Benserazide

257.24

257.24

1312995-182-4

DTXSID9022651

2928000090

148

-1.3

1.541 g/cm3

574.2ºC at 760 mmHg

301ºC

1.678

R36/37/38

S26

Xi

Overdosage may lead to cardiovascular side effects like cardiac arrhythmias, psychiatric disturbances like confusion and insomnia, gastrointestinal effects like nausea and vomiting, and abnormal involuntary movements. Various LD50 values have been established for the rat model, including an oral LD50 of 5300 mg/kg in rats [MSDS].

Benserazide is observed as experiencing 0% protein binding.

The primary therapeutic use for which benserazide is currently indicated for is as a combination therapy with levadopa for the treatment of Parkinson's disease in adults > 25 years of age, with the exception of drug-induced parkinsonism. At certain doses, the combination product of levodopa and benserazide may also be used to treat restless legs syndrome, which is sometimes associated with Parkinson's disease. There have also been some studies that have prompted the European Medicines Agency to confer orphan designation upon benserazide hydrochloride as a potential therapy for beta thalassaemia. Although studies are ongoing, no evidence has been formally elucidated as of yet.

When used as a therapy for treating Parkinson's disease, levadopa's specific mechanism of action revolves around its metabolism into dopamine in the body. Unfortunately, the resultant increase in the levels of circulating dopamine in the blood and to various extracerebral tissues can result in a number of side effects like nausea, vomiting, or even cardiac arrhythmias that may diminish patient adherence. A decarboxylase inhibitor like benserazide is consequently an effective compound to combine with levadopa as it is incapable of crossing the blood-brain barrier itself and therefore allows levadopa to elicit its primary action in the central nervous system, but will prevent the formation of dopamine from levadopa in extracerebral tissues - thereby acting to minimize the occurrence of extracerebral side effects.

Agents used in the treatment of Parkinson's disease. The most commonly used drugs act on the dopaminergic system in the striatum and basal ganglia or are centrally acting muscarinic antagonists. (See all compounds classified as Antiparkinson Agents.)|Any drugs that are used for their effects on dopamine receptors, on the life cycle of dopamine, or on the survival of dopaminergic neurons. (See all compounds classified as Dopamine Agents.)|Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. (See all compounds classified as Enzyme Inhibitors.)

In a study, three patients were administered 50 mg of radiolabelled 14C-benserazide by both intravenous and oral routes. Three additional patients received oral doses of 50 mg 14C-benserazide alone. Comparison of the time-plasma concentration curves of total radioactivity in the patients receiving oral and intravenous 14C-benserazide indicated that between 66% and 74% of the administered dose was absorbed from the gastrointestinal tract. Peak plasma concentrations of radioactivity were detected one hour after oral administration in five of the six patients.|Benserazide is rapidly excreted in the urine in the form of metabolites, mostly within the first 6 hours of administration, 85% of urinary excretion occurs within 12 hours. Elimination of radiolabelled 14C-benserazide was primarily by urinary excretion with 86% to 90% of an intravenous dose recovered in the urine while 53% to 64% of an oral dose was detected in the urine. The majority of the 14C-benserazide was ultimately accounted for in the urine within 48 hours after administration. Fecal recovery studies conducted over five to eight days accounted for the majority (about 30%) of the remainder of the administered 14C-benserazide. Ultimately, benserazide is almost entirely eliminated by metabolism. These metabolites are mainly excreted in the urine (64%) and to a smaller extent in the feces (24%).|Readily accessible data regarding the volume of distribution of benserazide is not available.|Readily accessible data regarding the clearance of benserazide is not available.

Benserazide is hydroxylated to trihydroxybenzylhydrazine in the intestinal mucosa and the liver. Trihydroxybenzylhydrazine is a potent inhibitor of the aromatic acid decarboxylase, and it is believed that the levodopa in a levodopa/benserazide combination product is largely protected against decarboxylation mainly by way of this benserazide metabolite.

The half-life of benserazide is documented as 1.5 hours.

The combination of levodopa and benserazide is an anti-Parkinsonian agent. Levodopa itself is the metabolic precursor of dopamine. In Parkinson's disease, dopamine is depleted to a large degree in the striatum, pallidum, and substantia nigra in the central nervous system (CNS). The administration of levodopa to treat the disease is subsequently proposed to facilitate raises in the levels of available dopamine in these areas. The metabolism of levodopa to dopamine occurs via the enzyme dopa decarboxylase, although unfortunately, this metabolism can also occur in extracerebral tissues. As a result, the full therapeutic effect of an administered dose of levodopa may not be obtained if portions of it are catabolized outside of the CNS and various patient adherence diminishing extracerebral side effects due to the extracerebral presence of dopamine like nausea, vomiting, or even cardiac arrhythmias can also happen. Subsequently, a peripheral decarboxylase inhibitor like benserazide, which blocks the extracerebral decarboxylation of levodopa, when administered in combination with levodopa has obvious and significant advantages. Such benefits include reduced gastrointestinal side effects, a more rapid and complete response at the initiation of therapy, and a simpler dosing regimen. It is important to note, however, that benserazide is hydroxylated to trihydroxybenzylhydrazine in the intestinal mucosa and the liver, and that as a potent inhibitor of the aromatic amino acid decarboxylase, it is this trihydroxybenzylhydrazine metabolite of benserazide that mainly protects levodopa against decarboxylation to dopamine in the gut and also around the rest of the body outside of the blood-brain barrier. Regardless, because Parkinson's disease progresses even with the therapy of levodopa and benserazide, this kind of combined therapy is only ever indicated if it is capable of improving the quality of life and adverse effect profile of using such drugs for Parkinson's patients and there is little to be gained by switching to or starting this combination therapy if patients are already being managed with stable, effective, and well-tolerated levadopa-only therapy. Finally, it is also proposed that benserazide hydrochloride may be able to treat beta thalassaemia by maintaining the active expression of the gene for fetal hemoglobin so that constant production of fetal hemoglobin may replace the missing adult hemoglobin variation that is characteristic of patients with the condition, thereby decreasing the need for blood transfusion therapy.

Benserazide