Amantadine Treatment Research Articles

Early Amantadine Treatment Does Not Delay Onset of Dyskinesias in Parkinson's Disease (P02.080)

Early Amantadine Treatment Does Not Delay Onset of Dyskinesias in Parkinson's Disease (P02.080)

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.

Corneal toxicity due to amantadine

Case reportA 64year-old female with Parkinson disease treated with amantadine for two years who suddenly suffered bilateral corneal oedema. It was initially treated as herpetic endotheliitis without improvement as we lacked information on her chronic treatment. The corneal oedema finally resolved after withdrawing the drug. DiscussionAmantadine hydrochloride may produce endothelial dysfunction. Once the amantadine treatment is stopped, the corneal oedema may be reversible but endothelial density remains low. An ophthalmologist examination should be performed before the initiation of amantadine treatment in order to establish a risk: benefit ratio, especially in those patients with low endothelial density or any endothelial anomaly.

Toxicidad corneal por amantadina

Case reportA 64 year-old female with Parkinson disease treated with amantadine for two years who suddenly suffered bilateral corneal oedema. It was initially treated as herpetic endotheliitis without improvement as we lacked information on her chronic treatment. The corneal oedema finally resolved after withdrawing the drug. DiscussionAmantadine hydrochloride may produce endothelial dysfunction. Once the amantadine treatment is stopped, the corneal oedema may be reversible but endothelial density remains low. An ophthalmologist examination should be performed before the initiation of amantadine treatment in order to establish a risk: benefit ratio, especially in those patients with low endothelial density or any endothelial anomaly.

Preliminary study of intravenous amantadine treatment for ataxia management in patients with probable multiple system atrophy with predominant cerebellar ataxia.

Background and Purpose:Multiple system atrophy with predominant cerebellar ataxia is a disabling neurologic disease. However, effective management has not yet been established. We conducted a short-term, open-label preliminary study to assess the benefits of intravenous amantadine treatment in patients with probable multiple system atrophy with predominant cerebellar ataxia.Methods:Twenty patients (10 male, 10 female) with probable multiple system atrophy with predominant cerebellar ataxia received 400 mg of amantadine by intravenous per day for 5 days. Ataxia severity was evaluated by the International Cooperative Ataxia Rating Scale before and after intravenous amantadine therapy and all subjects reported subjective improvement after intravenous amantadine treatment using a patient global impression scale. We analyzed the total and subscale scores by the ataxia scale and patient global impression scale.Results:The mean age was 57.4 years (range: 47–72) and the mean disease duration was 30.8 months (range: 11–79). The ataxia severity significantly decreased after intravenous amantadine therapy from 42.5 to 37.3 (p < 0.001). The mean patient global impression scale for improvement was 2.9 and there were no side effects of intravenous amantadine treatment observed. When we assessed responders, the duration of intravenous amantadine effect was more than 1 month in 4 subjects of 7 responders.Conclusions:Our findings suggest that intravenous amantadine treatment can be a safe management option in cerebellar ataxia, although the mechanism is unclear. Thus, further double-blind, long-term studies with a larger sample size are needed.

Late onset of livedo reticularis induced by amantadine treatment concomitant with erythrocytosis

ejd.2012.1642 Auteur(s) : Sachiko Ono, Hideaki Tanizaki, Yoshiki Miyachi, Kenji Kabashima kaba@kuhp.kyoto-u.ac.jp Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawara Sakyo, Kyoto 606-8507, Japan Livedo reticularis (LR) is a mottled reticulated vascular pattern that appears as a lace-like purplish discoloration. It is caused by increased prominence of the venous beds in the skin, arising from impediments to arterial flow, venous dilation, or obstruction of venous [...]

Likely Amantadine‐Induced Livedo Reticularis in a Child

We present an 11-year-old boy with livedo reticularis (LR) secondary to amantadine treatment for his attention deficit hyperactivity disorder (ADHD). We are unaware of previous reports of amantadine-induced LR associated with treatment for ADHD in the pediatric population.

Effect of amantadine on oxymorphone‐induced thermal antinociception in cats

This study examined the effect of amantadine, an N-methyl-d-aspartate receptor antagonist, on the thermal antinociceptive effect of oxymorphone in cats. Six adult healthy cats were used. After baseline thermal threshold determinations, oxymorphone was administered intravenously to maintain plasma oxymorphone concentrations of 10, 20, 50, 100, 200, and 400 ng/mL. In addition, amantadine, or an equivalent volume of saline, was administered intravenously to maintain a plasma amantadine concentration of 1100 ng/mL. Thermal threshold and plasma oxymorphone and amantadine concentrations were determined at each target plasma oxymorphone concentration. Effect maximum models were fitted to the oxymorphone concentration-thermal threshold data, after transformation in % maximum response. Oxymorphone increased skin temperature, thermal threshold, and thermal excursion (i.e., the difference between thermal threshold and skin temperature) in a concentration-dependent manner. No significant difference was found between the amantadine and saline treatments. Mean ± SE oxymorphone EC(50) were 14.2 ± 1.2 and 24.2 ± 7.4 ng/mL in the amantadine and saline groups, respectively. These values were not significantly different. Large differences in oxymorphone EC(50) in the saline and amantadine treatment groups were observed in two cats. These results suggest that amantadine may decrease the antinociceptive dose of oxymorphone in some, but not all, cats.

Comparison of the efficacies of amantadine treatment of swine-origin influenza virus A H1N1 and seasonal influenza H1N1 and H3N2 in Japan (2008–2009)

Amantadine is not thought to be effective for the treatment of swine-origin influenza virus (S-OIV) based on an analysis of genetic sequences of the M2 protein. However, the actual clinical efficacy of amantadine has not been well documented. Here, we were able to compare the efficacies of amantadine and neuraminidase inhibitors. Subjects consisted of 428 patients, including 144 with seasonal influenza (flu) identified between 2008 and 2009, and 284 with S-OIV identified between July 1 and November 30, 2009. Diagnosis of flu was established using a rapid diagnostic kit obtained commercially in Japan. Body temperature sheets were obtained from 95% of the S-OIV patients. Times required to recover normal body temperature were compared among subjects using different antiviral drugs. Genetic abnormalities in the M2 protein were also investigated in 66 randomly selected subjects from within the patient pool. Overall, the average hours required to recover normal body temperature in S-OIV patients treated with amantadine (160 cases), with oseltamivir (59 cases), or with zanamivir (65 cases) were 33.9±20.7, 31.7±16.0, or 36.3±21.6, respectively. These differences were not statistically significant. The N31S abnormality was found in all 14 samples taken from the H3N2 patients and in all of the 23 samples taken from in S-OIV patients. However, this abnormality was not found in any of the 30 samples taken from seasonal H1N1 patients. Amantadine was found to be equally effective in treating S-OIV patients as neuraminidase inhibitors. The genetic abnormality resulting in S31N amino acid conversion identified in some of the H3N2 and S-OIV patients is thought to alter the function of M2 protein only mildly.

Amantadine for Dyskinesias in Parkinson's Disease: A Randomized Controlled Trial

BackgroundDyskinesias are some of the major motor complications that impair quality of life for patients with Parkinson's disease. The purpose of the present study was to investigate the efficacy of amantadine in Parkinson's disease patients suffering from dyskinesias.MethodsIn this multi-center, double-blind, randomized, placebo-controlled, cross-over trial, 36 patients with Parkinson's disease and dyskinesias were randomized, and 62 interventions, which included amantadine (300 mg /day) or placebo treatment for 27 days, were analyzed. At 15 days after washout, the treatments were crossed over. The primary outcome measure was the changes in the Rush Dyskinesia Rating Scale (RDRS) during each treatment period. The secondary outcome measures were changes in the Unified Parkinson's Disease Rating Scale part IVa (UPDRS-IVa, dyskinesias), part IVb (motor fluctuations), and part III (motor function).ResultsRDRS improved in 64% and 16% of patients treated with amantadine or placebo, respectively, with significant differences between treatments. The adjusted odds-ratio for improvement by amantadine was 6.7 (95% confidence interval, 1.4 to 31.5). UPDRS-IVa was improved to a significantly greater degree in amantadine-treated patients [mean (SD) of 1.83 (1.56)] compared with placebo-treated patients [0.03 (1.51)]. However, there were no significant effects on UPDRS-IVb or III scores.ConclusionsResults from the present study demonstrated that amantadine exhibited efficacious effects against dyskinesias in 60–70% of patients.Trial RegistrationUMIN Clinical Trial Registry UMIN000000780

Effects of Amantadine on Tardive Dyskinesia

The objective of the study was to demonstrate whether the N-methyl-D-aspartate antagonist, amantadine, can safely ameliorate tardive dyskinesia (TD) without deteriorating the mental state of the patients. Twenty-two TD patients, with a mean age 52 years, participated in the study. A double-blind, placebo-controlled, crossover design was used. Patients were randomly assigned to receive either amantadine or placebo for 2 weeks followed by a washout period of 4 days. Subsequently,the groups were crossed over, and the procedure repeated. Participants received amantadine (100 mg) or placebo. Tardive dyskinesia was assessed by means of the Abnormal Involuntary Movements Scale(AIMS). The primary efficacy end point was changes in AIMS score, at baseline and at the end of the 2-week treatment period. After amantadine treatment, patients exhibited a reduced average score of total AIMS (from 13.5 before treatment to 10.5 after treatment,P = 0.000), of facial and oral AIMS (from 5.5 before treatment to 4.2 after treatment, P = 0.002), of extremity AIMS (from 4.18 before treatment to 2.8 after treatment, P = 0.000), and of severity AIMS (from 2.04 before treatment to 1.54 after treatment, P = 0.002). With amantadine,the average total AIMS reduction was 21.81%. On the contrary with placebo treatment, no reduction was noted.In addition, amantadine administration exhibited a positive effect,which was statistically significant for incapacitation and Clinical Global Impression score. Amantadine did not alter any of the cognitive measures used in this study, as Mini-Mental State Examination, distress, and Brief Psychiatric Rating Scale. Amantadine may be an effective and safe treatment for TD. The severity of TD movements in patients receiving amantadine improved significantly more than in those receiving placebo, as measured by the AIMS score.

Inhibition of influenza virus replication by plant-derived isoquercetin

Influenza virus infects the respiratory system of human and animals causing mild to severe illness which could lead to death. Although vaccines are available, there is still a great need for influenza antiviral drugs to reduce disease progression and virus transmission. Currently two classes (M2 channel blockers and neuraminidase inhibitors) of FDA-approved influenza antiviral drugs are available, but there are great concerns of emergence of viral resistance. Therefore, timely development of new antiviral drugs against influenza viruses is crucial. Plant-derived polyphenols have been studied for antioxidant activity, anti-carcinogenic, and cardio- and neuroprotective actions. Recently, some polyphenols, such as resveratrol and epigallocatechin gallate, showed significant anti-influenza activity in vitro and/or in vivo. Therefore we investigated selected polyphenols for their antiviral activity against influenza A and B viruses. Among the polyphenols we tested, isoquercetin inhibited the replication of both influenza A and B viruses at the lowest effective concentration. In a double treatment of isoquercetin and amantadine, synergistic effects were observed on the reduction of viral replication in vitro. The serial passages of virus in the presence of isoquercetin did not lead to the emergence of resistant virus, and the addition of isoquercetin to amantadine or oseltamivir treatment suppressed the emergence of amantadine- or oseltamivir-resistant virus. In a mouse model of influenza virus infection, isoquercetin administered intraperitoneally to mice inoculated with human influenza A virus significantly decreased the virus titers and pathological changes in the lung. Our results suggest that isoquercetin may have the potential to be developed as a therapeutic agent for the treatment of influenza virus infection and for the suppression of resistance in combination therapy with existing drugs.

Analysis of in vivo dynamics of influenza virus infection in mice using a GFP reporter virus

Influenza A virus is being extensively studied because of its major impact on human and animal health. However, the dynamics of influenza virus infection and the cell types infected in vivo are poorly understood. These characteristics are challenging to determine, partly because there is no efficient replication-competent virus expressing an easily traceable reporter gene. Here, we report the generation of a recombinant influenza virus carrying a GFP reporter gene in the NS segment (NS1-GFP virus). Although attenuated when compared with wild-type virus, the NS1-GFP virus replicates efficiently in murine lungs and shows pathogenicity in mice. Using whole-organ imaging and flow cytometry, we have tracked the dynamics of influenza virus infection progression in mice. Imaging of murine lungs shows that infection starts in the respiratory tract in areas close to large conducting airways and later spreads to deeper sections of the lungs. In addition to epithelial cells, we found GFP-positive antigen-presenting cells, such as CD11b(+)CD11c(-), CD11b(-)CD11c(+), and CD11b(+)CD11c(+), as early as 24 h after intranasal infection. In addition, a significant proportion of NK and B cells were GFP positive, suggesting active infection of these cells. We next tested the effects of the influenza virus inhibitors oseltamivir and amantadine on the kinetics of in vivo infection progression. Treatment with oseltamivir dramatically reduced influenza infection in all cell types, whereas, surprisingly, amantadine treatment more efficiently blocked infection in B and NK cells. Our results demonstrate high levels of immune cells harboring influenza virus antigen during viral infection and cell-type-specific effects upon treatment with antiviral agents, opening additional avenues of research in the influenza virus field.

Influence of amantadine on CD81 expression on lymphocytes in chronic hepatitis C

Introduction Interferon alpha (IFN) down regulates CD81 expression on peripheral blood mononuclear cells (PBMC) in patients with chronic hepatitis C virus (HCV) infection. Aim of our study was to investigate whether amantadine alters IFN associated down regulation of CD81 expression on PBMC in patients with chronic hepatitis C. Methods Nineteen patients with chronic HCV infection received peginterferon alpha-2a/ribavirin (SOC) for 48 weeks. Patients were randomised to 12 weeks amantadine therapy ( n = 12) or no additional treatment ( n = 7). FACS analysis of CD81 expression on CD4(+), CD8(+), CD19(+), and CD56(+) cells was performed at baseline, week (TW) 4, TW12, and TW24 of antiviral therapy. Results A significant decline of CD81 expression was observed on CD4(+), CD8(+), and CD56(+) cells ( p = 0.011, p < 0.001, p = 0.015, respectively) but not on CD19(+) cells ( p > 0.2). CD81 expression on CD4(+), CD8(+), CD19(+), and CD56(+) cells was not different between patients treated with SOC plus amantadine and patients treated with SOC alone. Conclusion The current study confirms that CD81 expression is down regulated by SOC on CD4(+), CD8(+) and CD56(+) cells. Amantadine treatment was not associated with CD81 expression. Interaction between amantadine and CD81 is unlikely to be involved in potential antiviral activity of amantadine in chronic HCV infection.

Inhibitory effects of amantadine on the production of pro-inflammatory cytokines by stimulated in vitro human blood

Treatment with amantadine (AMA), an N-methyl-D-aspartate (NMDA) receptor antagonist and antidepressant drug, increased the antidepressant activity of subsequent drugs in experimental studies and in patients suffering from treatment-resistant depression (TRD). Recent evidence indicates that depression may be accompanied by activation of an inflammatory response. These data indicate that pro-inflammatory cytokines may play a role in the etiology of depression, particularly in TRD. The present in vitro study shows the ability of AMA, used at concentrations between 10−7 to 10−5 M, to reduce the production of the pro-inflammatory cytokines, specifically interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). In addition, AMA treatment increased the production of the negative immunoregulator, interleukin-10 (IL-10). Furthermore, the combined treatment of AMA with fluoxetine (FLU), but not imipramine (IMI), had a stronger immunomodulatory effect on cytokine production than AMA alone. The above data provide additional rationale for the treatment of patients suffering from depression with a combination of AMA and a selective serotonin reuptake inhibitor.

50. The effects of amantadine on memory and cognition in early Parkinson’s disease

Aim: To assess the effects of amantadine treatment for early Parkinson’s disease (PD) on memory and cognition.

A Case of Amantadine-Induced Corneal Edema

Purpose: To report a rare case of corneal edema caused by amantadine. Case summary: A 35-year-old man was diagnosed with hypoxic brain damage caused by ventricular fibrillation. The patient showed Parkinsonism and was started on treatment with amantadine. Thirty-seven months after the commencement of amantadine treatment, the patient suffered a corneal ulcer in his right eye, which healed with opacity and thinning after medical treatment. After healing, slit-lamp examination revealed a bilateral, epithelial and stromal edema without obvious guttae and keratic precipitates. The corneal edema did not improve with topical treatment of 5% NaCl and 0.02% fluorometholone in both eyes. Three months after leaving the hospital, the patient’s corrected visual acuity decreased to 0.2 (-2.0 Dsph -0.5 Dcyl Ax 90) in the right eye and 0.4 (-0.75 Dsph -2.0 Dcyl Ax 90) in the left eye. Amantadine medication was discontinued after discussion with the patient’s neurologist. At the 1-month follow-up, corneal examination revealed resolution of the epithelial and stromal edema in both eyes. Corrected visual acuity was improved to 0.5 (-1.5 Dsph) in the right eye and 0.7 (-1.0 Dsph -1.0 Dcyl Ax 90) in the left eye. Conclusions: In cases of corneal edema without an obvious causative disease, the patient’s systemic medication list must be reviewed and amantadine should be considered as a possible cause.

In Vivo and In Vitro Alterations in Influenza A/H3N2 Virus M2 and Hemagglutinin Genes: Effect of Passage in MDCK-SIAT1 Cells and Conventional MDCK Cells

No mutations were detected in the hemagglutinin gene of influenza A/H3N2 virus isolates from patients undergoing short-term amantadine treatment. However, genetic changes occurred after serial passage in either MDCK or MDCK-SIAT1 cells. Our results showed that only a few mutations were observed in MDCK-SIAT1-passaged isolates in the presence of amantadine.

Plasma amantadine concentrations in patients with Parkinson's disease

We determined plasma amantadine concentrations in patients with Parkinson's disease (PD) in daily clinical practice and investigated the relationship between plasma concentration and adverse reactions to clarify the safe therapeutic range. Seventy-eight consecutive PD patients on stable amantadine treatment were recruited. Plasma concentration of amantadine was measured 3 h after the administration of morning amantadine dose. Serum creatinine was measured to estimate renal function. The mean daily dose of amantadine was 135.1 ± 62.3 mg/day, and the mean plasma amantadine concentration was 812.5 ± 839.5 ng/ml (range, 91–4400 ng/ml). Plasma amantadine concentration increased according to increasing renal dysfunction. Three patients exhibited adverse reactions, such as myoclonus, hallucinations, and delirium, and all of them showed plasma amantadine concentration >3000 ng/ml. None of the three cases had previously shown such side effects. PD patients who have not developed any psychiatric symptoms as adverse reactions to the treatment may develop myoclonus, hallucination, or delirium when the plasma concentration of amantadine exceeds 3000 ng/ml. It is therefore recommended to use amantadine at the plasma concentration of less than 3000 ng/ml in the treatment of Parkinson's disease, especially in elderly patients.

Modeling amantadine treatment of influenza A virus in vitro

We analyzed the dynamics of an influenza A/Albany/1/98 (H3N2) viral infection, using a set of mathematical models highlighting the differences between in vivo and in vitro infection. For example, we found that including virion loss due to cell entry was critical for the in vitro model but not for the in vivo model. Experiments were performed on influenza virus-infected MDCK cells in vitro inside a hollow-fiber (HF) system, which was used to continuously deliver the drug amantadine. The HF system captures the dynamics of an influenza infection, and is a controlled environment for producing experimental data which lend themselves well to mathematical modeling. The parameter estimates obtained from fitting our mathematical models to the HF experimental data are consistent with those obtained earlier for a primary infection in a human model. We found that influenza A/Albany/1/98 (H3N2) virions under normal experimental conditions at 37 ∘ C rapidly lose infectivity with a half-life of ∼ 6.6 ± 0.2 h , and that the lifespan of productively infected MDCK cells is ∼ 13 h . Finally, using our models we estimated that the maximum efficacy of amantadine in blocking viral infection is ∼ 74 % , and showed that this low maximum efficacy is likely due to the rapid development of drug resistance.