Decarboxylase inhibitors

Eflornithine (difluoromethylornithine, DFMO) inhibits the ornithine decarboxylase of the polyamine pathway, in both the trypanosome and the mammalian cell, by acting as an irreversible competitor of the natural substrate ornithine. Inhibition of ornithine decarboxylase results in depletion of the polyamines, putrescine, spermidine and spermine, which are essential for cell proliferation. Eflornithine selectively harms the parasite and not the mammalian cells, despite acting as an ornithine decarboxylase inhibitor in both cell types. This selectivity is explained by the lower rate of ornithine decarboxylase production in the parasite, as compared to mammalian cells. Due to the high turnover rate, mammalian cells are capable of quickly replenishing inhibited ornithine decarboxylase by newly... 

EP 436 252 (AKZO appl. 19.12.1990 NL-prior. 30.12.1989). combination with L-amino acid decarboxylase inhibitors ... 

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). 

Carbidopa, a dopa-decarboxylase inhibitor, is added to the levodopa in order to decrease the peripheral conversion of levodopa to dopamine. It does not cross the blood-brain barrier and does not interfere with levodopa conversion in the brain. Concomitant administration of carbidopa and levodopa allows for lower levodopa doses and minimizes levodopa peripheral side effects such as nausea, vomiting, anorexia, and hypotension. For most patients, at least 75 to 100 mg daily of carbidopa is required to adequately block dopamine decarboxylase in the peripheral metabolism of levodopa in most patients. Taking extra carbidopa may reduce nausea related to initiating levodopa.8,16... 

Allenic amino acid derivatives 50, which are of special interest as selective vitamin Bg decarboxylase inhibitors [35], are accessible through 1,6-cuprate addition to 2-amino-substituted enynes 49 (Eq. 4.22) [36]. Because of the low reactivity of these Michael acceptors, however, the reaction succeeds only with the most reactive cuprate the t-butyl cyano-Gilman reagent tBu2CuLi-LiCN. Nevertheless, the addition products are obtained with good chemical yields, and selective deprotection of either the ester or the amino functionality under acidic conditions provides the desired target molecules. 

Drugs have been developed which specifically inhibit the L-aromatic amino acid decarboxylase step in catecholamine synthesis and thereby lead to a reduction in catecholamine concentration. Carbidopa and benserazide are examples of decarboxylase inhibitors which are used clinically to... 

Chlorpromazine is an aliphatic phenothiazine antipsychotic used in schizophrenia and which may exacerbate parkinsonism. Co-careldopa is a combination of levodopa and the peripheral dopa-decarboxylase inhibitor, carbidopa. Co-careldopa, amantadine, entacapone and bromocriptine are all indicated in the management of parkinsonism. 

Pharmacology Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT), which alters the plasma pharmacokinetics of levodopa. When entacapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor (such as carbidopa), plasma levels of levodopa are greater and more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. 

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. 

Combined with levodopa and a decarboxylase inhibitor more stable levodopa levels can be obtained. Tolcapon has been withdrawn in many countries because of serious liverfunction disturbances, rhab-domyolysis and neuroleptic malignant syndrome. 

All of the more recent compounds have been tested in randomized double-blind clinical trials using the Unified Parkinson s Disease Rating Scale (UPDRS). We do not however have studies comparing the different drugs nor different treatment durations. In addition, the length of these trials is totally different from that of the natural disease course (20 years). It is paradoxical that levodopa, developed in the sixties, remains today the mainstay treatment for Parkinson s disease (levodopa is always associated with a peripheral decarboxylase inhibitor, either car-bidopa or benzerazide). 

If levodopa is administered alone, it is extensively metabolized by L-aromatic amino acid decarboxylase in the liver, kidney, and gastrointestinal tract. To prevent this peripheral metabolism, levodopa is coadministered with carbidopa (Sinemet), a peripheral decarboxylase inhibitor. The combination of levodopa with carbidopa lowers the necessary dose of levodopa and reduces peripheral side effects associated with its administration. 

Geriatric Considerations - Summary Levodopa is a percursor to dopamine and is converted to dopamine in the CNS. Clinical effectiveness is increased by taking in combination with carbidopa, a dopa decarboxylase inhibitor. This combination is often the initial treatment for Parkinson s disease. 

Evidence on the potential antidepressant efficacy of L-dopa is more voluminous, but also discouraging [Kapur and Mann 1992 Oren et al. 1994). Despite the definite effects of L-dopa on mood, its antidepressant efficacy, given with or without a peripheral decarboxylase inhibitor, is not established even in the subset of patients with psychomotor retardation and low pretreatment CSF HVA who are supposed to be particularly sensitive to its effects. Standard antidepressants or electroconvulsive therapy are the methods of choice in treating depression in patients with Parkinson s disease, in whom L-dopa appears to have limited or no antidepressant efficacy and has been suspected of producing depression [Cummings 1992). Furthermore, pro-... 

Carbidopa (4.75), a hydrazine analog of a-methyldopa, is an important DOPA decarboxylase inhibitor. It is used to protect the DOPA that is administered in large doses in Parkinson s disease (section 4.4.4) from peripheral decarboxylation. DOPA concentrations in the CNS will therefore increase without requiring the administration of extremely high, toxic doses of DOPA. The exclusive peripheral mode of action of carbidopa is due to its ionic character and inability to cross the blood-brain barrier. Because of this effect, carbidopa is co-administered with DOPA in a single tablet formulation as a first-line therapy for Parkinson s disease. Benserazide (4.76) has similar activity. 

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. 

Levodopa and peripheral dopa-decarboxylase inhibitor, carbidopa or benserazide in the treatment of parkinsonism. 

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. 

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