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L-5-Hydroxytryptophan
Published in Stanley R. Resor, Henn Kutt, The Medical Treatment of Epilepsy, 2020
Melvin H. Van Woert, Eunyong Chung
Numerous different types of brain lesions are associated with myoclonus, There is evidence that certain types of myoclonus, particularly action or intention myoclonus secondary to postanoxic encephalopathy, may be related to a depletion or functional deficiency of the neurotransmitter serotonin in the brain. Postanoxic intention myoclonus may be generalized or localized to one extremity. The myoclonic movements are usually aggravated by visual, auditory, and tactile stimuli and are absent during sleep. Biochemical studies of cerebrospinal fluid from patients with postanoxic intention myoclonus have demonstrated that the concentration of 5-hydroxyindoleacetic acid (5H1AA), the major metabolite of serotonin, is consistently low (7–9). Drugs that enhance brain serotonergic function reduce myoclonic movements in this disorder. L-5-Hydroxytryptophan (L-5HTP), in combination with carbidopa, is the most effective antimyoclonic drug in this class of pharmacologic agents (7–12). L-5HTP is an amino acid which readily crosses the blood-brain barrier and is decarboxylated in the brain to form the neurotransmitter serotonin. Carbidopa is a peripheral decarboxylase inhibitor that prevents the conversion of L-5HTP to serotonin in extracerebral tissues such as kidney, liver, and small intestine. Thus, carbidopa reduces the formation of serotonin from L-5HTP in the gastrointestinal tract, which otherwise can produce diarrhea and nausea. In addition, carbidopa increases the amount of L-3HTP available for transport into the brain, thereby reducing the dose of L-5HTP required for its therapeutic effect.
Drugs Affecting the Central Nervous System
Published in Radhwan Nidal Al-Zidan, Drugs in Pregnancy, 2020
Risk Summary: It should be used with caution because the pregnancy experience in humans is limited, and the reproduction studies in animals have shown an increased risk of fetal deaths associated with the use of Carbidopa/Levodopa.
Neurotransmitters and pharmacology
Published in Mark J. Ashley, David A. Hovda, Traumatic Brain Injury, 2017
Ronald A. Browning, Richard W. Clough
Several reports in recent years suggest that enhancing DA neurotransmission may be beneficial to patients with TBI. Improving dopaminergic function appears to be useful for two types of deficits in these patients. First, some TBI patients display Parkinsonian-like symptoms, and second, dopaminergic agents may improve arousal and the ability to focus attention on the task at hand and generally improve cognitive ability.83,84 The latter effect may be mediated through the prefrontal cortex (PFC),95 but the level (regulated by dose) of DA receptor stimulation appears to be critical because of the inverted U-shaped function of DA receptor activation in the PFC.1,95 Just as l-DOPA (levodopa) is effective in Parkinson’s disease, it may help similar symptoms in patients with TBI. The combination of l-DOPA with a peripheral decarboxylase inhibitor will reduce the metabolism of l-DOPA in the periphery and increase the amount that actually reaches the brain. Thus, the combination of levodopa and carbidopa (a decarboxylase inhibitor) is often used in Parkinson’s disease. Sinemet® (a mixture of l-DOPA and carbidopa) has, in fact, been used successfully in some patients with TBI.96,97 There is also some evidence from animal studies that treatment with DA agonists (e.g., ropinirole) can either reduce or reverse the motor and cognitive deficits produced by brain injury.98
On demand therapy for Parkinson’s disease patients: Opportunities and choices
Published in Postgraduate Medicine, 2021
Robert A. Hauser, Peter A. LeWitt, Cynthia L. Comella
Another scenario where on-demand therapies may fill an unmet need is for those patients who would benefit from ‘spot’ therapy on occasion or who experience troublesome OFF episodes at unexpected times. The patient who reports unwanted OFF episodes even just a few times per week and without a predictable pattern might also be a good candidate for on-demand therapy. In addition, some patients anticipating an OFF episode might feel more comfortable carrying this treatment option every day. For some people, the need for an on-demand dose may be as infrequent as once per month, though the availability of such treatment may enhance their motivation and perception of safety, encouraging them to continue with more activities outside the home. Even the patient on immediate-release carbidopa/levodopa who leads an active lifestyle may want to stick with the convenience of that regimen as long as possible and supplement with an on-demand therapy only at times when OFF episodes interfere with activities.
Tryptophan 2,3-dioxygenase, a novel therapeutic target for Parkinson’s disease
Published in Expert Opinion on Therapeutic Targets, 2021
Fanni Annamária Boros, László Vécsei
Moreover, TDO inhibition in PD might hold risks as well. In their study Cuartero and colleagues identified L-KYN as an AHR agonist, thus playing a deleterious role in cerebral ischemia in a mouse model of stroke [57]. They found that diminishing L-KYN levels by the use of the TDO inhibitor 680C91 led to inhibition of AHR activation which resulted in decreased infarct volume. On the other hand, recent results in PD suggest a protective role of AHR activation in the disease via inducing Parkin expression that leads to a decrease of α-syn production [75]. Carbidopa, a widely used anti-PD drug, is also an AHR activator and recently dopamine itself has been shown to possess AHR agonist effects as well [76]. These results well demonstrate the complexity and differences of possible pathomechanisms underlying various neurological disorders and imply a potential pitfall of TDO inhibition in PD. Results on worsening/decline in cognitive functions of wild-type mice upon long term (4 weeks) TDO inhibitor treatment might also raise concerns [62].
Real-world assessment of “OFF” episode–related healthcare resource utilization among patients with Parkinson’s disease in the United States
Published in Journal of Medical Economics, 2021
Andrew Thach, Eddie Jones, Eric Pappert, James Pike, Jack Wright, Alexander Gillespie
The underlying cause of PD is the degeneration of dopamine neurons in the substantia nigra, leading to reduced dopaminergic neurotransmission6. To counteract this reduction in neurotransmission, the dopamine precursor levodopa has been used for the management of PD since the 1960s7. Oral levodopa administered with carbidopa is effective in reducing motor symptoms in most patients and is the gold standard for PD8. With disease progression, most patients on chronic carbidopa/levodopa therapy develop motor complications, including motor fluctuations and dyskinesia9. Motor fluctuations consist of periods when symptoms improve as a result of the beneficial effect of a dose of carbidopa/levodopa (“ON”) and periods when symptoms reappear or worsen (“OFF” episodes)10. Motor fluctuations have been reported in 50% of patients with PD after 5 years of initiating carbidopa/levodopa and in 70% of patients beyond 9 years of treatment11,12. The duration of “OFF” episodes that patients experience varies, but ∼65% of individuals reported spending at least 2 h of their day in “OFF” and >20% reported 4 h or more of “OFF” time per day in a survey conducted by the Michael J. Fox Foundation for Parkinson’s Research13.