Clinical analysis of nine infants with tyrosine hydroxylase deficiency / 中华神经科杂志

Objective:To explore the clinical characteristics of children with tyrosine hydroxylase deficiency (THD) in order to recognize this disease early as to optimize the treatment to improve the prognosis.Methods:A retrospective analysis was done on the clinical data of nine children with THD who were diagnosed at the Children′s Hospital of Fudan University from May 2018 to May 2020, including name, gender, age, age of onset, age of presentation, age of diagnosis, clinical manifestations, head imaging, tyrosine hydroxylase gene mutation, treatment, follow-up, and other results, which were classified according to Willemsen′s method, and the clinical characteristics were summarized and a literature review was carried out.Results:There were five males and four females with the age at onset ranged from newborn to two years and six months (median three months). The duration of diagnosis ranged from four months to five years and seven months (median nine months). The presenting symptom was motor retardation in seven cases. Clinical symptoms included hypokinesia in eight cases, limb dystonia in five cases, truncal hypotonia in four cases, dysphagia/dysarthria in four cases, oculogyric crises in four cases, tremor in three cases, rigidity in three cases, mask faces in three cases, bilateral ptosis in two cases, hypersalivation/sweating in two cases, diurnal fluctuation in two cases, myoclonic jerks in one case, and status dystonicus in one case. Cranial magnetic resonance imaging was normal in seven cases and non-specific in two cases (backward myelination in one case and bilateral ventricle enlargement and decreased white matter in another one). Eight tyrosine hydroxylase gene variants were found, including four missense variants, two frameshift variants, one shear variants and one nonsense variant, as well as three novel variants [c.1505_1518dup (p.R507Afs *23), c.1128_1138del (p.Q377Gfs *12), c.1058A>G(p.H353R)]. All patients were treated with levodopa and benserazide hydrochloride tables. The initial and maintenance doses of type A were 1.7-8.3 mg·kg -1·d -1 and 4.5-20.0 mg·kg -1·d -1, respectively. The initial and maintenance doses of type B were 1.7-12.5 mg·kg -1·d -1 and 4.6-12.0 mg·kg -1·d -1, respectively. In type A, four patients had dyskinesis which was relieved by decreasing the dose or maintaining the same dose of levodopa. One case of type B had dyskinesis which was self-resolving. Conclusions:Although the clinical manifestations of this disease are varied, the initial symptoms in children with onset within the first year of life are mostly hypokinesia, truncal hypotonia, and dystonia in limbs. It is recommended that children with THD, regardless of clinical type, should start at the minimum dose for easy segmentation in the range of 1.0-5.0 mg·kg -1·d -1, and the maintenance dose can be adjusted according to the individual response of the child. The incidence of dyskinesia of this disease is not low, but most can be treated by decreasing the initial dose and delaying the dosage rate.

Association of excessive daytime sleepiness and freezing of gait in Parkinson′s disease / 中华神经科杂志

Objective:To investigate the relationship between excessive daytime sleepiness and freezing of gait in Parkinson′s disease (PD).Methods:A total of 136 participants with PD were consecutively recruited between August 2017 and January 2018 at the Department of Neurology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. The patients were divided into freezers with 50 patients and nonfreezers with 86 patients. The clinical characteristics of freezers and nonfreezers in PD patients were assessed. In the longitudinal study, a cohort of nonfreezers with 86 patients at baseline clinical visit for a maximum of 18 months were prospectively followed. The patients were divided into the excessive daytime sleepiness group ( n=14) and the non-excessive daytime sleepiness group ( n=72). Then a Cox regression analysis was performed to further investigate the relationship between excessive daytime sleepiness and freezing of gait in PD, and explore risk factors for freezing of gait. Results:The freezers had significantly worse sleep compared with the nonfreezers. The proportion of patients with excessive daytime sleepiness in freezers was higher than nonfreezers [40% (20/50) vs 16% (14/86), χ2=9.49, P=0.002]. The proportion of freezers in the patients with excessive daytime sleepiness was significantly higher than that in the patients without excessive daytime sleepiness [59% (20/34) vs 29% (30/102), χ2 =9.49, P=0.002]. During a maximum of 18-month follow-up, freezing of gait incidence (6/7) in the excessive daytime sleepiness group was significantly higher than that in the non-excessive daytime sleepiness group [21% (8/39) , χ2 =9.04, P=0.003]. Excessive daytime sleepiness ( HR=8.03, 95% CI 2.58-24.99, P<0.01) and high L-dopa equivalent daily dose ( HR=5.92, 95% CI 1.95-17.93, P=0.002) were significantly associated with an increased hazard of freezing of gait. Conclusion:Excessive daytime sleepiness and high L-dopa equivalent daily dose may be risk factors for the development of freezing of gait in PD in the future.

Heterogeneous expression of DOPA decarboxylase to improve the production of dopamine in Escherichia coli / 生物工程学报

Dopamine is the precursor of a variety of natural antioxidant compounds. In the body, dopamine acts as a neurotransmitter that regulates a variety of physiological functions of the central nervous system. Thus, dopamine is used for the clinical treatment of various types of shock. Dopamine could be produced by engineered microbes, but with low efficiency. In this study, DOPA decarboxylase gene from Sus scrofa (Ssddc) was cloned into plasmids with different copy numbers, and transformed into a previously developed L-DOPA producing strain Escherichia coli T004. The resulted strain was capable of producing dopamine from glucose directly. To further improve the production of dopamine, a sequence-based homology alignment mining (SHAM) strategy was applied to screen more efficient DOPA decarboxylases, and five DOPA decarboxylase genes were selected from 100 candidates. In shake-flask fermentation, the DOPA decarboxylase gene from Homo sapiens (Hsddc) showed the highest dopamine production (3.33 g/L), while the DOPA decarboxylase gene from Drosophila Melanogaster (Dmddc) showed the least residual L-DOPA concentration (0.02 g/L). In 5 L fed-batch fermentations, production of dopamine by the two engineered strains reached 13.3 g/L and 16.2 g/L, respectively. The residual concentrations of L-DOPA were 0.45 g/L and 0.23 g/L, respectively. Finally, the Ssddc and Dmddc genes were integrated into the genome of E. coli T004 to obtain genetically stable dopamine-producing strains. In 5 L fed-batch fermentation, 17.7 g/L of dopamine was produced, which records the highest titer reported to date.

Diagnosis and treatment of parkinsonism with freezing of gait: A prospective study / 第二军医大学学报

[Abstract] Objective To study the clinical diagnosis and treatment of parkinsonism (PDS) with freezing of gait (FoG), so as to provide clues to delay the progress of the symptom. Methods A prospective study was designed. The outpatients of PDS with the main complaint of FoG were included and followed up for 2-6 years in the Department of Neurology, Changzheng Hospital, Naval Medical University (Second Military Medical University) from Nov. 2010 to Jan. 2016. The patients were given L-dopa first, and then antidepressants and other therapies (including other medication and surgery) were given if the previous treatments were not effective. The motor function of patients was evaluated by Hoehn-Yahr staging scale and the second and third part of the unified Parkinson disease rating scale (UPDRS); the general mental, behavior and emotional state were evaluated by the first part of UPDRS; the cognition was evaluated by minimum mental state examination (MMSE); depression and anxiety were evaluated by 17-item Hamilton depression scale (HAMD-17) and Hamilton anxiety scale (HAMA); and the severity of FoG was evaluated by the timed up and go test (TUGT). Results Six of the 15 cases with FoG were diagnosed as Parkinson disease (PD), and 9 had other disorders (2 with progressive supranuclear palsy, 3 with primary progressive FoG, 1 with frontotemporal dementia, 1 with vascular PDS, 1 with drug-induced PDS, and 1 with unknown-cause PDS). There were no significant differences in age, gender, severity of symptom or mental state (Hoehn-Yahr stage, UPDRS- score, UPDRS-Ⅱ score, UPDRS-III score, MMSE score, HAMD-17 score, HAMA score and TUGT time) between PD group and non-PD group (all P0.05). At the baseline, the FoG duration of PD patients ([7.50±2.66] years) was longer than that of non-PD patients ([2.56±0.88] years, P0.01). After treatment with increasing dose of L-dopa, 4 PD patients were improved while non-PD patients had no responses (4/6 vs 0/9, P＝0.01). Conclusion The causes of PDS with FoG are heterogeneous. The duration of FoG is helpful for diagnosis of idiopathic PD, while the severity of FoG has little value for etiological analysis. Increasing the dose of L-dopa is effective for FoG in advanced PD, while it has uncertain effect for FoG of other reasons.

In vitro dissolution and anti-vitiligo activity of isopsoralen nanostructured lipid carriers / 中草药

Objective To evaluate the in vitro dissolution characteristic of IPRN-NLC and to study its effects on B16F10 cells proliferation, melanin synthesis, and tyrosinase activity. Methods The dynamic dialysis was employed to compare the in vitro dissolution of IPRN and IPRN-NLC; MTT assay was used to detect the proliferation of B16F10; The tyrosinase activity was determined by L-DOPA-oxidation; The melain content was determined by GENMED Cell Melanin Quantitative Assay Kit. Results The accumulation dissolution of IPRN-NLC was 67.31% within 72 h, which showed sustained release; While the dissolution of IPRN-suspension, IPRN-physical mixture, and IPRN-DMSO were 53.34%, 90.30%, and 98.67%, respectively. The IPRN-NLC could significantly promote the proliferation, tyrosinase activity and melanin content compared with IPRN DMSO groups (P < 0.05) at the same concentration. Conclusion IPRN-NLC could increase the solubility of the drug with sustained release, and showed good cell biology intermiscibility, which could significantly increase the effects on B16F10 cells.

Evaluation of L-dopa, proximate composition with in vitro anti-inflammatory and antioxidant activity of Mucuna macrocarpa beans: A future drug for Parkinson treatment

Objective To investigate L-3, 4-dihydroxyphenylalanine (L-dopa, anti-Parkinson drug), anti-inflammatory activity, proximate nutritional composition and antioxidant potential of Mucuna macrocarpa (M. macrocarpa) beans. Methods L-dopa content was determined and quantified by high performance thin layer chromatography and reversed phase high-performance liquid chromatography (RP-HPLC) methods. Anti-inflammatory activity was performed by in vitro protein denaturation inhibition and human red blood cell membrane stabilisation activity. Proximate composition and elemental analysis were also investigated. The antioxidant potential (2,2-diphenyl-1-picrylhydrazyl, N-N-dimethyl-phenylenediamine and ferric-reducing antioxidant power) of M. macrocarpa beans were evaluated by using different extraction solvents. The RP-HPLC analysis also quantified significant phenolics such as gallic acid, tannic acid, p-hydroxybenzoic acid and p-coumaric acid. Results RP-HPLC quantification revealed that M. macrocarpa beans contain a high level of L-dopa [(115.41 ± 0.985) mg/g] which was the highest among the Mucuna species from Indian sub-continent. Water extract of seed powder showed strong anti-inflammatory and antioxidant potential. Proximate composition of M. macrocarpa beans revealed numerous nutritional and anti-nutritional components. RP-HPLC analysis of major phenolics such as tannic acid (43.795 mg/g), gallic acid (0.864 mg/g), p-coumaric acid (0.364 mg/g) and p-hydroxybenzoic acid (0.036 mg/g) quantified successfully from M. macrocarpa beans respectively. Conclusions This study suggests that M. macrocarpa is a potential source of L-dopa with promising anti-inflammatory, antioxidant and nutritional benefits.

Rational Drug Use Analysis of Parkinson's Disease with the First Time Attack of Epilepsy / 中国药师

Objective:To bring to doctors' attention to the first time attack of epilepsy in the patients with Parkinson' s disease, enhance the rational drug use and reduce the occurrence of adverse reactions in clinics. Methods: A Parkinson patient with the first time attack of epilepsy was synthetically analyzed on the mechanism of disease, therapy regimen and pharmaceutical care. Results:It was difficult to distinguish the symptom of epilepsy during the treatment of Parkinson' s disease from that of L-dopa induced dyskinesia, therefore, the suitable treatment was difficult to perform. Moreover, antiepileptic drug valproic acid could aggravate Parkinson syn-drome imperceptibly, which was easy to be ignored in clinics. Conclusion:L-dopa induced dyskinesia should try to avoid during the treatment of Parkinson, and should distinguish from the first time attack of epilepsy in order to choose proper antiepileptic drugs.

Evaluation of L-dopa, proximate composition with in vitro anti-inflammatory and antioxidant activity of Mucuna macrocarpa beans: A future drug for Parkinson treatment

Objective:To investigate L-3,4-dihydroxyphenylalanine (L-dopa,anfi-Parkinson drug),anti-inflammatory activity,proximate nutritional composition and antioxidant potential of Mucuna macrocarpa (M.macrocarpa) beans.Methods:L-dopa content was determined and quantified by high performance thin layer chromatography and reversed phase high-performance liquid chromatography (RPHPLC) methods.Anti-inflammatory activity was performed by in vitro protein denaturation inhibition and human red blood cell membrane stabilisation activity.Proximate composition and elemental analysis were also investigated.The antioxidant potential (2,2-diphenyl-1-picrylhydrazyl,N-N-dimethyl-phenylenediamine and ferric-reducing antioxidant power) of M.macrocarpa beans were evaluated by using different extraction solvents.The RP-HPLC analysis also quantified significant phenolics such as gallic acid,tannic acid,p-hydroxybenzoic acid and p-coumaric acid.Results:RP-HPLC quantification revealed that M.macrocarpa beans contain a high level of L-dopa [(115.41 ± 0.985) mg/g] which was the highest among the Mucuna species from Indian sub-continent.Water extract of seed powder showed strong antiinflammatory and antioxidant potential.Proximate composition of M.macrocarpa beans revealed numerous nutritional and anti-nutritional components.RP-HPLC analysis of major phenolics such as tannic acid (43.795 mg/g),gallic acid (0.864 mg/g),p-coumafic acid (0.364 mg/g) and p-hydroxybenzoic acid (0.036 mg/g) quantified successfully from M.macrocarpa beans respectively.Conclusions:This study suggests that M.macrocarpa is a potential source of L-dopa with promising anti-inflammatory,antioxidant and nutritional benefits.

Palmitoyl Serotonin Inhibits L-dopa-induced Abnormal Involuntary Movements in the Mouse Parkinson Model

L-3,4-dihydroxyphenylalanine (L-DOPA) is the most common treatment for patients with Parkinson's disease (PD). However, long term use of L-DOPA for PD therapy lead to abnormal involuntary movements (AIMs) known as dyskinesia. Fatty acid amide hydrolase (FAAH) is enriched protein in basal ganglia, and inhibition of the protein reduces dyskinetic behavior of mice. Palmitoyl serotonin (PA-5HT) is a hybrid molecule patterned after arachidonoyl serotonin, antagonist of FAAH. However, the effect of PA-5HT on L-DOPA-induced dyskinesia (LID) in PD have not yet been elucidated. To investigate whether PA-5HT relieve LID in PD and decrease hyperactivation of dopamine D1 receptors, we used the 6-hydroxydopomine (6-OHDA)-lesioned mouse model of PD and treated the L-DOPA (20 mg/kg) for 10 days with PA-5HT (0.3 mg/kg/day). The number of wall contacts with the forelimb in the cylinder test was significantly decreased by 6-OHDA lesion in mice and the pharmacotherapeutic effect of L-DOPA was also revealed in PA-5HT-treated mice. Moreover, in AIMs test, PA-5HT-treated mice showed significant reduction of locomotive, axial, limb, and orofacial AIMs score compared to the vehicle-treated mice. LID-induced hyper-phosphorylation of ERK1/2 and overexpression of FosB/ΔFosB was markedly decreased in 6-OHDA-lesioned striatum of PA-5HT-treated mice, indicating that PA-5HT decreased the dopamine D1 receptor-hyperactivation induced by chronic treatment of L-DOPA in dopamine-denervated striatum. These results suggest that PA-5HT effectively attenuates the development of LID and enhance of ERK1/2 phosphorylation and FosB/ΔFosB expression in the hemi-parkinsonian mouse model. PA-5HT may have beneficial effect on the LID in PD.

Effects of Gypenosides on Dopaminergic Neuronal Cell Death in 6-Hydroxydopamine-lesioned Rat Model of Parkinson's Disease with Long-term L-DOPA Treatment

The goal of this study was to determine whether gypenosides (GPS) exert protective effects against dopaminergic neuronal cell death in a 6-hydroxydopamine (OHDA)-lesioned rat model of Parkinson's disease (PD) with or without long-term 3,4-dihydroxyphenylalanine (L-DOPA) treatment. Rats were injected with 6-OHDA in the substantia nigra to induce PD-like symptoms; 14 days after injection, groups of 6-OHDA-lesioned animals were treated for 21 days with GPS (25 or 50 mg/kg) and/or L-DOPA (20 mg/kg). Dopaminergic neuronal cell death was assessed by counting tyrosine hydroxylase (TH)-immunopositive cells in the substantia nigra and measuring levels of dopamine, norepinephrine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in the striatum. Dopaminergic neuronal cell death induced by 6-OHDA lesions was ameliorated by GPS treatment (50 mg/kg). L-DOPA treatment exacerbated 6-OHDA-induced dopaminergic neuronal cell death; however, these effects were partially reversed by GPS treatment (25 and 50 mg/kg). These results suggest that GPS treatment is protective against dopaminergic neuronal cell death in a 6-OHDA-lesioned rat model of PD with long-term L-DOPA treatment. Therefore, GPS may be useful as a phytotherapeutic agent for the treatment of PD.

Antidepressant activity of spirulina platensis in experimentally induced dipression in mice.

The spray dried powder of Spirulina platensis was used to treatment of depression in different doses (100mg/kg, 200 mg/kg and 400 mg/kg) and Impramine (15mg/kg) as standard drug in experimental animal models like Forced swim test in mice, Tail suspension test in mice, Clonidine induced aggression behaviour in mice test, L-dopa induced hyper activity and aggressive behavior in mice, 5-HT induced head twitches in mice, From all the experimental model results were observed that the Spirulina platensis was possess the dose dependent anti depressant activity.

A Rat Model of Striatonigral Degeneration Generated by Simultaneous Injection of 6-Hydroxydopamine into the Medial Forebrain Bundle and Quinolinic Acid into the Striatum

A double toxin-double lesion strategy is well-known to generate a rat model of striatonigral degeneration (SND) such as multiple system atrophy-parkinsonian type. However, with this model it is difficult to distinguish SND from Parkinson's disease (PD). In this study, we propose a new rat model of SND, which is generated by simultaneous injection of 6-hydroxydopamine into the medial forebrain bundle and quinolinic acid into the striatum. Stepping tests performed 30 min after intraperitoneal L-dopa administration at 6 weeks post-surgery revealed an L-dopa response in the PD group but not the SND group. Apomorphine-induced rotation tests revealed no rotational bias in the SND group, which persisted for 2 months, but contralateral rotations in the PD group. MicroPET scans revealed glucose hypometabolism and dopamine transporter impairment on the lesioned striatum in the SND group. Tyrosine hydroxylase immunostaining in the SND group revealed that 74.7% of nigral cells on the lesioned side were lost after lesion surgery. These results suggest that the proposed simultaneous double toxin-double lesion method successfully created a rat model of SND that had behavioral outcomes, multitracer microPET evaluation, and histological aspects consistent with SND pathology. This model will be useful for future study of SND.

Mushroom tyrosinase inhibition activity of Aloe vera L. gel from different germplasms / 中国天然药物

In this study, lyophilized and methanolic extracts of aloe gel from different germplasms were evaluated for their potential to inhibit mushroom tyrosinase activity. The results showed potent inhibitory effect of Aloe vera gel extracts on L-dihydroxyphenylalanine (L-DOPA) oxidation catalyzed by tyrosinase in a dose-dependent manner. Significant differences in % inhibition of tyrosinase among the extraction methods and the germplasms were observed. The relative performance of the germplasms was evaluated with the help of posthoc multicomparison test. The methanolic extract was more effective than the lyophilized crude gel in all the germplasms. The inhibitory effect of the lyophilized gel and methanolic extract tested from five germplasms followed the order: RM > TN > S24 > OR > RJN. The germplasm RM showed the highest tyrosinase inhibition, and the maximum % inhibition noted was 26.04% and 41.18%, respectively for the lyophilized and methanolic extracts at 6 mg · mL(-1) concentration. Lineweaver-Burk plots of the different concentrations of L-DOPA in the absence and presence of lyophilized gel extract showed competitive inhibition of mushroom tyrosinase in all the germplasms. This study suggests that the germplasm RM could potentially be used for the isolation and identification of the effective tyrosinase inhibitory component, and ascertains the critical role of selecting the best source of germplasm for natural product isolation and characterization.

Epigallocatechin gallate attenuates L-DOPA-induced apoptosis in rat PC12 cells

In this study, the protective effects of EGCG on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced oxidative cell death in catecholaminergic PC12 cells, the in vitro model of Parkinson's disease, were investigated. Treatment with L-DOPA at concentrations higher than 150 microM caused cytotoxicity in PC12 cells, as determined using the 3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry detection. The apoptotic ratio was similar in cells treated with 100 microM EGCG plus 150 microM L-DOPA (5.02%) and the control (0.96%) (P > 0.05), and was lower than that of cells treated with L-DOPA only (32.24%, P < 0.05). The generation level of ROS (% of control) in cells treated with EGCG plus L-DOPA was lower than that in cells treated with L-DOPA only (123.90% vs 272.32%, P < 0.05). The optical density in production of TBARS in cells treated with L-DOPA only was higher than that in the control (0.27 +/- 0.05 vs 0.08 +/- 0.04, P < 0.05), and in cells treated with EGCG only (0.14 +/- 0.02, P < 0.05), and EGCG plus L-DOPA (0.13 +/- 0.02, P < 0.05). The intracellular level of GSH in cells treated with EGCG plus L-DOPA was higher than that in cells treated with L-DOPA only (233.25 +/- 16.44 vs 119.23 +/- 10.25, P < 0.05). These results suggest that EGCG protects against L-DOPA-induced oxidative apoptosis in PC12 cells, and might be a potent neuroprotective agent.

Treatment Results between Matched Pair of L-dopa Medication Treatment and Acupuncture Treatment Combination on Parkinson Disease / 日本東洋医学雑誌

Parkinson's disease is an incurable nerve disease.<br>We treated two groups randomly assigned to therapy with medications, or therapy with medications and acupuncture in combination.<br>The first group included 95 patients prescribed L-dopa medications and dopaminergic drugs, and the second group included 103 patients prescribed L-dopa and acupuncture treatment twice a month. We conducted follow-ups using Hoehn-Yahr index surveys and the UPDRS II and III for 5 years from treatment start.<br>Mean changes in the L-dopa group were 2.1±0.8 for the H-Y index, 12.2±7.2 for the UPDRS II, and 18.2±9.8 for the UPDRS III, while changes in the acupuncture combination group were 1.3±0.4 for the H-Y index, 7.6±5.0 for the UPDRS II, and 11.9±6.8 for the UPDRS III after 5 years.<br>Each result indicated a significant difference with repetition decentralization and statistical analysis methods.<br>Therefore, we believe acupuncture is a treatment for Parkinson's disease able to control its progress.

Lack of tolerance for the anti-dyskinetic effects of 7-nitroindazole, a neuronal nitric oxide synthase inhibitor, in rats

7-Nitroindazole (7-NI) inhibits neuronal nitric oxide synthase in vivo and reduces l-DOPA-induced dyskinesias in a rat model of parkinsonism. The aim of the present study was to determine if the anti-dyskinetic effect of 7-NI was subject to tolerance after repeated treatment and if this drug could interfere with the priming effect of l-DOPA. Adult male Wistar rats (200-250 g) with unilateral depletion of dopamine in the substantia nigra compacta were treated with l-DOPA (30 mg/kg) for 34 days. On the 1st day, 6 rats received ip saline and 6 received ip 7-NI (30 mg/kg) before l-DOPA. From the 2nd to the 26th day, all rats received l-DOPA daily and, from the 27th to the 34th day, they also received 7-NI before l-DOPA. Animals were evaluated before the drug and 1 h after l-DOPA using an abnormal involuntary movement scale and a stepping test. All rats had a similar initial motor deficit. 7-NI decreased abnormal involuntary movement induced by l-DOPA and the effect was maintained during the experiment before 7-NI, median (interquartile interval), day 26: 16.75 (15.88-17.00); day 28: 0.00 (0.00-9.63); day 29: 13.75 (2.25-15.50); day 30: 0.5 (0.00-6.25); day 31: 4.00 (0.00-7.13), and day 34: 0.5 (0.00-14.63), Friedman followed by Wilcoxon test,vs day 26, P < 0.05;. The response to l-DOPA alone was not modified by the use of 7-NI before the first administration of the drug (l-DOPA vs time interaction, F1,10 = 1.5, NS). The data suggest that tolerance to the anti-dyskinetic effects of a neuronal nitric oxide synthase inhibitor does not develop over a short-term period of repeated administration. These observations open a possible new therapeutic approach to motor complications of chronic l-DOPA therapy in patients with Parkinson’s disease.

Effects of L-dopa methyl ester on the strabismic amblyopia cats / 中国药理学通报

Aim To observe the effects of the L-dopa methyl ester (LDME) on the pattern visual evoked potentials (P-VEP) and the expression of c-fos mRNA in neurons of the visual cortex of kittens with strabismic amblyopia, and explore the therapeutic effect of L-dopa methyl ester on amblyopia and its action mechanism.Methods 30 normal kittens were randomly divided into 6 groups: low dose of L-dopa methyl ester (20 mg·kg~(-1)), medium dose of L-dopa methyl ester (40 mg·kg~(-1)), and high dose of L-dopa methyl ester (80 mg·kg~(-1)),positive control (L-dopa 40 mg·kg~(-1)),normal control, and model control group.The surgery for producing iatrogenic convergent strabismus was performed on 4 weeks old kittens(normal control group excluded). After the confirmation of the development of amblyopia by pattern visual evoked potential,L-dopa methyl ester,L-dopa and normal saline were given to the corresponding animals, respectively. The P-VEP of amblyopia eyes was observed after one month, and the technique of in situ hybridization was used to detect the expression of c-fos mRNA.Results L-dopa methyl ester could reduce obviously the length of P100 peak latency of the cat strabismic amblyopes, and increase the amplitude of P100. The positive staining cells of strabismic cat visual cortex were less than those of normal cats, whose difference was significant (P<0.01).Positive staining cells in the treatment group were significantly increased when compared with that of the model group (P<0.01).Conclusion L-dopa methyl ester can significantly improve the conduction and sensory function in the model of strabismic amblyopia cats. The mechanism may be related to the increased amount of L-dopa methyl ester into the cerebral cortex and regulation of the expression of c-fos mRNA.

Long-Term Study of Levodopa/Carbidopa for Refractory Childhood Amblyopia

PURPOSE: To evaluate the long-term (12 to 30 months) effect of L-dopa with part-time occlusion in patients in which occlusion therapy failed. METHODS: Seventeen eyes of 12 amblyopic children who failed with part-time occlusion (4 to 8 hours/day) treatment for a minimum period of 6 months were studied. The follow-up period was 12 to 30 months. The average best corrected visual acuity (BCVA) before treatment was 0.28+/-0.20 (0.05-0.5). After full informed consent was obtained from their parents, the children received levodopa (2 to 4 mg/kg) for 8 weeks combined with part-time occlusion and spectacles. RESULTS: The average age of the subjects was 7.0+/-2.7 years and the mean follow-up period was 23.7+/-7.7 (12 to 30) months. After the administration of levodopa for 8 weeks, 9 eyes (53%) showed improvement in BCVA, and only 4 eyes showing a mean regression of 0.20+/-0.11 logMAR visual acuities. The BCVA reached the maximum value after a mean of 8.47 months. After 8 weeks from baseline, 13 eyes (76%) reached the maximum BCVA. After 12 to 30 months of follow-up, 12 out of 17 eyes (70.6%) showed a BCVA improvement of 0.14+/-0.19 logMAR. CONCLUSIONS: After the long-term (12 to 30 months) follow-up, L-dopa with part-time occlusion in patients in which occlusion therapy failed showed improved visual acuities in 76% of the cases.

Clinical Observation on Acupuncture Treatment of Parkinson's Syndrome / 针灸推拿医学（英文版）

Objective:To explore if the therapeutic effect can be enhanced, the dose of levodopa-like medications can be decreased and the complications can be reduced by acupuncture treatment in the patients with Parkinson's disease (PD) who took levodopa-like medications for a long time. Methods: thirty cases of the patients, most of whom were noticed with the decreased therapeutic effect and drug-induced complications, were treated by puncturing Shuigou (GV 26) and Baihui (GV 20), by reduction of Madopa dose, and the patients' conditions and complications were evaluated six months later. Results:After treatments for six months, the physiological functions were improved and the dose of Madopa was reduced and the total effective rate was 66.7%. Conclusion: After acupuncture treatments in PD patients, the therapeutic effects of levodopa were enhanced, with its dose and complications reduced.

The Effect of L-dopa in Amblyopic Children for Whom Occlusion Therapy Failed

PURPOSE: This study was undertaken to evaluate the effect of L-dopa in amblyopic children for whom occlusion treatment failed. METHODS: We studied nine amblyopic children (11 eyes) for whom part-time occlusion (4~8 hours/day) treatment for a minimum period of 6 months had failed. The types of amblyopia included: anisometropic (1 patient, 1 eye), stimulus deprivation (4 patients, 6 eyes) and mixed (anisometropic and strabismic: 2 patients, 2 eyes; anisometropic and organic: 2 patients, 2 eyes). Best corrected visual acuity before treatment was between 0.05 and 0.5. They received, with full informed consent of the parent, levodopa (2~4 mg/kg) for 8 weeks combined with part-time occlusion. RESULTS: The children were between 4 and 11 years old (mean 5.8+/-2.05). Of the subjects, 45.5% (4 patients, 5 eyes) had improved visual acuity after 8 weeks of treatment. In one patient with anisometropic, two patients with mixed (anisometropic and strabismic), and one patient with stimulus deprivation (ametropic) amblyopia, visual acuity improved by one to five lines. CONCLUSIONS: In anisometropic, strabismic amblyopes and mild deprivational amblyopes for whom occlusion treatment failed, L-dopa improved visual acuity. L-dopa may be an additional option for treatment of amblyopic patients with a guarded visual prognosis.