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Advanced Neurology George Cotzias and L-DOPA therapy

of Physiology. 7,45 Cotzias had knowledge of common 5. The outstanding therapy
precursors of dopamine and neuromelanin – one of
which was L-DOPA. 7,38 This knowledge was informed 5.1. The discovery
by earlier findings: in 1951, Raab and Gigee identified Cotzias discovered a method to study manganese
7,45
catecholamine in humans, and in 1957, Kathleen distribution in human tissues. Despite the failure
Montagu’s landmark paper in Nature first documented of previous researchers who focused on dopamine
the existence of dopamine in the brain. 1,3,7,16,33,52 Knowing levels as a treatment for PD without demonstrating the
the presence of catecholamines and their function in practical therapeutic efficacy of L-DOPA, 41,47,55-57 Cotzias
humans, Cotzias began his studies on them. He suspected recognized the potential benefits of L-DOPA for PD
that catecholamine and vasomotor action were affected patients. However, at the time, its utility was limited to
by diamine and histamine. 7,38 Cotzias detected the theoretical dimensions due to its inability to cross the
connection between catecholamine, manganese, and blood–brain barrier. 1,3,7,33,38,41,47,55,58 His incorrect – as he
L-DOPA in the brain and opined that catecholamines, later self-acknowledged – hypothesis that the increase of
diamines, and histamine had vasomotor action. 38,53 In neuromelanin levels in SN could ameliorate the health
addition to linking angiomotor action with hypertension, of Parkinsonian patients was the motivation to initiate
Cotzias also focused on enzymes that limit their the study of L-DOPA. 1,7,19,33,45 Thus, in 1966, Cotzias
biological activity by oxidation. 7,38 These foundational commenced a research project in BNL investigating the
studies prompted Cotzias to begin his first research on oral use of D-DOPA or otherwise named D, L-DOPA in 17
L-DOPA, laying the groundwork for his groundbreaking Parkinsonian patients treated in his clinic. 3,7,8,21,33,47 Cotzias
2,3
discoveries. 7,38 was closely following the health progress of his patients.
He made a twice-per-day assessment and a cinematographic
When Cotzias accepted the proposal of the World recording of the patient’s health condition. 2,3,7,26,59 He
Health Organization, he remained in BNL, but from began to increase the dose every 2 h over the course of
1963 and for the next 7 years, he and the professor of the several weeks until signs of health amelioration were
Catholic University of Chile, Ismael Mena, were chosen to observed. 2,7,38,41 The highest dose administered was 16 g/
be the head chiefs of a scientific research team established day. 4,5,14,17 The findings and characteristics of D-DOPA
in the Catholic University of Chile. The team’s primary were presented in his article “Aromatic amino acids and
7,46
objective was to conduct a longitudinal study investigating modification of Parkinsonism,” published in the New
chronic manganese poisoning in Chilean miners. 38,45,46 England Journal of Medicine. 7
The study included 13 adult miners, all under the age
of 56. The duration of manganese exposure among Cotzias also found that the inactive isomer, D-DOPA,
45
participants varied between 6 months and 21 years, while which constituted 50% of the administered dose, caused
the onset of manganese intoxication varied between 3 and toxicity and intense gastrointestinal and hematological
7,8,32,33,56
25 years. All participants experienced positive effects injuries while lacking any therapeutic properties.
45
when treated with L-DOPA, also known as the amino acid Driven by a priority to alleviate his patients’ pain, Cotzias
L-dihydroxyphenylalanine. 7,8,10 considered pain relief to outweigh concerns over potential
13
drug dependency. In 1967, knowing that L-DOPA did
In the meantime, Cotzias considered seriously the not cause toxicity, Cotzias initiated a study involving 28
relationship between the detailed activation of metal adult participants diagnosed with PD. 2-5,7,19,32,33,35,38 The
traces in tissue and blood samples using high-energy highest dose of L-DOPA administered to the patients was
neutron beams. 7,38,45,46 As part of the longitudinal study, 8 g/day. 17,19,32,33 Cotzias attributed the success of this therapy
he identified common neurological factors – including to the gradual increase of the final high doses of L-DOPA and
injuries in SN due to reduced neuromelanin – between PD the continuous observation of his inpatients for months.
7,19
and manganese toxicity. 3,7,19,38,46 Later, Cotzias completed This marked the first successful attempt to achieve practical
several studies explaining the distribution, absorption, therapeutic results using L-DOPA. The participants of
kinetic elimination, and probable function of manganese. 38 Cotzias’ study became the first individuals to overcome the
During this collaboration, Cotzias also identified refractory nature of PD, which, until that time, had been
the common neurological symptoms between PD and unresponsive to all other treatments. 1,7,30,33,46,55,60 Although its
manganese toxicity, such as rigid facial expression, curable features, Cotzias assessed L-DOPA not as a treatment
38
clenched hands, speech difficulties, balance disorders, per se, but as a step toward developing a definitive treatment.
hand tremors, facial rigid expression, slowed movements, 1 He persuaded doctors to give morphine (a significantly
speech tremors, lack of coordination, and difficulty in addictive substance) to his mother till she would have a
maintaining balance. 7,19,38,46,54 relief from severe cancer pain. 3

Volume 4 Issue 2 (2025) 44 doi: 10.36922/an.5177