Zonisamide added to treat Parkinson’s disease 1 Current status of Parkinson’s disease treatment The prevalence of Parkinson’s disease (PD) is second only to Alzheimer’s disease. It is generally estimated that the prevalence of PD in the general population of developed countries is 0.3%, which increases to 1% for those over 60 years of age and 4% to 5% for those over 85 years of age. Recent studies have reported that the prevalence of PD in the Japanese general population has increased from 145.8 per 100,000 in 1980 to 166.8 per 100,000 in 2004.PD is characterized by both motor and non-motor features. Early motor features include tremor, bradykinesia and bradykinesia, and postural instability is common in the late stages of the disease. Non-motor features include cognitive and psychiatric changes, autonomic dysfunction and sleep disturbances. Neuropathologically, there is a loss of dopaminergic neurons in the striatal nigrostriatal pathway, and Lewy vesicles are seen in the remaining neurons.The pathogenesis of PD is unknown. There is no cure, only symptomatic treatment. First-line drugs recommended for early application, such as levodopa, dopamine agonists and monoamine oxidase B inhibitors (MAO-B), can enhance dopaminergic neurotransmission. With the continuation of time, attenuation of levodopa efficacy and dyskinesia occur, and end-of-dose phenomenon, switch phenomenon, and dopa-induced dyskinesia are common in the clinic, affecting the quality of life. Although multidrug and combination therapy can be applied, PD symptoms remain uncontrolled in certain patients, and deep brain stimulation therapy is required in the advanced stage of the disease [1-4]. Wang Ye, Department of Neurology, The First Affiliated Hospital of Harbin Medical University 2 Zonisamide Zonisamide (ZNS), known as 1,2-benzisoxazole-3-formaldehyde sulfonamide, is an antiepileptic drug with a long half-life that was first synthesized in Japan.ZNS It is now approved for antiepileptic treatment in the United States, Europe, and Korea, and is also used for the treatment of migraine, obesity, affective disorders, eating disorders, and neuralgia [1, 5].The bioavailability of ZNS is about 100%.A single dose of 25 mg orally in 12 normal subjects resulted in a mean maximum plasma concentration of 0.118 mg/ml after 4 h. It takes 13-14 days to reach steady state. Bioavailability is not affected by food. In vitro studies have confirmed that 48.6% of ZNS is bound to human plasma proteins, with a distribution of 1.1 to 1.7 L/kg.ZNS can be detected in cord blood, breast milk, and cerebrospinal fluid. The distribution of breast milk and cerebrospinal fluid concentrations was 93% and 75% of plasma. In healthy volunteers, erythrocyte ZNS concentrations are 2-4 times higher than plasma.ZNS clearance is 1.91 L/h, and the half-life of a single dose of 25 mg in healthy adults is 94 h. With repeated administration of 14C-labeled ZNS, 62% of the radioactivity is detected in the urine, and 3% is seen in the feces [2]. 3 Clinical research on ZNS treatment of Parkinson’s disease ZNS treatment of PD belongs to the accidental discovery. 2001 Japanese scholars Murata et al [6] reported a case of PD patients with seizures, that is, ZNS 300mg treatment, found that seizures are well controlled at the same time, PD symptoms also dramatically improved, especially motor fluctuations that is the end of the dose phenomenon improved most obviously. After that, related studies were gradually carried out.Murata et al[5,6] studied an open ZNS trial in 9 patients with advanced PD and confirmed that 50-100 mg of additive therapy per day significantly reduced symptoms, improved limb tonus, tremor, and postural instability, especially end-of-agent phenomena, and was well tolerated.The efficacy gradually declined after 1.5 years, but the improvement in the total UPDRS score was sustained in more than 30% of the patients. In the last 3 years [7], Nakanishi et al [8] studied the effect of ZNS on tremor in 9 cases of PD.The PD patients had satisfactory control of their pre-existing symptoms, but their tremor was poorly treated. The addition of ZNS significantly reduced the degree of tremor in 7 of these cases. Murata et al[5] reported the results of a nationwide randomized, double-blind, controlled multicenter trial of ZNS in Japan, which evaluated the efficacy, safety, and tolerability of single daily doses of 25, 50, and 100 mg of ZNS in the adjuvant treatment of PD patients. A total of 58 units participated in the trial, and 326 patients were enrolled who were 20-80 years old with PD and who had multiple problems associated with levodopa therapy, such as end-of-dose phenomenon, on-off phenomenon, freezing phenomenon, no or delayed “on”, or insufficient levodopa dose. Inadequate dosage, etc. Finally, 279 cases completed the treatment and 47 cases stopped (8 in the placebo group, 7 in the 25 mg group, 11 in the 50 mg group, and 21 in the 100 mg group). The most common reason was side effects (4 cases in the placebo group, 5 cases in the 25mg group, 4 cases in the 50mg group and 9 cases in the 100mg group) [5]. Patients with levodopa-ineffective PD were given placebo for 2 weeks followed by 12 weeks of ZNS 25, 50 or 100 mg/d or placebo in addition to levodopa, followed by a 2-week tapering period. The primary end point was the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III. Secondary end points included total “day off” time, UPDRS I, II, and IV scores, and the Modified HYS (Modified Hoehn and Yahnson) Part III. Secondary endpoints included total “day off” time, UPDRS I, II, and IV scores, and Modified HYS (Modified Hoehn and Yahr Scale) score. The primary endpoint events were significantly improved in the 25 and 50 mg groups and the duration of “off time” was significantly shorter in the 50 and 100 mg dose groups compared to placebo. patients in the ZNS group did not have an increase in dyskinesia. side effects were similar in the 25 mg, 50 mg, and placebo groups, but were significantly higher in the 100 mg group. increased. It is proposed that ZNS 25-100mg/d adjuvant therapy for PD is safe, effective and well tolerated [5]. Regarding clinical trials of ZNS adjuvant therapy for PD, there are two 12-week multicenter randomized double-blind controlled phase IIb/III trials and one 1-year open trial, and only the results of phase IIb/III trials have been published. Doses of 50 and 100 mg/d have been studied, but efficacy was not superior to 25 mg/d. For the 12-week clinical trials, patients were randomized to ZNS 25 mg, 50 mg, 100 mg, or placebo orally 1/d. Original levodopa therapy was maintained for the first 4 weeks of the study, and treatment of dyskinesias and psychiatric symptoms was excluded. a total of 92 patients in the 1-year trial were given ZNS 25 to 100 A total of 92 patients in the 1-year trial took ZNS 25 to 100 mg/d. Points were scored according to the Modified UPDRS scale. It was found that the most significant improvement in motor function was achieved with the addition of ZNS 25 mg treatment [2]. Other clinical applications. Overlap between essential tremor (ET) and PD is common in clinical practice.ET precedes the onset of PD symptoms, and the presence of Lewy’s vesicles in patients with ET is confirmed at autopsy, with overlapping abnormalities on functional neuroimaging and midbrain ultrasound, among other evidence to support the existence of an overlap between the two.Shahed and Jankovic1 have proposed that this should be referred to as the ET-PD syndrome. To date, only a few studies have used beta blockers to treat PD tremor and stimulation of the thalamic ventral mesencephalic nucleus, and single-pharmacological treatment does not control the other disorder.Bermejo[9] evaluated the efficacy of ZNS in the treatment of ET-PD syndrome.Six patients were enrolled, all of whom had postural or movement tremor, which had persisted for at least 5 years prior to the symptoms of hemorrhagic PD.Two patients had tremor of the limbs and voice, and two had tremor of the head and voice, and two had tremor of the head and voice. 2 had head and limb tremor, 1 had trunk and limb tremor, and finally 1 had limb tremor only. 4 had action tremor and 2 had both action and postural tremor. Concurrent PD manifestations such as bradykinesia, tonus and gait instability were present.5 cases of resting tremor, 5 cases of reproducible tremor and 5 cases of reproducible tremor, the latter referring to the reappearance of resting tremor after a variable delay. ET-PD syndrome was diagnosed in these patients. ZNS 50 mg/d add-on therapy was given, titrating the dose to 200 mg/d. The course of treatment was a minimum of 60 days, with a maximum dose of a minimum of 45 days. The results revealed improvement in 4 cases of tremor, including action, postural, and resting; and in P5 cases of D symptoms, such as tonicity and bradykinesia. The main side effects were drowsiness in 2 cases and sensory abnormalities in 1 case. However, no one discontinued the drug. It is proposed that ZNS can effectively treat patients with ET or PD[9] . 4 Mechanism of action The mechanism of action of ZNS in PD is unknown. 4.1 Pharmacodynamics ZNS is thought to activate dopamine synthesis. Elevated levels of striatal and hippocampal levodopa and dopamine and their metabolites have been demonstrated in rat models. 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-treated mice and chorister monkeys administered ZNS showed elevated striatal dopamine conversion rates. ZNS inhibited MPTP-induced depletion of dopamine, the metabolites dihydroxyphenylacetic acid and homovanillic acid in the striatum.ZNS potentiated and prolonged the effects of levodopa in a rat model of PD and in patients with PD. Rat ex vivo studies confirm that ZNS greatly inhibits striatal MAO-B. Rat ex vivo studies confirm that ZNS has no effect on catechol methyltransferase or calcium-dependent dopamine release, and has no affinity for 5 hydroxytryptamine (5-HT1,2,3,4,5A,6,7), glutamate (NMDA, AMPA, or erythrocyanine), or adenosine receptors (A1, A2A, or A2B). Increased dopamine release from the anterior medial frontal cortex was seen in rats given ZNS, but disappeared with pretreatment with a 5-HT1A receptor antagonist (WAY100635).Whether ZNS metabolites have an anti-PD effect is not known.2 Murata[7] demonstrated that ZNS increased striatal dopamine content, via activation of dopamine synthesis and stimulation of tyrosine hydroxylase mRNA levels.ZNS moderately inhibits the monoamine oxidase MAO-B. It has no effect on dopamine receptors, dopamine transporters, or dopamine release.ZNS has no effect on glutamate receptors, adenosine receptors, or the 5-hydroxytryptaminergic system, and it is believed that the above systems are effective sites of action for anti-PD drugs other than the dopamine system. Therefore, activation of dopamine synthesis and moderate inhibition of MAOB levels were proposed as the main mechanisms of ZNS [7]. Experimental studies confirmed that ZNS inhibits tremor induced by camptothecin (harmaline) and oxidized tremorine (oxytremorine oxotremorine) in rats [1,10]. Gluck et al [11] used a microdialysis technique to study an excised substantia nigra rat model, and after administration of exogenous ZNS, dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) levels were detected in the dialysates of the striatum ipsilateral to the nigra excision. Levels. ZNS itself was found to have no effect on DA, DOPAC, HVA or rotational behavior. Administration of carbidopa-levodopa resulted in a slight improvement in rotational behavior contralateral to the substantia nigra resection, and there was no corresponding increase in striatal catecholamine release indices. In contrast, animals treated with carbidopa and ZNS followed by levodopa showed a significant increase in contralateral rotational behavior visible after 30 minutes, which persisted for at least 90 minutes after 20 minutes of ZNS-levodopa injection. In contrast to the consistent rotational behavior of nigrostriatalectomized animals, neurobiochemical evidence of dopamine release was visible in less than half of the rats. A 300% increase in DOPAC levels was seen after administration of carbidopa-levodopa-ZNS in those validated above. It is proposed that ZNS has an antiparkinsonian effect and that the dose of levodopa can be reduced. 4.2 Ion Channels. ZNS exerts an inhibitory effect on voltage-gated sodium channels and regulates epilepsy-associated neuronal ignition, and also blocks T-type calcium channels without affecting L-type channels, which leads to diminished repetitive ignition activity and exerts antiepileptic activity, similar to valproic acid and ethosuximide [1,10].ZNS exerts a significant effect on T-type calcium channels and oxidative stress, which also exerts therapeutic benefit [2,7,9]. 4.3 Neurotransmitters ZNS also acts on neurotransmitters, which include monoaminergic, glutamatergic, 5-hydroxytryptaminergic and cholinergic transmitters. Recent experimental studies have found that ZNS has GABA receptor modulation, albeit with no affinity for it.ZNS causes an increase in neuronal levels of excitatory amino acid transporter 1, which leads to a decrease in levels of excitatory amino acids.ZNS, although it does not act directly on GABA or glutamatergic receptors, indirectly modifies GABAergic and glutamatergic neurotransmission [1,10]. Recent clinical observations have found that ZNS is still effective when given again to PD patients who are already taking adequate amounts of selegiline, suggesting that there is no clinical relevance to the inhibitory activity of ZNS on MAOB [1, 9-10, 12]. 4.4 Neuroprotective effects In vitro studies have revealed that ZNS is seen to have neuroprotective effects, including conversion to melanin, stabilization of extracellular excess dopamine and dopamine kunst, increase in glutathione levels and expression of manganese dioxide dismutase, blocking of ischemic and hypoxic injury, scavenging of hydroxyl and nitric oxide radicals, inhibition of nitric oxide synthase activity, and reduction of lipid peroxidation. administration of ZNS to MPTP treated mice inhibited the neuronal inhibitory activity of ZNS [1, 12]. ZNS inhibits neuronal tyrosine hydroxylase deletion (involved in dopa formation) and increases the levels of glial protofibrillary acidic protein in striatum and nigrostriatal astrocytes, and the reduced levels of the latter can lead to neurodegeneration [1,2]. Oxidative stress is generally considered to be the prominent mechanism of dopaminergic neuronal degeneration in PD, and the above mechanisms may be effective [1,13,14]. Neurotoxicity of dopamine quinone leading to dopaminergic neuron-specific oxidative stress plays an important role in the pathogenesis and/or progression of PD because dopamine quinone can conjugate with several PD-causing molecules (e.g., tyrosine hydroxylase, α-congruent nucleoprotein, and parkin) to form protein-bound quinones and therefore inhibit protein function.Asanuma et al [15] studied the effect of cell free systems and cultured neurotoxicity against excess cytosolic free dopamine-induced quinone after ZNS treatment of cells. Co-incubation of dopamine and ZNS in the free cell system resulted in the conversion of DA to stable melatonin via the formation of dopamine-semiquinone and dopamine chromium. Prolonged treatment (5 d) resulted in a decrease in kunins and an increase in dopamine/dopamine chromium. zNS significantly inhibited tetrahydrobiopterin-induced kunin formation and increased cytosolic free dopamine. This suggests that ZNS exerts an anti-dopamine kunai formation effect by inducing an increase in cytosol dopamine content outside the vesicle.Yano et al[16] examined the neurotoxicity of ZNS against MPTP in mice. ZNS was found to reduce striatal MPTP-induced dopamine, DOPAC, and HVA deficits, decrease tyrosine hydroxylase-positive neuronal deletion, and increase the number of striatal and substantia nigra glial fibrillary acidic protein (GFAP)-positive astrocytes 5 days after administration of ZNS.Western blot studies have also confirmed that The drug prevented the decrease in tyrosine hydroxylase protein levels and increased striatal GFAP protein levels after 5 days of administration. There were no significant changes in striatal dopamine, DOPAC and HVA levels in normal mice given the drug. It suggests that ZNS may provide neuroprotection in the MPTP mouse model of PD via enhancement of tyrosine hydroxylase activity in the dopamine system. 5 Dosage and safety The recommended dose of ZNS for antiepileptic therapy is 400-600 mg/d. Side effects include Stevens-Johnson syndrome, toxic epidermal necrolysis, erythroderma, hypersensitivity reactions, dysplastic anemia, granulocyte deficiency, pure red blood cell aplasia, thrombocytopenia, acute renal dysfunction, interstitial pneumonia, hepatic dysfunction, jaundice, and Rhabdomyolysis, renal calcification, heat shock due to decreased sweating, hallucinations, paranoia, confusion, delirium and psychotic symptoms. Abnormal serum immunoglobulin levels and sudden death are rare. The FDA has reported an increased risk of metabolic acidosis and suicide [2, 8]. ZNS has been used as an antiepileptic drug for more than 15 years, and the daily dose of less than 100 mg for the treatment of PD is significantly lower than the therapeutic dose for epilepsy, but it should be noted that patients with PD are generally significantly older than epileptic patients and may have PD-specific side effects. These generally include somnolence, apathy, weight loss, and constipation. The incidence of hallucinations and dyskinesia was similar in the ZNS and control groups, suggesting that ZNS 25 to 100 mg/d could be tolerated.ZNS 25 mg/d and 50 mg/d were well tolerated, and the incidence of side effects did not differ from placebo. However, 100 mg/d had significant side effects. The main side effects are dyskinesia, decreased appetite, drowsiness, hallucinations, and elevated serum creatinine. Certain side effects such as insomnia, weakness, somnolence, and nausea were significantly higher in the 50 mg/d dose group than in the 25 mg/d dose group.Phase 3 trial found one case of sudden death, and other serious complications included malignant syndromes, rhabdomyolysis, and renal calculi [2, 8]. ZNS is used as levodopa add-on therapy in Japan at an approved dose of 25 mg orally, 1/day, independent of food. Contraindications are pregnant women or those who are allergic to the drug. It is contraindicated in epileptic patients who are allergic to aminoglutethimide drugs. Use with caution in severe liver disease or in the elderly [2]. Concomitant use of certain drugs such as carbamazepine, phenytoin, phenobarbital and rifampicin can affect ZNS drug metabolism and increase ZNS clearance. Therefore dosage adjustment is required. Concomitant administration of lamotrigine or sodium valproate, ketoconazole and cimetidine did not affect ZNS pharmacokinetics.ZNS and metabolites are mainly excreted from the kidneys, and should be discontinued promptly in cases of acute renal dysfunction or persistent elevation of serum creatinine. Lack of information on the application of hepatic dysfunction, severe hepatic dysfunction patients are not recommended, mild to moderate hepatic dysfunction patients should be used with caution [2]. 6 Prospects The 21st century has begun to put forward a new concept of PD treatment, levodopa has toxic effects, dopamine agonists can play a neuroprotective role; PD patients without dementia or psychosis should be treated with dopamine agonists initially. Dopamine agonist therapy has fewer motor complications associated with levodopa but more side effects such as hallucinations and drowsiness than levodopa.ZNS (25-50 mg/d) improves motor and end-of-agent phenomena in patients with late-stage PD without significantly aggravating dyskinesia [1,3]. A large sample detailed study on this drug is expected to be conducted.