Discovery and Development of Carbidopa Levodopa

Discovery and Development of Carbidopa Levodopa

Carbidopa levodopa is a combination of two different medicines: carbidopa, an inhibitor of aromatic amino acid decarboxylation, and levodopa, an aromatic amino acid.1 Levodopa occurs naturally in plants, such as fava beans. However, a semi-synthetic form of levodopa is used in medicine.2 Similarly, semi-synthetic methods are also used in the preparation of carbidopa.3 The combinatory product carbidopa levodopa is taken by mouth 3 to 4 times daily, with its primary function being to manage the symptoms of Parkinson's disease, a chronic and progressive movement disorder.

In 1960, Austrian biochemist Oleh Hornykiewicz first suggested that Parkinson’s disease is associated with, or caused by, a reduction in the levels of dopamine in the brain. Since dopamine cannot enter the brain, he attempted to treat twenty patients with a racemic mixture of dihydroxyphenylalanine (DOPA), which could enter the brain and be converted to dopamine via the action of aromatic L-amino acid decarboxylase. His results were positive, as were those in another trial run by André Barbeau in Montreal. In the late 1960s, Curt Porter at Merck discovered that levodopa was the active stereoisomer of racemic DOPA, which enabled the dose to be effectively reduced to half. In 1962, Victor Lotti at Merck synthesized and patented carbidopa, and in 1971, Lotti showed that the use of the L-form of carbidopa further reduced the necessary dosage of levodopa. The combination of L-carbidopa and levodopa was marketed under the brand name of Sinemet.4

As previously mentioned, Parkinson's disease is thought to be caused by a deficiency of dopamine in the brain. However, because dopamine cannot cross the blood-brain barrier, the administration of dopamine is ineffective in the treatment of Parkinson's disease1. Consequently, levodopa helps to control movement by converting into dopamine in the brain. Levodopa is converted to dopamine via aromatic L-amino acid decarboxylase both peripherally and in the central nervous system after levodopa has crossed the blood-brain barrier. Levodopa is generally combined with carbidopa, an inhibitor of aromatic amino acid decarboxylase that cannot cross the blood-brain barrier.5 Carbidopa thus prevents the breakdown of levodopa in the bloodstream so that more levodopa can enter the brain.

Carbidopa can also reduce some of levodopa's side effects. While the activation of central dopamine receptors improves symptoms of Parkinson’s disease, the activation of peripheral dopamine receptors causes side effects, such as nausea and vomiting.6 Thus, levodopa is usually combined with carbidopa to prevent the peripheral conversion of levodopa and decrease the chance of negative side effects.7, 8

Common side effects in patients taking carbidopa levodopa include nausea, vomiting, loss of appetite, trouble sleeping, weight loss, hallucinations, dyskinesias, and depression.1 In addition, some products may interact with the medication; these include antipsychotic drugs (such as chlorpromazine, haloperidol, thioridazine) and certain drugs used to treat high blood pressure (such as methyldopa). Furthermore, taking certain monoamine oxidase (MAO) inhibitors with carbidopa levodopa may cause a serious and potentially fatal drug interaction.9 Alternative medications include dopamine agonists, like pramipexole, which may be used in the early stages of Parkinson’s disease.
These drugs have many of the same side effects; however, such dopamine agonists do not require modification from brain enzymes to stimulate dopamine receptors, as levodopa does.10 Nevertheless, carbidopa levodopa is still largely considered the most effective medication in the treatment of Parkinson’s disease.

Bibliography
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