Treatment levodopa

The dopamine precursor l-DOPA (levodopa) is commonly used in TH treatment of the symptoms of PD. l-DOPA can be absorbed in the intestinal tract and transported across the blood-brain barrier by the large neutral amino acid (LNAA) transport system, where it taken up by dopaminergic neurons and converted into dopamine by the activity of TH. In PD treatment, peripheral AADC can be blocked by carbidopa or benserazide to increase the amount of l-DOPA reaching the brain. Selective MAO B inhibitors like deprenyl (selegiline) have also been effectively used with l-DOPA therapy to reduce the metabolism of dopamine. Recently, potent and selective nitrocatechol-type COMT inhibitors such as entacapone and tolcapone have been shown to be clinically effective in improving the bioavailability of l-DOPA and potentiating its effectiveness in the treatment of PD. 

Amantadine is less effective than levodopa in the treatment of Fhrkinson s disease but more effective than die anticholinergics. Amantadine may be given alone or in combination witii an antiparkinsonism drug witii anticholinergic activity. Amantadine is also used as an antiviral drug (see Chap. 14). 

During early treatment witii levodopa and carbidopa, adverse reactions are usually not a problem. But as the disease progresses, die response to die drug may become less, and the period of time tiiat each dose is effective begins to decrease, leading to more frequent doses, and more adverse reactions. 

While a number of drugs, e.g. a-methyl dopa, inhibit the enzyme they have little effect on the levels of brain DA and NA, compared with inhibition of tyrosine hydroxylase and they also affect the decarboxylation of other amino acids. Some compounds, e.g. a-methyl dopa hydrazine (carbidopa) and benserazide, which do not easily enter the CNS have a useful role when given in conjunction with levodopa in the treatment of Parkinsonism (see Chapter 15) since the dopa is then preserved peripherally and so more enters the brain. 

Monoamine oxidase exists in two forms, MAOa and MAOb. The former is more active against NA and 5-HT than it is against DA, which is a substrate for both, even though, like S-phenylethylamine, it is more affected by MAOb. H seems likely that MAOb is the dominant enzyme in human brain and inhibitors of it, such as selegiline, have some value in the treatment of Parkinson s disease by prolonging the action of the remaining endogenous DA as well as that formed from administered levodopa. 

Despite all these problems there has been considerable progress in the treatment of disease states through NT manipulation. Before the advent of levodopa therapy in Parkinsonism the treatment of neurological and psychiatric disorders had little... 

It is not the object of this text to cover the detailed pharmacology and use of drugs but levodopa must be an exception. Its use in PD illustrates the problems that still have to be overcome even after the cause of a disease of the CNS has been established and a treatment devised. 

These effects could result from the progression of the disease but as they are a feature of levodopa therapy a change in the central response to levodopa or changes in its peripheral kinetics are more likely. The latter does not occur since the maximum plasma concentration, the time to reach it and the plasma half-life are still similar after 10 years of treatment to those achieved initially, although continuous infusion of dopa can smooth out the swings. 

Antimuscarinic drugs such as atropine have been used to modest effect in the treatment of PD for more than a century attenuating tremor and rigidity but with little effect on akinesia. Currently benzhexol and benztropine are sometimes added to levodopa therapy but peripheral effects such as dry mouth, blurred vision and constipation are unpleasant. They are also often used to counteract neuroleptic-induced extrapyramidal effects. 

Henry, B and Brotchie, JM (1996) Potential of opioid antagonists in the treatment of levodopa, induced dyskinesias in Parkinson s disease. Drugs and Ageing 9 149-158. 

A number of azetidine-based compounds have been disclosed in patent applications from Aventis Pharma for CBi-modulated treatment of diseases such as obesity, Parkinson s disease, schizophrenia, respiratory and neurological diseases [330-334]. Compound (556) was specifically claimed for use in two formulation patent applications [330, 331] for a stable semi-solid composition and oral emulsion composition, respectively. The optional coadministration of an agent that activates norepinephrinergic and se-rotoninergic neurotransmission (for example, sibutramine) or dopaminergic neurotransmission was also claimed for the treatment of obesity. The optional use of a dopamine agonist (for example, levodopa) was claimed... 

MAOb inhibitors include selegiline and rasagaline. They may provide mild symptomatic benefit for those patients who choose to delay dopaminergic medications. Combining selegiline or rasagaline with levodopa in early treatment may delay motor complications. In patients with advanced disease, they decrease off time and improve wearing-off symptoms in patients with motor fluctuations. 

Dopamine agonists are useful as initial therapy, as they can delay the need to start levodopa and can decrease the risk of developing motor fluctuations by two- to threefold during the first 4 to 5 years of treatment. After a few years, dopamine agonists inadequately control the patient s symptoms and levodopa needs to be started. In advanced disease, dopamine agonists can be added to levodopa because they have a longer duration of action, minimize fluctuations in dopamine blood concentrations, decrease off-time, improve wearing-off symptoms, allow a reduction in levodopa dose, and improve ADLs.1-3,16,22,23,26... 

NG Gillespie, I Mena, GC Cotzias, MA Bell. Diets affecting treatment of parkinsonism with levodopa. J Am Diet Assoc 62 525-528, 1973. 

Dystonia due to identifiable structural or biochemical abnormalities ( secondary dystonia) often occurs weeks or months after strokes or other focal lesions, which commonly involve the basal ganglia, but may also involve the thalamus or cerebellum. Dystonia is also seen in children with cerebral palsy and in patients with abnormalities of dopaminergic transmission. For instance, dystonia may develop in the context of Parkinson s disease, either as an early parkinsonian sign, or in response to dopaminergic drugs. A particularly interesting inherited disease results in a combination of dystonia and parkinsonian features at a young age, which responds dramatically to treatment with low-dose levodopa ( dopamine-responsive dystonia ). 

Administration of levodopa plus carbidopa (or benserazide) remains the most effective treatment, but does not provide benefit beyond 3-5 y and is followed by gradual loss of symptom control, on-off fluctuations, and development of orobuccofacial and limb dyskinesias. These long-term drawbacks of levodopa therapy may be delayed by early monotherapy with dopamine receptor agonists. Treatment of advanced disease requires the combined administration of antiparkinsonian agents. 

Recently we have been working on Parkinson s disease. This and other similar diseases are due to a depletion of dopamine in the corpus striatum. Direct addition of dopamine is not effective in the treatment presumably because it does not cross the blood-brain barrier. However, levodopa, the metabolic precursor of dopamine, does cross the blood brain barrier and is believed to then be converted to dopamine in the basal ganglia. 

In clinical trials, the majority of patients required a decrease in daily levodopa dose if their daily dose of levodopa had been 800 mg or more, or if they had moderate or severe dyskinesias prior to treatment with entacapone. 

Parkinson s disease Initiate treatment at a low dosage and individualize increase the daily dosage slowly until a maximum therapeutic response is achieved. If possible, maintain the dosage of levodopa during this introductory period. 

Parkinsonian patients receiving levodopa/carbidopa therapy who demonstrate a deteriorating response to this treatment 10 mg per day administered as divided doses of 5 mg each taken at breakfast and lunch. There is no evidence that additional benefit will be obtained from the administration of higher doses. 

After 2 to 3 days of treatment, attempt to reduce the dose of levodopa/carbidopa. A reduction of 10% to 30% appears typical. Further reductions of levodopa/carbidopa may be possible during continued selegiline therapy. 

Parkinson cf/sease Adjunctive treatment to levodopa/carbidopa in the management of the signs and symptoms of Parkinson disease. 

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