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Advanced Neurology George Cotzias and L-DOPA therapy

is not because of the drug per se, but due to other factors A lesser known but significant achievement of Cotzias
independent of it, like gut abnormalities, the presence of was the discovery of severe L-DOPA-induced dyskinesia
protein, and other pharmacokinetic or pharmacodynamic (LID), which, although not present in all cases, emerged
disorders. 28,36 In cases where the faster deterioration of as a consequence of nigrostriatal lesions and high doses
PD after initiating L-DOPA therapy was attributed to the of L-DOPA. 39,43,67,70,76 Other factors contributing to the
drug, several factors, like assessment of intestinal disorder, development of dyskinesia were unconscious movements.
7
the neuroimaging before and after beginning L-DOPA The fluctuation of the movements depended on the dose of
therapy, protein accumulation, and many other factors, L-DOPA. The dyskinesias disappeared in the absence of
7
were overlooked. 20,66 L-DOPA and came back after restarting the therapy. It was
In many cases, there was the same death percentage Cotzias who proved that LID was a phenomenon related to
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in PD patients receiving L-DOPA and PD patients the drug’s chemical memory storage in the brain. Cotzias,
not receiving L-DOPA. Indeed, the longevity of the in collaboration with Lily Tang, named the mechanism of
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patients who received L-DOPA was equal to the normal this phenomenon “L-DOPA-induced super-sensitivity.”
population. In addition, in other cases, the patients with This concept formed the foundation for understanding
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L-DOPA therapy lived longer than those who did not have the “priming” phenomenon, initially named “neuroleptic-
the therapy. 17,34,37,69,71 Its impact on the conceptualization of induced dyskinesias,” which was later studied extensively
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neurodegenerative diseases and other neurological illnesses to explain the molecular events that caused dyskinesias. It
was more than significant. Its therapeutic properties is now obvious that dyskinesia is a common disability that
7,56
were also extended to non-neurological diseases. 56,72 comes as a consequence of excessive dopaminergic action
in therapy. 23,65,66,77 Therefore, when Cotzias’ patients used
6. Cotzias’ achievements L-DOPA, it caused a high dopaminergic response. Cotzias
While being in BNL, Cotzias accomplished new studies on was the first to note practical benefits from L-DOPA and
7,38
cyclotrons and discovered a method to study manganese no one had recorded the presence of dyskinesia before him.
distribution in human tissues. 7,45 This suggested that dyskinesia was a reaction of the brain to
the drastic change from dopamine depletion to dopamine
In his 1964 and 1967 studies, it was obvious that rats adequacy, causing an intense dopaminergic response. In
receiving the high concentration of dopamine experienced addition, the absence of dyskinesia corresponds to the
a 50% longer lifespan compared to those without the ineffectiveness of L-DOPA. The main factors that affect
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treatment. In September 1967, when speaking at the Second LID are the presence or absence of tremor as an initial
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International Congress of Neurophthalmology in Montreal, manifestation of PD, disease duration, the age at onset,
Cotzias gave the first scientific findings on the practical the duration of PD before treatment, the equivalent daily

therapeutic impact of L-DOPA for PD patients. Cotzias was L-DOPA dose, the initial dose, dose duration, disease
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also the first to prove the emergence of dyskinetic and motor severity, the presence of motor fluctuations, and the
fluctuations as negative features of L-DOPA. 49,50,53,56,70,76 severity of motor symptoms, especially those caused by
Cotzias holds the title of the pioneer of the practical prolonged L-DOPA therapy. 13,28,39,40,42,77
potency of L-DOPA, marking it as the first long-term Dyskinesia’s presence was noted even in therapy
treatment capable of crossing the blood–brain barrier change from dopamine agonist medicine to L-DOPA.
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and restoring dopamine deficiency in the brains of Yet, many physicians refuse to propose L-DOPA as a
Parkinsonian patients. 7,19,34,46,76 Cotzias was also the first treatment for PD due to its side effects, ignoring the fact
to prove that L-DOPA could defeat PD, whether it was that even dopamine agents, which these physicians prefer,
caused by idiopathic, post-encephalitic, or manganese possess serious complications too. Since dyskinesias is
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factors. At this point, it is worth noting that Cotzias, in also present when treated with dopamine agonists, it is
7
his cutting-edge scientific study, had shown that L-DOPA the dopamine stimulation that causes dyskinesias and not
could stop the exacerbation of PD symptoms. He was L-DOPA per se. Another explanation for dyskinesias is
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13
the first to establish the role of dopamine and L-DOPA in that their occurrence can be influenced by the method
cerebrospinal fluid, and the interaction between L-DOPA, 17
aging, and fertility, as well as identify the presence of of administration. While LID can affect the QoL and, in
42
dyskinesias linked to melatonin and growth hormone many cases, increase the risk of falls, it does not always
in patients undergoing L-DOPA therapy. Furthermore, affect QoL to a significant degree, though it can lead to
7
increased healthcare costs.
13
Cotzias proved that L-DOPA could improve the health
of people suffering from chronic manganese poisoning LID has led to disruptions of carbidopa/L-DOPA
without causing any involuntary movements. 3,46,69 therapy and it has been the factor limiting the clinical use
Volume 4 Issue 2 (2025) 46 doi: 10.36922/an.5177