Benserazide, levodopa with

Levodopa, the metabolic precursor of dopamine, is the most effective agent in the treatment of Parkinson s disease but not for drug-induced Parkinsonism. Oral levodopa is absorbed by an active transport system for aromatic amino acids. Levodopa has a short elimination half-life of 1-3 hours. Transport over the blood-brain barrier is also mediated by an active process. In the brain levodopa is converted to dopamine by decarboxylation and both its therapeutic and adverse effects are mediated by dopamine. Either re-uptake of dopamine takes place or it is metabolized, mainly by monoamine oxidases. The isoenzyme monoamine oxidase B (MAO-B) is responsible for the majority of oxidative metabolism of dopamine in the striatum. As considerable peripheral conversion of levodopa to dopamine takes place large doses of the drug are needed if given alone. Such doses are associated with a high rate of side effects, especially nausea and vomiting but also cardiovascular adverse reactions. Peripheral dopa decarboxylase inhibitors like carbidopa or benserazide do not cross the blood-brain barrier and therefore only interfere with levodopa decarboxylation in the periphery. The combined treatment with levodopa with a peripheral decarboxylase inhibitor considerably decreases oral levodopa doses. However it should be realized that neuropsychiatric complications are not prevented by decarboxylase inhibitors as even with lower doses relatively more levodopa becomes available in the brain. 

Dopamine precursors are considered first-line in adults. Side effects include orthostatic hypotension, insomnia, daytime fatigue, and somnolence nausea, and augmentation may occur. Levodopa with benserazide or carbidopa (Sinemet) 100-125 mg or 200-250 mg at bedtime and additional doses may be needed. Dopamine agonists are becoming more popular because of the fewer side effects, and less augmentation. These are used to treat RLS and PLMD. Their side effects include nausea, orthostatic hypotension, insomnia, and somnolence also, the potential for tolerance exists. 

Minimisation of unwanted effects. Combining levodopa with benserazide (Madopar) or with carbidopa (Sinemet) slows its metabolism outside the central nervous system so that smaller amounts of levodopa can be used this reduces adverse effects. 

Very occasionally there are falls in white blood cell connt, hemoglobin, and hematocrit. The Coombs test can be positive and there is an isolated report of hemoljdic anemia and another of thrombocytopenia with a positive antinuclear antibody test (SED-12, 315). An otherwise unexplainable acnte severe non-hemolytic anemia in an elderly man taking levodopa with benserazide has also been observed (SEDA-12,124). 

CO-beneldopa benserazide levodopa. cocaine (ban, usan] (cocaine hydrochloride (jan, usan)) is an ester of benzoic acid and methylecgonine and the principal alkaloid of Erythroxylum coca and other Erythroxylum spp. (Erythroxylaceae). It is a LOCAL ANAESTHETIC (used topically because of toxicity), and has pronounced indirect-acting SYMPATHOMIMETIC actions by virtue of being an UPTAKE INHIBITOR (interferes with Uj active uptake of noradrenaline into noradrenergic nerve terminals). It is a VASOCONSTRICTOR and can be used as a topical mydriatic and ocular diagnostic agent. It is a powerful CNS stimulant (similar in action to amphetamine), with considerable abuse potential, cocaine hydrochloride cocaine. 

Methyldopa can increase the effects of levodopa and permit a reduction in the dosage in some patients taking levodopa alone, but it can aiso worsen dyskinesias in others. This interaction would not be expected to be significant in a patient taking levodopa with benserazide or carbidopa but this does not appear to have been studied. A small increase in the hypotensive actions of methyldopa may also occur. 

Clinically benserazide+levodopa treatment improved the therapeutic results, decreased the required levodopa dose (to about 1/5) and decreased the incidence of nausea and vomiting. It generally did not decrease the involuntary movements but increased them. Benserazide seems to be well tolerated on a long term administration at the lOO-liOO mg/day levels, with few transient changes in liver biopsies and enzyme levels. ... 

The main clinical use of COMT inhibitors is as adjunct (or additional adjunct) in the therapy of Parkinson s disease. The standard therapy of Parkinson s disease is oral L-dopa (as a drug levodopa) given with a dopa decarboxylase (DDC) inhibitor (e.g. carbidopa and benserazide), which does not reach the brain. When the peripheral DDC is inhibited, the concentration of 3-O-methyldopa (3-OMD), a product of COMT, in plasma is many times that of L-dopa. Since the half-life of 3-OMD is about 15 h, compared to about 1 h for L-dopa, the concentration of 3-OMD remains particularly high during chronic therapy, especially if new slow release L-dopa preparations are used. A triple therapy (L-dopa plus DDC inhibitor plus COMT-inhibitor) will... 

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. 

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. 

Figure 15.4 The central and peripheral metabolism of levodopa and its modification by drugs, (a) Levodopa alone. After oral administration alone most dopa is rapidly decarboxylated to DA in the gut and blood with some o-methylated (COMT) to o-methyl/dopa (OMD). Only a small amount (3%) enters the CNS to be converted to DA. (b) After an extracerebral dopa decarboxylase inhibitor. Blocking just the peripheral dopa decarboxylase (DD) with inhibitors like carbidopa and benserazide, that cannot enter the CNS (extra cerebral dopa decarboxylase inhibitors, ExCDDIs), stops the conversion of levodopa to DA peripherally, so that more enters the CNS or is o-methylated peripherally to OMD.

Blocking the conversion to DA would appear stupid unless this could be restricted to the periphery. More dopa would then be preserved for entry into the brain, where it could be decarboxylated to DA as usual. Drugs like carbidopa and benserazide do precisely that and are used successfully with levodopa. They are known as extracerebral dopa decarboxylase inhibitors (ExCDDIs). Carbidopa (a-methyldopa hydrazine) is structurally similar to dopa but its hydrazine group (NHNH2) reduces lipid solubility and CNS penetration (Fig. 15.4). 

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. 

Since Parkinson s disease arises from a deficiency of DA in the brain, the logical treatment is to replace the DA. Unfortunately, dopamine replacement therapy cannot be done with DA because it does not cross the blood-brain barrier. However, high doses (3-8 g/day, orally) of L(-)-DOPA (levodopa), a prodrug of DA, have a remarkable effect on the akinesia and rigidity. The side effects of such enormous doses are numerous and unpleasant, consisting initially of nausea and vomiting and later of uncontrolled movements (limb dyskinesias). The simultaneous administration of carbidopa (4.75) or benserazide (4.76)—peripheral DOPA decarboxylase inhibitors—allows the administration of smaller doses, and also prevents the metabolic formation of peripheral DA, which can act as an emetic at the vomiting center in the brainstem where the blood-brain barrier is not very effective and can be penetrated by peripheral DA. 

Carbidopa and benserazide are peripheral decarboxylase inhibitors used in combination with levodopa. They do not penetrate blood-brain barrier and do not inhibit the conversion into dopamine from levodopa in brain. 

Carbidopa is a peripheral decarboxylase inhibitor that is given in conjunction with levodopa to prevent peripheral decarboxylation (see Fig. 10 1)48,66 Use of carbidopa with levodopa dramatically decreases the amount of levodopa needed to achieve a desired effect.48 Another decarboxylase inhibitor known as benserazide is available outside of the United States ... 

Monolithic non-gas-generating systems are matrix tablets consisting of hydrocolloids that form an external gel layer when hydrated. The internal tablet core remains dry with an overall density lower than that of the gastric fluid. Hydroxypropylmethycellulose (HPMC) is the most commonly used hydrocolloid. This approach has been developed into marketed drug products as the Hydrodynamically Balanced System (HBS) invented by Sheth and Tossounian.93 Gastric retention and flotation times up to 6 hours were achieved. Valrelease (diazepam) and Madopar (levodopa and benserazide) were two marketed products developed using this approach. 

Later, the disease does not respond to the drug and doses are required to be given in combination with carbidopa. Levodopa is effective in relieving bradykinesia and other disorderly voluntary movements. Parkinson s disease is not a hereditary disease. Drugs such as levodopa, carbidopa, benserazide, bromocriptine, pergolide, selegiline, and amantadine are used as therapeutic agents.61... 

LEVODOPA, SELEGILINE, POSSIBLY RASAGILINE, ENTACAPONE, TOLCAPONE MAOIs Risk of adrenergic syndrome -hypertension, hyperthermia, arrhythmias - and dopaminergic effects with selegiline Levodopa and related drugs are precursors of dopamine. Levodopa is predominantly metabolized to dopamine, and a smaller proportion is converted to epinephrine and norepinephrine. Effects are due to inhibition of MAOI, which breaks down dopamine and sympathomimetics Avoid concurrent use. Onset may be 6-24 hours after ingestion. Carbidopa and benserazide, which inhibit dopa decarboxylase that converts L-dopa to dopamine, is considered to minimize this interaction. However, MAOIs should not be used in patients with Parkinson s disease on treatment with levodopa. Imipramine and amitriptyline are considered safer by some clinicians... 

Dose. Usually the equivalent of 50 mg of benserazide daily, increasing to 100 to 250 mg daily (given in combination with levodopa in the treatment of parkinsonism). 

Two men aged 76 and 72 years presented with advanced symptoms of Parkinson s disease and were treated with levodopa. Disabling dyskinesia occurred within days of reaching maintenance dosages of levodopa (1-1.5 g/day with benserazide). 

Levodopa combined with a peripherai dopa-decarboxyiase inhibitor Co-beneldopa (levodopa + benserazide) Co-careldopa (levodopa 1 carbidopa)... 

Josamycin. An elderly man with Parkinson s disease, well-controlled for 10 months with daily levodopa/benserazide, bromocriptine 70 mg and domperidone, was additionally given josamycin 2 g daily for a respiratory infection. Shortly after the first dose he became drowsy with visual hallucinations, and began to show involuntary movements of his limbs, similar... 

A 73-year-old man taking levodopa/benserazide and bromocriptine for Parkinson s disease was given lansoprazole 15 mg daily to treat reflux oesophagitis. Two days later, the patient exhibited akinesia (more motor difficulties and slowness in movements) associated with frequent falls. Lansoprazole was discontinued, with disappearance of the symptoms the day after. About 3 months later the patient was prescribed omeprazole 20 mg daily, which caused no aggravation of Parkinson s disease over the following 6 months. 

In a study using Madopar HBS, a sustained-release preparation of levodopa and benserazide, the concurrent use of an unnamed antacid reduced the levodopa bioavailability by about one-third in healthy subjects. The manufacturers of Madopar CR state that antacids reduce the bioavailability of levodopa from the controlled-release preparation in comparison with conventional Madopar. ... 

Entacapone and tolcapone increase the AUC of levodopa given with benserazide or carbidopa. This may require a reduction in the levodopa dose to avoid symptoms of dopamine excess when first starting the COMT inhibitor. Tolcapone increases the levels of benserazide, but neither entacapone nor tolcapone alters carbidopa pharmacokinetics. 

The effects of COMT inhibitors on the pharmacokinetics of dopa-decar-boxylase inhibitors has also been studied. Neither entacapone nor tolcapone altered the pharmacokinetics of carbidopa. However, tolcapone increased the serum levels of benserazide in patients with Parkinson s disease. The benserazide levels remained within the usual range in patients taking levodopa products containing benserazide 25 mg and tolcapone 200 mg three times daily. However, with a 50-mg dose of benserazide the AUC of benserazide was increased 4.8-fold with standard-release preparation and 2.3-fold with a controlled-release preparation. ... 

---