Disease relevance of benserazide

• Treatment with the drug combination of levodopa methylester and benserazide, supplemental ascorbate, and dietary deficiencies of tyrosine and phenylalanine more than doubled the median survival time of female (C57BL/6 X DBA/2)F1 mice bearing B16 melanoma tumors [1].
• Comparison of levodopa with carbidopa or benserazide in parkinsonism [2].
• During the initial stages of Parkinson's disease, treatment with levodopa plus a decarboxylase inhibitor (carbidopa or benserazide) provides adequate control of symptoms [3].
• METHODS: In the present study, we used six MPTP-exposed cynomolgus monkeys already primed and exhibiting L-dopa-induced dyskinesias to evaluate both the antiparkinsonian and dyskinetic effect upon challenge with two oral doses (60 and 90 mg/kg) of KW-6002 administered alone or in combination with L-dopa/benserazide (50/12.5 mg) [4].
• Large doses of benserazide (1.5 gm) did not modify the hypotensive effect of 1.0 gm of alpha methyldopa in untreated hypertension but significantly reduced the central nervous side effects of sedation and dry mouth [5].

Psychiatry related information on benserazide

• However, the combination of SIB-1508Y and levodopa/benserazide caused significant improvements in both cognition and motor aspects of task performance, and did so at one third to one sixth of the levodopa dose necessary to improve only motor function [6].
• When co-administered, KW-6002 potentiated the effects of L-dopa/benserazide on motor activity (up to 30%) without affecting the dyskinetic response [4].
• However, when given ICV twice daily in concentrations of 10 ng-2.0 micrograms per 5.0 microliters volume, benserazide attenuated the rats' alcohol drinking significantly [7].
• After a 2-5 hour control period the subjects received 150 mg of benserazide, and pulsatile L-5-hydroxytryptophan (every 30 minutes in the Kallmann's patients and every 45 minutes in the subjects with anorexia nervosa) [8].
• In cats pretreated with Ro 4-4602, an inhibitor of peripheral decarboxylase, both drugs did not produce drowsiness and markedly activated self-stimulation [9].

High impact information on benserazide

• In a study of 3 patients in whom L-dopa/benserazide was started, plasma ALAAD rose gradually over 3 to 4 weeks [10].
• The hyperinsulinaemic and hypoglycaemic actions of 5HTP in normal mice were prevented completely by pretreatment with benserazide, an inhibitor of aromatic amino acid decarboxylase [11].
• Among the catechol drugs used in the L-DOPA treatment of Parkinson's disease, the COMT inhibitors entacapone and tolcapone were not methylated, whereas the DOPA decarboxylase inhibitor benserazide was 15 times more specific substrate than L-DOPA, the target of COMT inhibition [12].
• A single morning dose of dual-release formulation was compared with a slow-release formulation of L-dopa plus benserazide in a randomized, double-blind, cross-over study in 16 fluctuating patients with PD [13].
• RESULTS: Preservation of the hippocampal CA1 cells was found in the brains treated with 300 mg/kg DOPS plus benserazide (neuronal density, 125 +/- 24 cells per millimeter) compared with the vehicle-treated ones (49 +/- 11 cells per millimeter) (P < .01) [14].

Chemical compound and disease context of benserazide

• In four patients with Parkinson disease, we compared carbidopa combined with levodopa (Sinemet) and benserazide combined with levodopa (Madopar) [15].
• Twenty-six patients affected by Parkinson's disease were treated with a 2-Br-alpha-ergocriptine (CB 154): 14 cases were given CB 154 alone, and 12 were given CB 154 along with L-dopa plus benserazide (Madopar) [16].
• Alternatively, benserazide could act by its central inhibition of aldehyde dehydrogenase, which in turn would concomitantly elevate levels of acetaldehyde and thereby reduce alcohol drinking [7].
• Four other MPTP-monkeys received LD/benserazide plus CI-1041; only one of them developed mild dyskinesias at the end of the fourth week of treatment [17].
• The data gathered indicate that benserazide-induced hyperprolactinemia in parkinsonian patients could be due to a direct effect of the drug at the hypothalamic level and consequently to an inhibition of dopamine decarboxylation in the tuberoinfundibular dopaminergic system [18].

Biological context of benserazide

• The pharmacokinetics of levodopa differs when it is combined with benserazide or carbidopa [19].
• In the absence of benserazide, only a limited amount of the L-DOPA taken up was decarboxylated to dopamine in cell monolayers; the Km value (in microM) for decarboxylation of intracellular L-DOPA in LLC-PK1 and OK cells was 61 +/- 14 and 108 +/- 36, respectively [20].
• By means of the aromatic L-amino acid decarboxylase inhibitors Ro 4-4602 and NSD 1015, an enhancement of TP hydroxylation of about 35% was demonstrated [21].
• A DOPA decarboxylase inhibitor in clinical use, benserazide, is, however, a much superior catechol-O-methyltransferase substrate and may have the therapeutic advantage of decreasing methylation of L-DOPA [2] [22].
• CONCLUSIONS: Our study is the first investigation where the kinetics of benserazide and Ro 04-5127 have been described by a compartmental model [23].

Anatomical context of benserazide

• METHODS: Male mongolian gerbils were treated with DOPS (30, 100, or 300 mg/kg IP) plus benserazide (10 mg/kg IP) (n = 28) or vehicle (n = 7) before 3.5 minutes of forebrain ischemia [14].
• 5-HT (10 micrograms in 0.5 microliter) injected in the substantia nigra, pars compacta, like GBL, significantly increased Ro 4-4602-induced accumulation of DOPA in the striatum [24].
• Differential effect of benserazide (Ro4-4602) on the concentration of indoleamines in rat pineal and hypothalamus [25].
• 2. In the presence of benserazide (50 microM), L-DOPA was rapidly accumulated in LLC-PK1 cells (cultured in collagen-treated plastic) attaining equilibrium at 30 min of incubation [26].
• Differential effect of benserazide on catecholamine concentrations in the rat pineal, cerebral cortex and hypothalamus [27].

Associations of benserazide with other chemical compounds

• The effect of benserazide administration on the secretion of GH, PRL, and TSH has been considered as an index of dopamine regulatory actions [28].
• High salt suppressed cortical COX-2 expression, which was attenuated by inhibition of dopamine production with benserazide or the DA1 receptor antagonist, SCH-23390 [29].
• 3. Prevention by allopurinol or benserazide of the tryptophan-induced increase in the haem saturation of tryptophan pyrrolase renders this haem available for further repression of synthase synthesis [30].
• Levodopa treatment, alone or in combination with two different dopa-decarboxylase inhibitors, benserazide and carbidopa, does not modify the renin response to posture or to frusemide [31].
• The selectivity of benserazide and phenelzine toward inhibition of benzylamine oxidase (BzAO) and monoamine oxidases (MAO-A and MAO-B) was studied in homogenates of rat skull and lung [32].

Gene context of benserazide

• To minimize side-effects, peripheral decarboxylase inhibition was achieved with benserazide (Ro 4-4602.) PRL increased significantly (P less than 0.01) after benserazide alone in all subjects [33].
• Benserazide administration had no effect of basal GH levels, but a significant increase of GH release (P less than 0.01) was noticed 30-120 min after the end of 1-5 HTP infusion in both men and women [33].
• Tyrosine hydroxylase inhibitor (H44/68) blocked SG behaviors, but dopamine-beta-hydroxylase inhibitors (FLA 63 and U-14, 624) and combined administration of L-3,4-dihydroxyphenylalanine and Ro-4-4602 enhanced it [34].
• This protective effect resulted from inhibition of TH and the consequent decrease in DA concentration, because treatment with L-DOPA/benserazide, which bypasses TH inhibition induced by alpha-MPT, reversed the protective effect produced by this drug [35].
• Nine acromegalic patients and nine normal subjects were given a single 125 mg oral dose of benserazide, and serum GH, PRL, and TSH were determined by RIA methods every 30 min for 4 h [28].

Analytical, diagnostic and therapeutic context of benserazide

• The patients were then given one tablet of Madopar((R)) (100 mg of L-dopa and 25 mg of benserazide), and the microdialysis was continued for another 210 min [36].
• The aromatic amino acid decarboxylase inhibitor used was difluoromethyl-DOPA, which was shown to be more stable than NSD 1015 or Ro 4-4602 in the perfusion fluid [37].
• 2. Studies were performed at 5-7 days post lesion (group 1 animals), at 21 days (group 2) when denervation supersensitivity was evident by contralateral turning to apomorphine and at the same time but following 7 days dosing with LDME plus benserazide (group 3) [38].
• However, in benserazide- or L-dopa-treated animals, basal urine flow was not different from the control group [39].
• After treatment with benserazide plus L-DOPA, an acute injection of L-DOPA evoked a release of dopamine which was twice as large in the as/agu rats compared with controls [40].

References