Effects of supplementary Da Dingfeng Zhu therapy on patients with Parkinson's disease of liver-kidney yin deficiency pattern.

BACKGROUND: This study aimed to verify whether the combined use of Da Dingfengzhu and Western medicine in treating Parkinson's disease (PD) can lead to therapeutic efficacy and symptom alleviation, thereby achieving a complementary and synergistic effect. METHODS: In this study, 158 patients were initially enrolled, with 116 eligible patients randomly divided into a control and an observation group. The control group received levodopa/benserazide and pramipexole, while the observation group received Da Dingfengzhu combined with levodopa/benserazide and pramipexole for 12 weeks. Baseline patient characteristics, adverse reactions, and blood samples were collected at baseline and 12 weeks post-treatment. The Unified Parkinson's Disease Rating Scale (UPDRS) was used to assess symptom severity at baseline, four weeks into treatment, and 12 weeks post-treatment. RESULTS: Adverse reactions during treatment were similar in both groups, suggesting that the combined therapy in the observation group did not increase adverse effects. Both groups showed improvements in UPDRS scores, with the observation group displaying more significant symptom alleviation at 4 and 12 weeks. Moreover, the observation group exhibited more pronounced increases in serum neurotrophic factor-3 and dopamine levels and greater reductions in oxidative stress and inflammatory response markers. CONCLUSION: In conclusion, the combination of Da Dingfengzhu with levodopa/benserazide and pramipexole for treating PD shows significant clinical potential and is worthy of broader application.

Yokukansan, a Traditional Japanese Medicine, Enhances the L-DOPA-Induced Rotational Response in 6-Hydroxydopamine-Lesioned Rats: Possible Inhibition of COMT.

The aim of the present study was to investigate the effects of the traditional Japanese medicine yokukansan (YKS) on the function of dopamine (DA) in the rat nigrostriatal system. Unilateral 6-hydroxydopamine lesions were produced in the rat nigrostriatal system. Despite a marked loss in the striatal immunoreactivity of tyrosine hydroxylase on the lesion side, striatal serotonin (5-HT) immunoreactivity was not affected. Treatment using L-3,4-dihydroxyphenylalanine (L-DOPA) in conjunction with benserazide for 15 d induced abnormal involuntary movements (AIMs) such as locomotive (rotational response), axial, forelimb, and orolingual movements in the lesioned rats. The L-DOPA-induced locomotive and axial, but not forelimb and orolingual, AIMs were significantly increased and prolonged by the pre-administration of YKS. We next investigated the effects of YKS on the production of DA from L-DOPA in 5-HT synthetic RIN 14B cells. RIN 14B cells produced DA and its metabolite, 3-methoxytyramine (3-MT), following L-DOPA treatment. YKS significantly augmented DA production and inhibited its metabolism to 3-MT in a manner similar to the catechol-O-methyltransferase (COMT) inhibitor entacapone. YKS and some alkaloids (corynoxeine: CX, geissoschizine methyl ether: GM) in Uncaria hook, a constituent herb of YKS, also inhibited COMT activity, indicating that the augmenting effect of YKS on L-DOPA-induced DA production in 5-HT synthetic cells was due to the inhibition of COMT by CX and GM. Our results suggest that YKS facilitates the DA supplemental effect of L-DOPA, and that COMT inhibition by CX and GM contributes, at least in part, to the effects of YKS.

Novel Inducers of Fetal Globin Identified through High Throughput Screening (HTS) Are Active In Vivo in Anemic Baboons and Transgenic Mice.

High-level fetal (γ) globin expression ameliorates clinical severity of the beta (ß) hemoglobinopathies, and safe, orally-bioavailable γ-globin inducing agents would benefit many patients. We adapted a LCR-γ-globin promoter-GFP reporter assay to a high-throughput robotic system to evaluate five diverse chemical libraries for this activity. Multiple structurally- and functionally-diverse compounds were identified which activate the γ-globin gene promoter at nanomolar concentrations, including some therapeutics approved for other conditions. Three candidates with established safety profiles were further evaluated in erythroid progenitors, anemic baboons and transgenic mice, with significant induction of γ-globin expression observed in vivo. A lead candidate, Benserazide, emerged which demonstrated > 20-fold induction of γ-globin mRNA expression in anemic baboons and increased F-cell proportions by 3.5-fold in transgenic mice. Benserazide has been used chronically to inhibit amino acid decarboxylase to enhance plasma levels of L-dopa. These studies confirm the utility of high-throughput screening and identify previously unrecognized fetal globin inducing candidates which can be developed expediently for treatment of hemoglobinopathies.

Mucuna pruriens in Parkinson Disease: A Kinetic-Dynamic Comparison With Levodopa Standard Formulations.

OBJECTIVES: We compared levodopa (LD) kinetic-dynamic profile of a dose of LD/aromatic amino acid decarboxylase peripheral inhibitors versus a nominally equivalent dose of a commercial Mucuna pruriens (Mucuna) seeds extract in 2 patients with Parkinson disease chronically taking LD standard combined with self-prescribed Mucuna. METHODS: Patients were challenged with a fasting morning dose of 100 mg LD/25 mg carbidopa (patient 1) or benserazide (patient 2) versus 100 mg LD from Mucuna capsules in 2 different sessions, after a 12-hour standard LD formulations' washout. They underwent kinetic-dynamic LD monitoring based on LD dose intake and simultaneous serial assessments of plasma drug concentrations and motor test performances. Quantitative analysis of LD in Mucuna capsules was also performed. RESULTS: Levodopa bioavailability was markedly lower after Mucuna administration compared with LD standard formulations: in patient 1, peak plasma LD concentration (Cmax) decreased from 2.0 to 1.0 mg/L and the area under the plasma concentration time curve from 137 to 33.6 mg/L per minute; in patient 2, Cmax was 0.7 mg/L after LD/benserazide and nearly undetectable after Mucuna. In patient 1, impaired LD bioavailability from Mucuna resulted in reduced duration and overall extent of drug response compared with LD/carbidopa. In patient 2, no significant subacute LD motor response was observed in either condition. Quantitative analysis of Mucuna formulation confirmed the 100 mg LD content for the utilized capsules. CONCLUSIONS: Our results show an impaired LD bioavailability from Mucuna preparation, as expected by the lacking aromatic amino acid decarboxylase inhibitors coadministration, which might explain the suggested lower dyskinetic potential of Mucuna compared with standard LD formulations.

An improved model to investigate the efficacy of antidyskinetic agents in hemiparkinsonian rats.

A number of experimental models of L-DOPA-induced dyskinesia have been proposed, but these models result in a low to medium rate of dyskinetic animals with mild to severe symptoms. The objective of this study was to combine a model of 6-OHDA-induced parkinsonism and of L-DOPA-induced dyskinesia in rats to establish a reliable preclinical model. Two stereotaxic injections of 6-OHDA were administered in the left striatum. This model led to 90-100% of rats with a marked contralateral circling behaviour, significant limb use asymmetry (20%), a decrease in ipsilateral striatal dopamine content (70%) and degeneration of dopamine neurons in the substantia nigra (70%). Chronic treatment with L-DOPA was administered for 35 days and consisted of three phases with incremental daily doses. The third phase resulted in 83-90% of rats developing severe abnormal involuntary movements (AIMs) which included limb and locomotive dyskinesia, axial dystonia and orolingual dyskinesia. Reproducibility of the model, criteria of strict blinding, placebo-controlled design, randomization of study subjects and pretrial determination of sample size were used to measure efficacy of amantadine and istradefylline and to validate the protocol design. Acute or subchronic post-treatment with amantadine reduced the severity of dyskinesia while istradefylline punctually attenuated AIMs. Our experimental conditions using gradual development of dyskinesia induced by increasing doses of L-DOPA resulted in a reliable model of L-DOPA-induced dyskinesia with a high rate of dyskinetic rats.

[Effects of bushenhuoxue granules on sleep quality in Parkinson's patients].

OBJECTIVE: To study the effects of Bushenhuoxue Granules on Parkinson's disease sleep scale (PDSS) score in Parkinson's patients. METHODS: 120 patients were enrolled and divided into two groups randomly,the control group were treated with placebo and treatment group with Bushenhuoxue Granules, both group based on Madopar treatment. Double-blinded clinical trial was adopted in treatment period. Follow-up period for 6 months, PDSS was adopted to measure sleep condition of PD patients at baseline time, after 3 months and after 9 months. RESULTS: Bushenhuoxue Granules treatment group showed a higher efficacy than the placebo group in relieving the sleep disorders of Parkinson disease patients,both in treatment and follow-up period (P < 0.01). No adverse effects were found in this trial. CONCLUSIONS: Bushenhuoxue Granules can markedly improve sleep disorders in Parkinson's patients. The effects are stable and obvious along with the process of treatment.

Endurance exercise modulates levodopa induced growth hormone release in patients with Parkinson's disease.

Acute levodopa (LD) application and exercise release human growth hormone (GH). An earlier trial showed, that combined stimulus of exercise and LD administration is the best provocative test for GH response in healthy participants. Objective was to show this combined effect of LD application and exercise on GH response and to investigate the impact on LD metabolism in 20 previously treated patients with Parkinson's disease (PD). We measured GH- and LD plasma concentrations following soluble 200 mg LD/50 mg benserazide administration during endurance exercise and rest on two separate consecutive days. GH concentrations significantly increased on both days, but GH release was significantly delayed during rest. LD metabolism was not altered due to exercise in a clinical relevant manner. Exercise induced a significant faster LD stimulated GH release in comparison with the rest condition. We did not find the supposed increase of LD induced GH release by endurance exercise. We assume, that only a limited amount of GH is available for GH release in the anterior pituitary following an acute 200 mg LD administration. GH disposal also depends on growth hormone releasing hormone (GHRH), which is secreted into hypothalamic portal capillaries. During the exercise condition, the resulting higher blood pressure supports blood flow and thus GHRH transport towards the GH producing cells in the pituitary. This might additionally have caused the significant faster GH release during exercise.

[The effect of shourong compound formula on levels of dopamine and its metabolites in brain of Parkinson's disease mice induced by reserpine].

OBJECTIVE: To investigate the effect of Shourong compound formula on treating Parkinson's disease. METHOD: Parkinson's disease model mice induced by reserpine was used and by HPLC-ED the levels of Dopamine (DA) and its metabolites were determined. RESULT: Madopar could increase the levels of DA in brain of PD mice. The effect of madopar together with Sourong compound formula was better than that of madopar(P < 0.001). CONCLUSION: Shourong compound formula together with madopar has synergic effect on increase of DA level in brain and can reduce clinic dose of madopar so that side effect of madopar can be decreased.

Neurotoxic effects of amphetamine plus L-DOPA.

1. Male Swiss Webster mice were administered a series of amphetamine injections preceded by either saline or L-DOPA. 2. This injection regimen was performed for either one, two or three consecutive weeks and neurotoxic effects of the drugs were determined one week later. 3. Amphetamine treatment for two weeks produced a greater striata-dopaminergic lesion that treatment for only one week. Three weeks of treatment did not exacerbate the lesion, indicating that the damage had reached maximal levels. 4. L-DOPA pretreatment did not significantly alter any of the toxic effects of the amphetamine. Therefore, some dopaminergic neurons may be resistant to the toxic effects of amphetamine.

Effects of Hemerocallis flava on motor activity and the concentration of central monoamines and its metabolites in rats.

In this study, we used behavioral and biochemical methods to investigate the effects of Hemerocallis flava (Liliaceae) (abbreviated as HF) on motor activity and the concentration of monoamines in rats. The water fraction of the resuspended HF extract was most active in reducing the motility in rats. The water fraction of the HF extract enhanced the reduction of locomotor activity produced by alpha-methyl-p-tyrosine and 5-hydroxytryptophan, but it reduced the increase of locomotor activity produced by L-dopa plus benserazide and p-chlorophenylalanine. Furthermore, the water fraction of the HF extract significantly decreased the concentration of norepinepherine in the cortex and the concentration of dopamine and serotonin in the brain stem. It also increased the concentration of vanilylmandelic acid in the cortex, homovanillic acid and 5-hydroxyindole-acetic acid in the brain stem. These results suggest that the reduction of locomotor activity produced by the water fraction of HF extract may be related to the decrease in the concentration of norepinepherine in the cortex and the concentration of dopamine and serotonin in brain stem.

Effect of L-dopa loading on 5-HTP decarboxylation in rat brain areas.

The time course of 5-hydroxytryptophan (5-HTP), serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in four rat brain areas (hypothalamus, hippocampus, striatum and olfactory bulbs) were investigated after treatment with L-dopa (125 mg/kg, ip) + benserazide (50 mg/kg, ip). 5-HTP levels increased as early as 0.5 h, showed maximum accumulation at 1.5 h and returned to control levels within 4 h, while 5-HT was markedly decreased in all four structures, with a maximum effect at 1.5 h (approximately -70%) in the four areas. The decrease in 5-HT was not accompanied by changes in 5-HIAA levels. In agreement with previous studies, these data demonstrate that L-dopa loading interferes with serotonin metabolism in the rat brain. However, in addition to the releasing action of newly-synthesized dopamine, the accumulation of 5-HTP and the parallel decrease in 5-HT indicate a reduction in 5-HT synthesis. This inhibition could be explained by a competitive effect of L-dopa for aromatic aminoacid decarboxylase activity.

Dissociation of receptor sensitivity changes in rat perifornical hypothalamus: a role for dopaminergic receptors in amphetamine anorexic tolerance.

Development of a contingent tolerance to amphetamine (AMPH) anorexia has been reported with chronic s.c. injections in rats (Ghosh and Parvathy, 1973, 1976). Using this model, the present study examined the role of potential receptor sensitivity changes in the beta adrenergic and/or dopamine (DA) receptors in the perifornical hypothalamus (PFH) during chronic central and peripheral drug injections. Chronic injections of AMPH into the PFH, or l-dopa injected s.c., resulted in persistent anorexia in the daily first 2 hr of eating on all test days compared with the next 2 hr that showed a progressive increase in eating with subsequent injections, the net effect being an apparent tolerance to its 4 hr anorexic effect. The tolerance patterns obtained with these two treatments were essentially the same as that of s.c. AMPH, suggesting a role for PFH catecholamine synapses, particularly at the postsynaptic receptor level. Selective beta adrenoceptor-mediated anorexia, as obtained with chronic PFH-injected nor-adrenaline and isoprenaline, was dose-dependent and persistent on all days, suggesting that no change in the sensitivity of PFH beta adrenoceptors had occurred. This contrasted with the PFH-injected DA, which produced a rapid tolerance development due to a progressive loss of effect in the first 2 hr. Present findings suggest that although beta adrenergic and DA mechanisms act in concert in eliciting the acute anorexic effects of AMPH, DA, rather than beta adrenergic system, has a predominant influence in the development of tolerance to the anorexic effect of AMPH.

Nicotinic acid or N-methyl nicotinamide prolongs elevated brain dopa and dopamine in L-dopa treatment.

A peripheral dopa decarboxylase inhibitor, benserazide, was given ip, followed by intubation with L-dopa. Brain dopa and DA levels were elevated maximally between 0.5-2.5 hr and 1.0-2.5 hr, respectively. Dopa in serum, liver, and brain were at control values after 4 hr. Supplementation of dopa with NAM or NAC, as possible methyl group acceptors to lower catabolism of DA, showed that NAM had no effect on DA levels or on SAM. However, with both NAC and N-methyl NAM (a methylated compound intended as a control) at time periods where dopa and DA were normally decreasing, the brain levels were increased over control values with benserazide and dopa alone. NAC or N-methyl NAM appeared to extend the period of elevated brain DA levels with L-dopa treatment. The mechanism responsible for these results is uncertain.

[Behavior disorder in rats induced by Madopar and its pharmacological correction]. / Narushenie povedeniia krys, vyzvannoe madoparom i ego farmakologicheskaia korrektsiia.

Administration to rats of madopar in a dose of 125 mg/kg produced stereotypy, decrease in the exploration activity in the open field test, loss of the ability to decide the extrapolation problem (escape out of acute stressful situation). The latter type of behavioral pathology alone was selectively averted by administering the classical neuroleptics fluorophenazine, haloperidol and its analog azaperone. Atypical neuroleptics and the the antidepressant imipramine were less effective and reduced but animals' motor excitation induced by madopar according to the extrapolation avoidance test. The tranquilizer phenazepam did not influence behavioral pathology in this test. The data obtained suggest that impairment of the animals' behavioral pattern in the extrapolation avoidance test on madopar administration in a dose of 125 mg/kg may serve an experimental model for evaluating the neuroleptic effect of the drugs.

Changes in brain catecholamine levels following DL-dopa are not potentiated by deuterium substitution.

Adult male Wistar rats were treated with either DL-dopa, D3-DL-dopa or vehicle and sacrificed at various time intervals after treatment. Brain dopamine and noradrenaline concentrations were measured using quantitative mass spectrometric analysis. After treatment with DL-dopa or D3-DL-dopa, total dopamine levels increased above control values; however, no differences were observed between the two drug treatments. Total noradrenaline levels were not significantly altered by treatment with either DL-dopa or D3-DL-dopa. Deuterium substitution did not appear to affect catecholamine deamination or beta-hydroxylation in vivo.

In vivo increase in hypothalamic cyclic AMP following 5-hydroxytryptophan administration in rats.

The administration of 5-hydroxytryptophan (5-HTP, 100 mg/kg, i.p.) consistently increased hypothalamic cyclic AMP levels in rats treated 10 days earlier with the serotonin neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), to produce 5-HT receptor supersensitivity. However 5-HTP (100 mg/kg), failed to cause an increase in hypothalamic cyclic AMP in rats not pretreated with 5,7-DHT. The 5-HTP-induced increase in cyclic AMP was blocked by the decarboxylase inhibitor, benserazide (RO 4-4602, 800 mg/kg) and by the 5-HT antagonist metergoline (5 mg/kg). Other treatments that caused a significant elevation of hypothalamic cyclic AMP included: (a) L-Tryptophan plus the monoamine oxidase inhibitor, tranylcypromine, and (b) the serotonin agonist, 1-(m-trifluromethylphenyl)-1-piperazine. The 5-HT antagonist, methysergide, blocked the serotonin receptor mediated behavioral syndrome, but failed to prevent the increase in hypothalamic cyclic AMP. Moreover, the 5-HT agonist, 5-methoxy-N, N-dimethyltryptamine, (5-Me-DMT), induced a strong behavioral syndrome but failed to significantly increase hypothalamic cyclic AMP. These findings suggest that activation of 5-HT receptors somewhere in the brain causes an increase in hypothalamic cyclic AMP, but further studies will be needed to determine whether this is a direct result of activation of the 5-HT receptors in the hypothalamus.

Differential effect of benserazide on catecholamine concentrations in the rat pineal, cerebral cortex and hypothalamus.

The effect of benserazide, an aromatic L-amino acid decarboxylase inhibitor, has been investigated simultaneously on the noradrenaline content of the pineal, hypothalamus and cerebral cortex of the rat. The dopamine concentration of the hypothalamus was investigated in the same animals. Benserazide had no effect on pineal noradrenaline content throughout the light phase and the early part of the dark phase but caused a drastic reduction in the latter part of the dark period. The drug had no significant effect on noradrenaline or dopamine contents of the hypothalamus. Benserazide treatment caused a large reduction in the noradrenaline content of the cerebral cortex throughout 24 hr. However, this effect is unlikely to be due to a differential penetration of benserazide into the brain areas as a similar degree of decarboxylase inhibition was observed in all three tissues.

The participation of hypothalamic dopamine in morphine-induced prolactin release in man.

In order to assess the role of dopamine in opiate-induced prolactin secretion, morphine alone or in combination with the dopamine blocker metoclopramide, or the L-aromatic aminoacid decarboxylase inhibitor benserazide, was administered to a group of normal adult men. Morphine (10 mg) stimulated prolactin release in all subjects; however, the effect was totally abolished when 10 mag metoclopramide or 200 mg benserazide were given before the opiate agonist. The prolactin releasing effect of a sub-maximal metoclopramide dose (1 mg) was potentiated by morphine. In vitro, benserazide was totally inactive in stimulating prolactin release by isolated anterior pituitary cells. Moreover, benserazide failed to alter the inhibiting action of dopamine on prolactin release. The data suggest that opiates stimulate prolactin release in man by acting through dopaminergic mechanisms.

Enhancement by the putative 5-HT receptor agonist 8-OH-2-(di-n-propylamino)tetralin of the acoustic startle response in the rat.

Two 2-(di-n-propylamino)tetralin (DPAT) compounds, 8-OH-DPAT and 5-OH-DPAT, with reported effects on central 5-HT and DA receptors respectively, were tested for their effects on the acoustic startle response in rats. 8-OH-DPAT was given in doses of 0.25-2.0 mg/kg IP and 5-OH-DPAT in doses of 1.0-8.0 mg/kg IP. Both compounds increased the startle response significantly in a dose-dependent manner, but 8-OH-DPAT appeared to be about 30 times as potent and to have a higher efficacy than 5-OH-DPAT. In addition, the effects on the startle response of L-5-HTP, 25-100 mg/kg IP, and L-dopa, 25-100 mg/kg IP, administration to animals pretreated with the inhibitor of aromatic L-amino acid decarboxylase, benserazide (25 mg/kg IP) were included for comparison. A small, but significant increase in the startle amplitude was found after the highest dose of L-5-HTP, whereas no effects were observed after L-dopa administration.

Differential effect of benserazide (Ro4-4602) on the concentration of indoleamines in rat pineal and hypothalamus.

1 Low doses (50 and 80 mg/kg) of benserazide (Ro4-4602), an aromatic amino acid decarboxylase inhibitor, markedly reduced 5-hydroxytryptamine and melatonin in the rat pineal gland without affecting hypothalamic 5-hydroxytryptamine. 2 This differential effect shows that inhibition of the pineal gland decarboxylase activity is possible, and confirms that the rat pineal gland is accessible to peripherally acting agents.