinson’s Disease – 30 Years Later
There is no question that levodopa is the most effective symptomatic
treatment of PD. However, it has only recently been compared with
other treatments, particularly orally active dopamine agonist
monotherapy.

All trials to date have shown that levodopa has a more
potent antiparkinsonian effect, especially in the first years, than
dopamine agonists such as bromocriptine, ropinirole, pergolide,
cabergoline and pramipexole.3–7

To compare the benefits of initiating therapy with levodopa or the
dopamine agonist bromocriptine, the Parkinson’s Disease Research
Group of the United Kingdom (PDRGUK) conducted a long-term
(10-year) open-label, randomised study in 782 previously untreated
PD patients.3 The study found that although bromocriptine-treated
patients had a lower incidence of dyskinesia and dystonia than the
levodopa-treated patients, they also had significantly worse disability
scores throughout the first five years of therapy.

June 30, 2014 Posted by Chris | Levadopa | Leave a Comment