Dose Of Amantadine Research Articles

Low Dose Amantadine and Escitalopram in Progressive Supranuclear Palsy and Multiple System Atrophy.

Background: Progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) are less responsive to usual antiparkinsonian drugs. Purpose: To assess the treatment outcome of the combination of low-dose amantadine and escitalopram in the study population. Methods: A retrospective study of PSP and MSA patients from June 2021 to December 2022 treated with the dose of amantadine 100 mg and escitalopram 5 mg per day with a follow-up of 2 months at a tertiary care centre in India. The primary outcome measure was a change in the PSP and MSA severity rating scale scores, while cognition, neuropsychiatric symptoms and functionality scale scores were secondary outcomes on follow-up visits. Repeated measures ANOVA and Friedman rank test were used to analyse the data. Results: A total of 21 patients (8 PSP and 13 MSA), including 19 males, with a mean age of 72.84 years, were included. The mean total PSP rating scale score had a significant decline from baseline to week 2 and 8 (p < .001), along with the scores for limb symptoms (p < .001), ocular (p = .001), history (p = .003), gait (p = .007), mentation (p = .014) and bulbar (p = .018) symptoms. Similarly, the mean score of the MSA rating scale significantly decreased on follow-up visits (p < .001). The cognition, functional disability and behavioural symptoms scores also had significant improvement with p < .01. Conclusion: The PSP and MSA patients had clinically significant improvement with the combination treatment in both motor and non-motor domains. Further prospective trials for longer durations are needed to establish the effect size and stability of response.

Effect of dopaminergic therapy on lacrimation in Parkinson's disease

The prevalence of dry eye syndrome (DES) in Parkinson's disease (PD) reaches 87% and leads to impaired quality of life in many patients.Objective: to evaluate the lacrimal function and the effect of dopaminergic therapy in patients with PD.Material and methods: 43 patients with stage II–III PD according to Hoehn and Yahr (H&amp;Y) receiving therapy with levodopa (n=17), amantadines (n=13) and dopamine receptor agonists (ADR) (n=28) were assessed using Schirmer's test (to estimate tear flow), sialometry, Unified Parkinson's Disease Rating Scale (UPDRSI-IV), Schwab and England Activities of Daily Living scale (Sch&amp;En), the Parkinson’s Disease Questionnaire Summary Index (PDQ-39), the Mini Mental State Examination Scale (MMSE), the Non-Motor Symptom Questionnaire (NMSQ), the American Urological Association Symptom Scale (AUA), the Gastrointestinal Symptom Rating Scale (GSRS), the Bristol Stool Form Scale (BSFS).Results. Lacrimal insufficiency was found in 49% of patients. It occurred more frequently (χ2=9.546; p=0.003) in patients taking amantadine and correlated with the daily dose of amantadine (r-S=-0.359). It did not depend on the intake of ADR and levodopa and their doses but correlated with the UPDRS-IV score (r-S= -0.463), namely with the presence and duration of OFF-periods. Lacrimal insufficiency correlated with the Sch&amp;En score (r-S=0.321) and non-motor parameters: UPDRSI (r-S =-0.302), NMSQ (r-S=-0.435), constipation domain of the GSRS (r-S=-0.362), BSFS (r-S=0.363). It was not related to age, gender, stage and duration of PD, motor symptoms of parkinsonism (assessed during the ON-phase) and was not related to salivation (although it was reduced in 39.5% of patients).Conclusion. Lacrimal insufficiency is observed in half of patients with stage II–III PD; it is related to the presence and duration of OFF-periods, the severity of other autonomic disorders and the use of amantadines, suggesting the role of dopamine dysregulation, neurodegeneration of autonomic centers and anticholinergic therapy in the development of DES in PD.

EFFECT OF THE ASSOCIATION OF AMANTADINE AND QUETIAPINE IN THE TREATMENT OF REM SLEEP BEHAVIOR DISORDER: CASE REPORT

The aim was to report the case of a patient with REM sleep behavior disorder, unresponsive to standard treatment and with complete control of the condition after association of amantadine. Female patient, 45 years old, with systemic arterial hypertension and hypothyroidism, referred to neurological care, reporting frequent episodes of nocturnal agitation in the first hours of sleep, with walking and vocalization, waking up easily if called. She complains of drowsiness and anxiety, secondary to the impact of the RBD on her personal life. She mentions previous attempts at drug treatment with benzodiazepines (Bromazepam and Clonazepam), Zolpidem and Trazodone, all without clinical improvement, with Quetiapine being introduced at a low dose (not yet tried) 25mg, with a therapeutic target of 50mg with partial improvement only with 25mg. When trying 50mg, presenting a worsening of the picture. In a new follow-up, therapy with Amantadine 50 mg/day associated with Quetiapine 25 mg/day was started. The patient returned reporting a significant improvement in the condition, less frequent episodes associated with reduced nocturnal movement. After adaptation of the combined therapy, with adjustments in the dose of Amantadine, an increase of 50mg every 14 days up to 200 mg/day, with the possibility of using quetiapine 50mg (balance between the drugs), the patient evolved stable, with a great improvement in the quality of life and absence of new episodes of the sleep disorder.

Bilateral Irreversible Amantadine-Related Corneal Edema Successfully Treated With Descemet Membrane Endothelial Keratoplasty (DMEK)

Corneal edema is a recognized adverse reaction of chronic amantadine hydrochloride use. Fortunately, it is usually reversible with prompt discontinuation of the medication. We report a case of a patient with schizoaffective disorder–bipolar treated with high doses of amantadine for drug-induced akathisia, who developed irreversible bilateral severe corneal edema, and was successfully treated with Descemet membrane endothelial keratoplasty (DMEK). This case highlights the importance of recognizing amantadine-induced endothelial toxicity and confirms the utility of DMEK in the treatment of the condition.

Low dose Amantadine and Escitalopram combination in Atypical Parkinsonian disorders- A Retrospective chart review

IntroductionThe response to conventional antiparkinsonian medications is elusive in atypical parkinsonian disorders. Improvement in parkinsonian symptoms in atypical parkinsonian disorders has been reported with anecdotal use of Amantadine. The role of serotonergic control over the nigrostriatal pathway led to the use of Escitalopram.ObjectivesTo examine the efficacy of low dose Amantadine and Escitalopram combination treatment in atypical parkinsonian disorderMethodsA retrospective chart review of Atypical Parkinsonian disorder patients who received the combination of low dose Amantadine and Escitalopram and had follow up assessment available for a minimum of four months were studied. The primary outcome measure was change in Progressive Supranuclear Palsy rating scale, Unified Multiple System Atrophy rating scale score and Clinical Global Improvement Scale Change score in follow up visits.ResultsA total of 8 patients with a mean age of 68.5 years, 6 with a diagnosis of Progressive Supranuclear Palsy(PSP) and 2 with a diagnosis of Multiple System Atrophy(MSA) met the selection criteria for the study. Patients were treated with the dose of Amantadine 50mg twice daily and Escitalopram 5mg once daily. The symptom domain to respond first was autonomic symptoms followed by gait, mentation, limb and bulbar symptoms. Amantadine has unique dopaminergic and NMDA antagonist properties. Serotonin has a role in modulation of the autonomic functions and nigrostriatal circuitry. Thus, combining Escitalopram with Amantadine can help ameliorate the array of symptoms in atypical parkinsonian disorders.ConclusionsThe PSP and MSA patients responded to the combination of low dose Amantadine and Escitalopram as evidenced by objective rating scales and subjective clinician assessment. Further prospective trials for longer duration are needed to establish the effect size and stability of response.KEYWORDS: steele richardson olszewski disease, shy dragger syndrome, antidepressantsDisclosure of InterestNone Declared

The effects of different doses of amantadine on lung tissue in lower extremity ischemia reperfusion injury in rats

Aim: Ischemia/reperfusion (I/R) injury is a common complication after abdominal aortic surgery. N-Methyl D-Aspartate (NMDA) antagonists protect many organs against to I/R injury. Therefore, in this study, we aimed to investigate the effects of 135 mg/kg and 90 mg/kg of amantadine, on lung tissue after lower extremity I/R injury in rats.&#x0D; Material and Methods: 36 wistar rats were randomly divided into 6 groups each containing six rats as follows; Sham group (Group S), Amantadine 90 group (Group A-90), Amantadine 135 group (Group A-135), Ischemia/Reperfusion group (Group I/R), Ischemia/Reperfusion + Amantadine 90 group (Group I/R-A 90), Ischemia/Reperfusion + Amantadine 135 group (Group I/R-A 135). At the end of procedure, all rats were sacrificed, and their lung tissues were obtained. Lung tissues were examined biochemical and histopathologically.&#x0D; Results: The lung tissue catalase, superoxide dismutase activities and malondialdehide levels were similar between the groups. Lung tissue neutrophil/lymphocyte infiltration score levels were higher in Group I/R than Group S, Group A-90 and Group A-135. Alveolar wall thickening score levels were higher in Group I/R than Group S, Group A-90, Group A-135 and Group I/R-A 135. &#x0D; Conclusion: Although we could not find a statistically significant difference between lung tissue biochemical values, we observed that lung tissue was histopathologically affected by I/R damage and the damage was less with amantadine use. In the reduction of I/R damage, 135 mg/kg administration of amantadine was more beneficial than 90 mg/kg.

Sıçanlarda Hepatik İskemi Reperfüzyon Hasarında Farklı Dozlarda Amantadin'in Akciğer Dokusu Üzerine Etkisi

Objective: N-Methyl D-Aspartate (NMDA) receptor blockers have been shown to have protective effects against ischemia/reperfusion (I/R) injury in various tissues. The aim of this study was to investigate the effects of 90 ve 135 mg/kg doses of amantadine on lung in hepatic I/R injury.&#x0D; Method: The rats were randomly divided into six groups: Group Sham, Group I/R, Group Amantadine-90, Group Amantadine-135, Group I/R-90 and Group I/R-135. In I/R, an atraumatic vascular clamp was applied to the structures in the left portal triad for 45 minutes and reperfusion period was 2 hours after ischemia. Malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) enzyme levels were performed the lung tissue and tissues were examined histopathologically.&#x0D; Result: A significant difference was found between the groups in terms of MDA, SOD, CAT levels (respectively; p &lt; 0.001, p=0.008, p &lt; 0.001). A significant difference was found between the groups in terms of lung tissue neutrophil/lymphocyte infiltration scores and alveolar wall thickening scores (respectively p=0.009, p=0.002).&#x0D; Conclusion: The biochemical and histopathological results of the present study suggested that amantadine, like other NMDA antagonist agents, may have a protective effect on lung tissues against the damage caused by hepatic I/R injury. Although we observed significant improvements after the administration of both doses studied, there was no significant difference between these two doses in terms of their success in protecting against distant organ lung injury. Amantadine appears promising as a therapeutic agent in treatment.

Prescribing Patterns of Amantadine During Pediatric Inpatient Rehabilitation After Traumatic Brain Injury: A Multicentered Retrospective Review From the Pediatric Brain Injury Consortium.

To describe dosing practices for amantadine hydrochloride and related adverse effects among children and young adults with traumatic brain injury (TBI) admitted to pediatric inpatient rehabilitation units. Eight pediatric acute inpatient rehabilitation units located throughout the United States comprising the Pediatric Brain Injury Consortium. Two-hundred thirty-four children and young adults aged 2 months to 21 years with TBI. Retrospective data revie. Demographic variables associated with the use of amantadine, amantadine dose, and reported adverse effects. Forty-nine patients (21%) aged 0.9 to 20 years received amantadine during inpatient rehabilitation. Forty-five percent of patients admitted to inpatient rehabilitation with a disorder of consciousness (DoC) were treated with amantadine, while 14% of children admitted with higher levels of functioning received amantadine. Children with DoC who were not treated with amantadine were younger than those with DoC who received amantadine (median 3.0 vs 11.6 years, P = .008). Recorded doses of amantadine ranged from 0.7 to 13.5 mg/kg/d; the highest total daily dose was 400 mg/d. Adverse effects were reported in 8 patients (16%); nausea/abdominal discomfort and agitation were most common, each reported in 3 patients. The highest reported dose without an adverse effect was 10.1 mg/kg/d. During pediatric inpatient rehabilitation, amantadine was prescribed to children across a range of ages and injury severity and was most commonly prescribed to older children with DoC. Dosing varied widely, with weight-based dosing for younger/smaller children at both lower and higher doses than what had been previously reported. Prospective studies are needed to characterize the safety and tolerability of higher amantadine doses and optimize amantadine dosing parameters for children with TBI.

Evaluation of Outcomes in Patients Receiving Amantadine to Improve Alertness After Traumatic Brain Injury.

Background: Amantadine has been used off-label to improve alertness after traumatic brain injury (TBI). The goal of this study is to assess the mean change at 72 hours and in course of therapy (COT) Glasgow Coma Scale (GCS) score after amantadine initiation and to correlate the change in GCS score with participation in physical therapy (PT) and occupational therapy (OT) among patients with TBI receiving amantadine during the first hospitalization. Methods: This single-center, retrospective, cohort study included patients ≥18 years old hospitalized for a TBI from August 2012 to February 2018 and received ≥1 dose of amantadine to increase alertness. The primary endpoint is the mean change in 72-hour GCS score after amantadine initiation. The secondary endpoint is the mean change in COT GCS score after amantadine initiation and the correlation between the change in GCS score and percent PT and OT participation at 72 hours and during the COT. Results: Seventy-nine patients were included. The mean age of patients was 41 years, and 79.8% of the patients were men. The mean change in 72-hour GCS score was +0.75 (95% confidence interval [CI] = 0.09-1.42, P = .027), and the mean change in COT GCS score was +2.29 (95% CI = 1.68-2.90, P < .001). There was no significant correlation between the increase in GCS score and percent PT/OT session participation at 72 hours and during the COT, r = -0.15 (P = .24) and r = -0.02 (P = .74), respectively. The percent PT/OT session participation at 72-hour post-amantadine initiation was 61.3% compared with 65.9% during the COT. Conclusion: There were small but statistically significant increases in the mean change at 72 hours and in COT GCS score; however, they were not correlated with percent PT/OT participation. Other studies are needed to determine the appropriate time and GCS score to initiate amantadine along with the optimal dose in the inpatient setting.

SAT-689 Amantadine Induced Severe Hypoglycemia in a Patient With Type 1 Diabetes and Multiple Sclerosis

Introduction: Amantadine is one of the few options commonly used to treat fatigue associated with multiple sclerosis. However, in a previous trial investigating the effect of amantadine on oral glucose tolerance test results, amantadine caused a reduction in plasma glucose and glucagon levels while increasing insulin levels in healthy volunteers [1]. If amantadine can reduce glucagon levels, we hypothesized that it might also cause hypoglycemia in patients with type 1 diabetes. Case presentation: The patient is a 34-year-old African American male who has a past medical history of type 1 diabetes and multiple sclerosis. His baseline hemoglobin A1c values ranged from 6.9% to 7.6% and his weight was 88 Kg. His insulin glargine dose was 28 units daily while his insulin lispro was 10 units before meals. For almost one year he was followed in clinic and had no episodes of severe hypoglycemia (defined as hypoglycemia requiring assistance from another person).The patient complained about gait imbalance and fatigue from multiple sclerosis for which he was followed by a neurologist. To treat these symptoms, he was prescribed amantadine 100 mg twice daily. A couple of hours following his first dose of amantadine after eating his usual breakfast (with his sister), the patient was found unconscious by his sister. Emergency Medical Services (EMS) was called and he was found to have a blood glucose of 22 mg/dL. He was admitted to the hospital. During that admission, amantadine was discontinued, and he was discharged on insulin glargine 24 units daily and insulin lispro 10 units with meals. Discussion: We present a case of suspected amantadine induced severe hypoglycemia. In patients with type 1 diabetes, there is a loss of the pancreatic β-cells while the α-cells are preserved [2, 3]. We hypothesize that if amantadine reduces glucagon production from the α-cells, patients would be prone to severe hypoglycemia, presumably because of the unopposed insulin action. Although it is unlikely that the severe hypoglycemia was secondary to insulin since the patient was on stable doses, it cannot be completely excluded. We recommend caution when prescribing amantadine to patients on insulin therapy particularly within the first two hours after rapid acting insulin administration. More research is needed to explore this possibility.

Dose-dependent neurorestorative effects of amantadine after cortical impact injury

Numerous pharmacotherapies have been evaluated after experimental traumatic brain injury (TBI). While amantadine (AMT) has shown potential for clinical efficacy, the few studies on its effectiveness have been mixed. It is possible that suboptimal dosing, due to the evaluation of only one dose, may be causing the discrepancies in outcomes. Hence, the goal of the current study was to conduct a dose response of AMT after TBI to determine an optimal behavioral benefit. Anesthetized adult male rats received either a cortical impact of moderate severity or sham injury and then were randomly assigned to receive once daily intraperitoneally injections of AMT (10, 20, or 40 mg/kg) or saline vehicle (VEH, 1 mL/kg) commencing 24 h after injury for 19 days. Motor and cognitive function were assessed on post-operative days 1–5 and 14–19, respectively. There were no statistical differences among the sham groups treated with AMT or VEH so the data were pooled. AMT (20 mg/kg) facilitated beam-balance recovery and spatial learning relative to VEH-treated controls (p < 0.05). No other doses of AMT were effective. These results indicate that dosing should be carefully considered when assessing the effects of pharmacotherapies after TBI so that potential benefits are not inadvertently missed.

Opioid analgesics-related pharmacokinetic drug interactions: from the perspectives of evidence based on randomized controlled trials and clinical risk management.

BackgroundMultimorbidity results in complex polypharmacy which may bear a risk of drug interactions. A better understanding of opioid analgesics combination therapy used for pain management could help warrant medication safety, efficacy, and economic relevance. Until now there has been no review summarizing the opioid analgesics-related pharmacokinetic drug interactions from the perspective of evidence based on randomized controlled trials (RCTs).MethodA literature search was performed using PubMed, MEDLINE, and the Cochrane Library, using a PRISMA flowchart.ResultsFifty-two RCTs were included for data interpretation. Forty-two RCTs (80.8%) were conducted in healthy volunteers, whereas 10 RCTs (19.2%) enrolled true patients. None of the opioid–drug/herb pairs was listed as contraindications of opioids involved in this review. Circumstances in which opioid is comedicated as a precipitant drug include morphine–P2Y12 inhibitors, morphine–gabapentin, and methadone–zidovudine. Circumstances in which opioid is comedicated as an object drug include rifampin–opioids (morphine, tramadol, oxycodone, methadone), quinidine–opioids (morphine, fentanyl, oxycodone, codeine, dihydrocodeine, methadone), antimycotics–opioids (buprenorphine, fentanyl, morphine, oxycodone, methadone, tilidine, tramadol), protease inhibitors–opioids (ritonavir, ritonavir/lopinavir–oxycodone, ritonavir–fentanyl, ritonavir–tilidine), grapefruit juice–opioids (oxycodone, fentanyl, methadone), antidepressants–opioids (paroxetine–tramadol, paroxetine–hydrocodone, paroxetine–oxycodone, escitalopram–tramadol), metoclopramide–morphine, amantadine–morphine, sumatriptan–butorphanol nasal sprays, ticlopidine–tramadol, St John’s wort–oxycodone, macrolides/ketolides–oxycodone, and levomepromazine–codeine. RCTs investigating the same combination, almost unanimously, drew consistent conclusions, except two RCTs on amantadine–intravenous morphine combination where a different amantadine dose was used and two RCTs on morphine–ticagrelor combination where healthy volunteers and true patients were enrolled, respectively. RCTs investigating in true patients may reflect a realistic clinical scenario and overcome the limitation of RCTs performed in healthy volunteers under standardized conditions. Further research opportunities are also presented in this review.ConclusionEffective and safe combination therapy of opioids can be achieved by promoting the awareness of potential changes in therapeutic efficacy and toxicities, prescribing alternatives or changing administration strategy, tailoring dose, reviewing the appropriateness of orders, and paying attention to medication monitoring.

Study on the abuse of amantadine in tissues of broiler chickens by HPLC-MS/MS.

To evaluate the residual target tissues for better monitoring of amantadine abuse in broiler chickens, 22-day-old commercial Arbor Acres broiler chickens were, respectively, fed with 10, 20, and 40mg/kg of amantadine for five consecutive days. Plasma, breast, and liver tissue samples from the chickens were collected 0, 4, 16, 24, 48, 96, 144, and 312h after amantadine withdrawal. The high-performance liquid chromatography-tandem mass spectrometry method was used to detect the concentrations of amantadine. The highest concentration was found in the chicken liver and it took the longest time for amantadine to vanish by metabolism. In the high-dose group, amantadine residues were still detected 312h after amantadine withdrawal. As the amantadine dose increased, amantadine residues in the chicken liver were more slowly to disappear than in other tissues. Even if approximately the same concentration of amantadine residues was found in chicken breast and plasma samples, it took a shorter time before the residues were eliminated. In the medium- and high-dose groups, the concentrations of amantadine residues in chicken liver samples were substantially higher than those in chicken breast and plasma samples, and it took more time to eliminate them. Therefore, the chicken liver can be used as a target tissue to detect illegal use of amantadine.

Antidyskinetic Effect of 7-Nitroindazole and Sodium Nitroprusside Associated with Amantadine in a Rat Model of Parkinson's Disease.

Amantadine is the noncompetitive antagonist of N-methyl-D-aspartate, receptor activated by the excitatory neurotransmitter glutamate. It is the only effective medication used to alleviate dyskinesia induced by L-3,4-dihydroxyphenylalanine (L-DOPA) in Parkinson's disease patients. Unfortunately, adverse effects as abnormal involuntary movements (AIMs) known as L-DOPA-induced dyskinesia limit its clinical utility. Combined effective symptomatic treatment modalities may lessen the liability to undesirable events. Likewise drugs known to interfere with nitrergic system reduce AIMs in animal models of Parkinson's disease. We aimed to analyze an interaction between amantadine, neuronal nitric oxide synthase inhibitor (7-nitroindazole, 7NI), and nitric oxide donor (sodium nitroprusside, SNP) in 6-hydroxydopamine-(6-OHDA)-lesioned rats (microinjection in the medial forebrain bundle) presenting L-DOPA-induced dyskinesia (20mg/kg, gavage, during 21days). We confirm that 7NI-30mg/kg, SNP-2/4mg/kg and amantadine-40mg/kg, individually reduced AIMs. Our results revealed that co-administration of sub-effective dose of amantadine (10mg/kg) plus sub-effective dose of 7NI (20mg/kg) potentiates the effect of reducing AIMs scores when compared to the effect of the drugs individually. No superior benefit on L-DOPA-induced AIMs was observed with the combination of amantadine and SNP. The results revealed that combination of ineffective doses of amantadine and 7NI represents a new strategy to increase antidyskinetic effect in L-DOPA-induced AIMs. It may provide additional therapeutic benefits to Parkinson's disease patients from these disabling complications at lower and thus safer and more tolerable doses than required when either drug is used alone. To close, we discuss the paradox of both nitric oxide synthase inhibitor and/or donor produced AIMs reduction by targeting nitric oxide synthase.

USE OF THREE-COMPONENT LEVODOPA (LEVODOPA/CARBIDOPA/ENTACAPONE) TO CORRECT NOCTURNAL SYMPTOMS OF PARKINSON,S DISEASE

Objective: to describe a clinical case of late-stage Parkinson’s disease (PD) with nocturnal symptoms and fluctuations and to present successful experience in using the three-component drug Stalevo (levodopa/carbidopa/entacapone) as a single dose prior to sleep. Patient V. aged 72 years took medical advice at the Department of Neurology, Russian Medical Academy of Postgraduate Education, for complaints of constrained movements, inability to turn in bed independently, painful muscle cramps, light sleep with nocturnal awakenings, and frequent (5–6 times) urinations at night. The first symptoms of the disease appeared 12 years ago when the patient began to notice sluggishness, altered handwriting, and clumsiness during small movements of the right hand. By taking into account symptoms (obvious nocturnal akinesia, overactive bladder, sleep disorders, and cramps) and the results of his examination, the patient was diagnosed with the akinetic-rigid form of PD (4 Hoehn-Yarh scores). Therapy was corrected as follows: the dose of amantadine remained the same (300 mg); its last administration is recommended to be at 16:00; the daily dose of levodopa was 700 mg; that of levodopa/benserazide was 550 mg/day (1 tablet × 3/4 tablet × 1 tablet). The evening intake of levodopa was changed for that of the three-component drug Stalevo (levodopa 150 mg/ carbidopa 37.5 mg/entacapone 200 mg). Results. After 3 months, the patient was observed to have significant health improvement: reduced nocturnal and morning akinesia, better gait, a considerably smaller number of nocturnal urinations (less than once per night), regression of painful calf muscle cramps, and improved sleep. Conclusion. The three-component drug Stalevo (levodopa/carbidopa/entacapone) is effective in treating late-stage PD. Its use as a single dose before going to bed has led to regressive nocturnal symptoms, better sleep, and lower motor fluctuations.

The H3 receptor agonist immepip does not affect l-dopa-induced abnormal involuntary movements in 6-OHDA-lesioned rats

The treatment of dyskinesia in Parkinson׳s disease remains poor but H3 receptor agonists have been suggested as a novel pharmacological approach. We examined the effects of the H3 agonist, immepip, in 6-OHDA-lesioned rats exhibiting AIMs (abnormal involuntary movements), a rat analogue of dyskinesia, in response to l-dopa compared to the known anti-dyskinetic agents amantadine, MK-801 and 8-OHDPAT. We then attempted to extend these studies in to dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated common marmosets.Amantadine, MK-801 and 8-OHDPAT all dose-dependently reduced l-dopa-induced axial, lingual and oral (ALO) AIMs in 6-OHDA-lesioned animals accompanied by a reduction in contralateral rotation with higher doses of amantadine and MK-801. By contrast, immepip had no effect on AIMs expression or contralateral rotation. In the MPTP-treated common marmoset exhibiting dyskinesia to l-dopa, immepip alone induced retching and in combination with l-dopa administered subcutaneously or orally induced the rapid onset of retching and vomiting which was not controlled by pretreatment with domperidone. Administration of the unrelated H3 agonist, imetit had the same effect. Despite causing negative side-effects, it appears that both agonists reduced the antiparkinsonian response to l-dopa resulting in reduced dyskinesia.H3 agonists appear unlikely candidates for the treatment of dyskinesia in PD based on lack of evidence of efficacy and potential adverse effects.

Double-Blind, Placebo-Controlled Trial of Risperidone Plus Amantadine in Children With Autism

This study aimed to investigate the effect of adding amantadine to risperidone for treatment of autism. Forty outpatients aged 4 to12 years, who were diagnosed with autism spectrum disorders based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria, were assigned to this double-blind clinical trial. The subjects were divided randomly into 2 groups. One group received risperidone plus amantadine, and the other group received risperidone plus placebo. The dose of risperidone was titrated between 1 and 2.0 mg/d, and the dose of amantadine was 100 or 150 mg/d for patients less than 30 kg or more than 30 kg, respectively. The patients were assessed using the Aberrant Behavioral Checklist-Community (ABC-C) and adverse effects checklist as well as clinical global impression-improvement (CGI-I) at2 checkpoints of 5-week intervals after the baseline. Informed consentwas obtained from the parents of each participant. Among ABC-C subscales, Hyperactivity and Irritability showed significantly greater reduction in the amantadine group than the placebo group. There was no significant difference in adverse effects between the 2 groups. The CGI-I scores show significant improvement in the amantadine group compared to the placebo group. The present study suggests that amantadine may be a potential adjunctive treatment strategy for autism and it was generally well tolerated.

Amantadine Improves Cognitive Outcome and Increases Neuronal Survival after Fluid Percussion Traumatic Brain Injury in Rats

This study evaluated the effects of clinically relevant concentrations of amantadine (AMT) on cognitive outcome and hippocampal cell survival in adult rats after lateral fluid percussion traumatic brain injury (TBI). AMT is an antagonist of the N-methyl-D-aspartate-type glutamate receptor, increases dopamine release, blocks dopamine reuptake, and has an inhibitory effect on microglial activation and neuroinflammation. Currently, AMT is clinically used as an antiparkinsonian drug. Amantadine or saline control was administered intraperitoneally, starting at 1 h after TBI followed by dosing three times daily for 16 consecutive days at 15, 45, and 135 mg/kg/day. Terminal blood draws were obtained from TBI rats at the time of euthanasia at varying time points after the last amantadine dose. Pharmacokinetics analysis confirmed that the doses of AMT achieved serum concentrations similar to those observed in humans receiving therapeutic doses (100-400 mg/day). Acquisition of spatial learning and memory retention was assessed using the Morris water maze (MWM) on days 12-16 after TBI. Brain tissues were collected and stained with Cresyl-violet for long-term cell survival analysis. Treatment with 135mg/kg/day of AMT improved acquisition of learning and terminal cognitive performance on MWM. The 135-mg/kg/day dosing of AMT increased the numbers of surviving CA2-CA3 pyramidal neurons at day 16 post-TBI. Overall, the data showed that clinically relevant dosing schedules of AMT affords neuroprotection and significantly improves cognitive outcome after experimental TBI, suggesting that it has the potential to be developed as a novel treatment of human TBI.

Assessment of Therapeutic Potential of Amantadine in Methamphetamine Induced Neurotoxicity

Methamphetamine epidemic has a broad impact on world's health care system. Its abusive potential and neurotoxic effects remain a challenge for the anti-addiction therapies. In addition to oxidative stress, mitochondrial dysfunction and apoptosis, excitotoxicity is also involved in methamphetamine induced neurotoxicity. The N-methyl-D-aspartate (NMDA) type of glutamate receptor is thought to be one of the predominant mediators of excitotoxicity. There is growing evidence that NMDA receptor antagonists could be one of the therapeutic options to manage excitotoxicity. Amantadine, a well-tolerated and modestly effective antiparkinsonian agent, was found to possess NMDA antagonistic properties and has shown to release dopamine from the nerve terminals. The current study aimed to evaluate the effect of amantadine pre-treatment against methamphetamine induced neurotoxicity. Results showed that methamphetamine treatment had depleted striatal dopamine, generated of reactive oxygen species and decreased activity of complex I in the mitochondria. Interestingly, amantadine, at high dose (10 mg/kg), did not prevent dopamine depletion moreover it exacerbated the behavioral manifestations of methamphetamine toxicity such as akinesia and catalepsy. Only lower dose of amantadine (1 mg/kg) produced significant scavenging of the reactive oxygen species induced by methamphetamine. Overall results from the present study suggest that amantadine should not be used concomitantly with methamphetamine as it may results in excessive neurotoxicity.

Amantadine improves gait in PD patients with STN stimulation

In advanced Parkinson's disease (PD), axial symptoms such as speech, gait, and balance impairment often become levodopa-unresponsive and they are difficult to manage, even in patients with subthalamic nucleus deep brain stimulation (STN-DBS). We anecdotally observed that oral administration of amantadine was very effective in treating both residual and stimulation-induced axial symptoms after bilateral STN-DBS in one PD patient. Therefore, we conducted a prospective multicenter observational study to evaluate the effects of amantadine on speech, gait and balance in PD patients with STN-DBS and incomplete axial benefit. Primary outcomes were changes in speech (UPDRS III, item 18), gait (item 29) and postural stability (item 30) with amantadine treatment compared to baseline. Secondary outcome was the patients' subjective scoring of axial symptoms with amantadine compared to baseline. Forty-six PD patients with STN-DBS were enrolled in the study and followed for 10.35 ± 8.21 months (median: 9.00; range: 1–31). The mean daily dose of amantadine was 273.44 ± 47.49 mg. Gait scores significantly improved (from 1.51 ± 0.89 to 1.11 ± 0.92, P = 0.015) with amantadine treatment, whereas postural stability and speech scores were similar before and after treatment. Thirty-five (76.1%) patients reported subjective improvement in speech, gait or balance with amantadine, whereas thirty (65.2%) patients reported improvement in gait and balance. In conclusion, our data suggest that amantadine may have new beneficial effects on axial symptoms in PD patients with STN-DBS.