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Advanced Neurology George Cotzias and L-DOPA therapy

of L-DOPA. 28,39,78 It is suggested that the presence of resting The efficacy of apomorphine as a treatment was closely
tremor may be associated with secondary compensatory linked to the patient’s response to L-DOPA; only if the
mechanisms that could mitigate LID, even with L-DOPA health condition of the patient was getting better by the
treatment. 76,79 In some cases, LID occurs as a progression use of L-DOPA, there would be amelioration by the use
following other motor fluctuations. 13 of apomorphine. In addition, N-propylnoraporphine
80
Moreover, lower-than-expected rates of LID were was shown to minimize certain L-DOPA-related adverse
observed when low daily doses of carbidopa/L-DOPA effects, though it was ineffective in reducing dyskinesias
7
were administered. The pathophysiology of L-DOPA- when their underlying cause was not L-DOPA.
39
associated response fluctuations is complex and not yet Moreover, the suspicion that carbidopa might be
28
fully understood. Indeed, it is understood that choosing effective in the treatment of chorea led Cotzias to pioneer
L-DOPA as a first-line therapy results in significant the revolutionary carbidopa/L-DOPA combination, also
functional improvements for patients, particularly in terms known as the peripheral amino acid decarboxylase inhibitor
of symptomatic relief, during the early years following the (DDI) medication. 1,3,7,19,32 This therapy is primarily used in
25
st
onset of PD. During the final years of his life, Cotzias the early stages of PD. Cotzias tried for the 1 time the
28
provided significant data on the relationship between synthesis of this drug in 1968 by adding carbidopa to the
cancer and the features of L-DOPA. 7 already administered L-DOPA. 3,7
7
7. Development of new drugs by Cotzias The benefits of this medicine were reduced doses of
L-DOPA, 1,5,8,23,28,32,36,48 faster efficacy of L-DOPA, and milder
Although the adverse effects of L-DOPA therapy were harms caused by the latter. 28,32,33,40,48,60 In 1972, Cotzias
significant, they could neither win over the exceptional published the study of DDI in a scientific article. The
7,48
potency of the therapy nor deter Cotzias from using therapy’s results were so extraordinary that the first oral
L-DOPA to treat his patients. On the contrary, the form of the DDI, marketed under the trademark Sinemet,
3,7
side effects of L-DOPA became a strong motivation for was released in 1973. 3,5,32
Cotzias to create new medications combining L-DOPA Since then, various research studies have confirmed
with various adjuncts like dopamine agonists – substitute the valuable impact of the new formula on Parkinsonian
compounds capable of crossing the blood–brain barrier patients. 5,17,23,36 Carbidopa/L-DOPA increases the level
without being converted by local enzymes. 3,36,38 The new of L-DOPA in the brain from 1% in carbidopa’s absence
drugs led to a reduction in the required L-DOPA dose and to 10% in carbidopa’s presence. L-DOPA/carbidopa is
23
minimized irregularities associated with its use. 3
considered the most efficient symptomatic treatment for
Cotzias recommended the use of apomorphine, PD, the easiest drug to source, the most affording drug
the dopamine agonist that could pass the blood–brain and can be easily monitored. To address the issue of
39
barrier without being converted by local enzymes. When gastrointestinal problems, in the 1990s, the compound
selected as a treatment option, apomorphine stimulated was released in Sweden as an intestinal gel. 5,10,19 This
all dopaminergic receptors, exhibited antidyskinetic formulation has since become a cost-effective therapy
evidence, and demonstrated an efficacy nearly equal to that not only for gastroenterological disorders but also for
of L-DOPA in improving PD symptoms. 7,32,38 patients with acute abnormalities. The gel formulation
20
Apomorphine was a reliable substance to assess the maintains nearly stable plasma concentrations of L-DOPA,
28
dopaminergic receptor responsiveness and the presence of contributing to its effectiveness. It is commercialized in
™28
dyskinesia. It cured various stages of PD before functional Europe under the trade name Duodopa and is considered
7,80
neurosurgery and was used as a treatment for patients safer and better tolerated compared to the immediate-
24
who became disabled following deep cerebral stimulation release form of carbidopa/L-DOPA. In 2006, an oral
or pallidotomy. 7,32,80 Later, the use of apomorphine solution of carbidopa/L-DOPA was commercialized in the
17
was permitted in European countries and Canada. USA. In addition, a skin patch of carbidopa was developed
80
Furthermore, it was estimated to be a successful drug for for patients with metabolism dysfunction, overcoming
patients resistant to other therapies experiencing motor the skin barriers and improving the drug’s duration and
2,5,8,32
distortions during the last stages of PD. 3,7,80 At present, a concentration.
sublingual form of apomorphine is available. Moreover, At present, carbidopa/L-DOPA is defined as the most
64
apomorphine can serve as a temporary perioperative impactful oral medicine in PD. It is the most prescribed
81
treatment during abdominal surgery for patients with PD. treatment as it improves PD symptoms, especially at the
80
An important parameter to assess the efficacy of dopamine early stages of PD. It offers mild and infrequent side effects,
23
agonists was the patient’s reaction to L-DOPA. 80 including dyskinesia, as well as a positive influence on the
Volume 4 Issue 2 (2025) 47 doi: 10.36922/an.5177