Dose Of Amantadine Research Articles

Intravenous amantadine is safe and effective for the perioperative management of patients with Parkinson’s disease

The perioperative management of Parkinson’s disease (PD) patients is difficult, especially when they are on nothing per oral (NPO) [1, 2]. Most parkinsonian medications are taken orally, which increases the risk of complications such as Parkinsonism hyperpyrexia syndrome if these medications need to be stopped. The situation is especially difficult when patients undergo abdominal surgery requiring prolonged NPO. Intravenous (IV) forms of levodopa [3], subcutaneous apomorphine [4], or a rotigotine patch [5] may be considered, but these may not be available in some countries, including Korea. We found that PD patients who were on NPO due to surgery could be successfully managed using IV amantadine. All interviews were carried out with the adequate understanding of the subjects involved. This study was approved by the institutional review board at our institution. Between December 2009 and November 2010, 13 PD patients (5 males and 8 females) underwent surgery and received IV amantadine during the perioperative period. Our standard regimen was IV amantadine at 200 mg in 500 cm of saline solution administered over a 3-h period, twice a day when the patients were on NPO. All other antiparkinsonian medications were stopped when IV amantadine was administered. Antiparkinsonian medications were restarted at their previous dose and amantadine was stopped when oral feeding was allowed. Baseline and post-operative follow-up laboratory blood investigations which include renal panel were performed on a routine basis. The mean age of the subjects was 68.7 years (range from 52 to 82 years), and their mean duration of PD was 7.6 years (range from 1 to 15 years). The levodopa equivalent daily dose before surgery was 789.6 ± 347.5 mg (mean ± SD). The types of surgery comprised six cases of abdominal surgery (three gastric cancers, two colorectal cancers, and one intestinal perforation), one of thyroid surgery (one thyroid cancer), one of breast surgery (one breast cancer), three of orthopedic surgery (three femur fractures), one of spinal surgery (one spinal stenosis), and one of gynecologic surgery (one uterine prolapse). The mean overall duration of amantadine use was 3.0 days (range from 1 to 6 days); the mean duration was 4.2 days for the six cases of abdominal surgery. The total amantadine dose in individual patients varied from 400 to 2,400 mg. Only one patient complained that IV amantadine was less effective than oral medication, but it was still tolerable. Some patients experienced improvement in their dyskinesia and off symptoms. No patients experienced severe worsening of parkinsonian features, including neuroleptic malignant syndrome, or Parkinsonism hyperpyrexia syndrome. No patients experienced known side effects of amantadine including hallucination, cardiopulmonary, or eye problems. The baseline and follow-up renal function was normal in all of the patients. Our preliminary experience shows that IV amantadine is safe and useful for the perioperative management of PD patients when medications cannot be administered orally.

Anorexia nervosa versus hyperinsulinism: therapeutic effects of neuropharmacological manipulation

Background:We have demonstrated that anorexia nervosa is underpinned by overwhelming adrenal sympathetic activity which abolishes the neural sympathetic branch of the peripheral autonomic nervous system. This physiological disorder is responsible for gastrointestinal hypomotility, hyperglycemia, raised systolic blood pressure, raised heart rate, and other neuroendocrine disorders. Therefore, we prescribed neuropharmacological therapy to reverse this central and autonomic nervous system disorder, in order to normalize the clinical and neuroendocrine profile.Methods:The study included 22 female patients with anorexia nervosa (10 restricted type, 12 binge-eating type) who received three months of treatment with amantadine 100 mg/day. We measured blood pressure, heart rate, and circulating neurotransmitters, (noradrenaline, adrenaline, dopamine, platelet serotonin, free plasma serotonin) during supine resting, one minute of orthostasis, and a five-minute exercise test before and after one, two, and three months of treatment with amantadine, a drug which abrogates adrenal sympathetic activity by acting at the C1(Ad) medullary nuclei responsible for this branch of the peripheral sympathetic activity.Results:We found the amantadine abolished symptoms of anorexia nervosa from the first oral dose onwards. Normalization of autonomic and cardiovascular parameters was demonstrated within the early days of therapy. Abrupt and sustained increases in the plasma noradrenaline:adrenaline ratio and disappearance of abnormal plasma glucose elevation were registered throughout the three-month duration of the trial. Significant and sustained increases in body weight were documented in all cases. No relapses were observed.Conclusion:We have confirmed our previously published findings showing that the anorexia nervosa syndrome depends on the hypomotility of the gastrointestinal tract plus hyperglycemia, both of which are triggered by adrenal sympathetic hyperactivity. The above neuroendocrine plus neuroautonomic and clinical disorders which underpinned anorexia nervosa were abruptly suppressed since the first oral dose of amantadine, a drug able to revert the C1(Ad) over A5(NA) pontomedullary predominance responsible for adrenal and neural sympathetic activity, respectively.

DNA damage in brain cells and behavioral deficits in mice after treatment with high doses of amantadine

Amantadine (AMA) is an uncompetitive antagonist of the N-methyl-d-aspartate receptor, with clinical application, acting on treatment of influenza A virus and Parkinson's disease. It has been proposed that AMA can indirectly modulate dopaminergic transmission. In high doses, the central nervous system is its primary site of toxicity. To examine deleterious effects on CNS induced by AMA, this study evaluated possible neurobehavioral alterations induced by AMA such as stereotyped behavior, the effects on locomotion and memory and its possible genotoxic/mutagenic activities. Adult male CF-1 mice were treated with a systemic injection of AMA (15, 30 or 60 mg kg(-1) ) 20 min before behavioral tasks on open field and inhibitory avoidance. Higher AMA doses increased the latency to step-down inhibitory avoidance test in the training session in the inhibitory avoidance task. At 60 mg kg(-1) AMA induced impairing effects on locomotion and exploration and hence impaired habituation to a novel environment. Stereotyped behavior after each administration in a 3-day trial was observed, suggesting effects on dopaminergic system. Amantadine was not able to induce chromosomal mutagenesis or toxicity on bone marrow, as evaluated by the micronucleus assay. At the lowest dose tested, AMA did not induce DNA damage and it was unable to impair memory, locomotion, exploration or motivation in mice. However, higher AMA doses increased DNA damage in brain tissue, produced locomotor disturbances severe enough to preclude testing for learning and memory effects, and induced stereotypy, suggesting neurotoxicity.

Effects of amantadine on circulating neurotransmitters in healthy subjects

Considering that glutamatergic axons innervate the C1(Ad) medullary nuclei, which are responsible for the excitation of the peripheral adrenal glands, we decided to investigate catecholamines (noradrenaline, adrenaline and dopamine) plus indolamines (plasma serotonin and platelet serotonin) at the blood level, before and after a small oral dose of amantadine, a selective NMDA antagonist. We found that the drug provoked a selective enhancement of noradrenaline plus a minimization of adrenaline, dopamine, plasma serotonin and platelet serotonin circulating levels. Significant enhancement of diastolic blood pressure plus reduction of systolic blood pressure and heart rate paralleled the circulating parameter changes. The above findings allow us to postulate that the drug was able to enhance the peripheral neural sympathetic activity. Minimization of both adrenal sympathetic and parasympathetic activities was also registered after the amantadine challenge. The above findings supported the postulation that this drug should be a powerful therapeutic tool for treating diseases affected by adrenal sympathetic hyperactivity.

Amantadine as a regulator of internal ribosome entry site

Studies of eukaryotes have yielded 2 translation initiation mechanisms: a classical cap-dependent mechanism and a cap-independent mechanism proceeding through the internal ribosomal entry site (IRES). We hypothesized that it might be possible to identify compounds that may distinguish between cap-dependent translation and cap-independent IRES-mediated translation. To facilitate compound screening, we developed bicistronic reporter constructs containing a beta-galactosidase gene (beta-gal) and a secreted human placental alkaline phosphatase (SEAP) reporter gene. Following transcription, the beta-gal gene is translated by a cap-dependent mechanism, while SEAP expression is controlled by the IRES derived from either enterovirus 71 (EV-71) or encephalomyocarditis virus (EMCV). This assay could potentially identify compounds that inhibit SEAP expression (cap-independent) without affecting beta-gal activity (cap-dependent). Using a bicistronic plasmid-based transient transfection assay in the COS-1 cells, we identified amantadine, a compound that inhibited the IRES of EV71- and EMCV-mediated cap-independent translation but did not interfere with cap-dependent translation when the dose of amantadine was lower than 0.25 mg/mL. These results imply that amantadine may distinguish between cap-dependent translation and cap-independent IRES-mediated translation and can be used to regulate gene expression at a translational level.

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.

Memantine-Induced Myoclonus and Delirium Exacerbated by Trimethoprim

To report a case of myoclonus and delirium seen in a patient taking a combination of memantine and trimethoprim. A 78-year-old woman was admitted to the medical center in October 2007 with rapid deterioration of Alzheimer's dementia and progressive myoclonus. In 2003, donepezil 5 mg/day had been initiated and her disease slowly progressed. In 2006, memantine 10 mg twice daily was added. Myoclonic activity and delirium were noted in 2007 when a urinary tract infection (UTI) was treated with double-strength trimethoprim/sulfamethoxazole (TMP/SMX 160 mg/800 mg). After discontinuation of TMP/SMX, the patient's condition returned to baseline level. Several weeks later, trimethoprim 100 mg daily was added for UTI prophylaxis. Within weeks, spontaneous generalized myoclonic activity resumed to the extent that the patient was unable to walk. She became increasingly delirious. A week before admission, levodopa/carbidopa 250 mg/100 mg was added for presumptive restless legs syndrome and the patient became extremely delirious and combative, requiring hospitalization. Because of the striking similarity of dose-related toxicities reported with amantadine, a slightly different aminoadamantane, memantine was withheld. Trimethoprim was discontinued due to a likely interaction with memantine. Donepezil and famotidine were withheld due to questions of therapeutic necessity. After 3 days, the myoclonus had completely resolved and the patient was no longer agitated or combative during the remainder of her hospitalization. She was cooperative and ambulatory and was discharged. Memantine is cleared primarily through the kidneys and should be renally dosed. Drugs that interfere with elimination-that is, other drugs utilizing the organic cation transporter-2 in the tubule, such as trimethoprim, metformin, or imipramine-may lead to drug accumulation. Our patient, who had impaired renal function, developed severe myoclonus and delirium after trimethoprim was added to therapy with memantine. As there were no reports of myoclonus and delirium with this drug combination and because of the structural, pharmacologic, and pharmacokinetic similarities between the aminoadamantanes memantine and amantadine, we researched similar dual adverse effects reported with amantadine. Amantadine has led to the same adverse effects noted in our patient, not only in patients with renal impairment, but also in one patient when trimethoprim was added to a stable dose of amantadine. This is the first reported case of a drug interaction between memantine and trimethoprim, which resulted in clinically significant myoclonus and delirium. Clinicians should be aware of this potential interaction, since there have been reports of this adverse effect with the use of amantadine. Because memantine chemically and pharmacologically resembles amantadine, it is quite possible that their toxicities are similar.

Possible role for chlorpheniramine in the treatment of l-DOPA induced dyskinesia in Parkinson’s disease

Dopamine (DA) replacement therapy with L-3,4-dihydroxyphenylalanine (L-DOPA) remains the most effective medication for the symptomatic relief of Parkinson’s disease (PD). However, chronic L-DOPA treatment is often complicated by a variety of involuntary movements, termed L-DOPA-induced dyskinesia (LID), which represents one of the major limitations in the treatment for PD. Depending on clinical presentation and chronology after a dose of L-DOPA, LID can be classified in peak-dose, diphasic, and off period dyskinesias. Peak-dose dyskinesia occurs at the time of the highest brain concentration of LDOPA and represents the most common type of LID. The current pharmacological treatment of this form of dyskinesia involves, as a first measure, the reduction of individual L-DOPA doses, which indeed can lead to improvement of dyskinesia, exacerbating however the symptoms of the disease. Slow-release L-DOPA preparations or spreading of the daily dose of L-DOPA into smaller but more frequent doses has been also used; however, only limited improvements have been reported so far. On the other hand, the only currently available drug with an evidence-based recommendation for dyskinesia is the glutamate antagonist amantadine, even though no large scale study of this drug has been conducted. Moreover, only a number of patients can tolerate effective doses of amantadine, and its effects decline over time. Finally, dyskinesias that become disabling must often be managed surgically, despite the high cost and risk for serious adverse events of such intervention. Thus, it is a common belief that the development of new safe and effective therapies that treat dyskinesias without aggravating parkinsonism are urgently needed. A rapid and excessive increase in extracellular DA, after L-DOPA administration, is considered one of the major causes for peak-dose LID. This is due to the fact that oral formulations of L-DOPA have short plasma half-lives, so each dose causes a rapid increase followed by a rapid decrease in striatal dopamine levels, leading to intermittent stimulation of striatal dopamine receptors. Interestingly, in experiments with rats, administration of 8-hydroxy-2-(d-npropylamino) tetralin (8-OH-DPAT), a selective 5-HT1A receptor agonist, attenuated the increase in L-DOPA-induced extracellular DA [1] while alleviated L-DOPA induced motor complications, including LID [2]. In support of a role in receptor specificity, it was shown that these effects of 8-OH-DPAT were mediated mainly via stimulation of 5-HT1A receptors, since co-administration of a 5HT1A receptor antagonist (WAY100635) abolished the above mentioned effects of 8-OH-DPAT [1]. Moreover, in compliance with these animal studies, the use of the clinically available 5-HT1A agonist sarizotan, in the context of a multicenter trial, was proved to be effective in the treatment of LID in PD patients [3]. Taken together, all these data suggest that pharmaceutical agents capable of stimulating 5-HT1A receptors could avert the induction of L-DOPA induced motor complications in patients with PD. P. N. Karamanakos P. Pappas M. Marselos Department of Pharmacology, Medical School, University of Ioannina, Ioannina 451 10, Greece

Modulation of Human Motor Cortex Excitability by Single Doses of Amantadine

Amantadine-sulfate has been used for several decades to treat acute influenza A, Parkinson's disease (PD), and acute or chronic drug-induced dyskinesia. Several mechanisms of actions detected in vivo/in vitro including N-methyl-D-aspartate (NMDA)-receptor antagonism, blockage of potassium channels, dopamine receptor agonism, enhancement of noradrenergic release, and anticholinergic effects have been described. We used transcranial magnetic stimulation (TMS) to evaluate the effect of single doses of amantadine on human motor cortex excitability in normal subjects. Using a double-blind, placebo-controlled, crossover study design, motor thresholds, recruitment curves, cortical stimulation-induced silent period (CSP), short intracortical inhibition (ICI), intracortical facilitation (ICF), and late inhibition (L-ICI) in 14 healthy subjects were investigated after oral doses of 50 and 100 mg amantadine with single and paired pulse TMS paradigms. Spinal cord excitability was investigated by distal latencies and M-amplitudes of the abductor digiti minimi muscle. After intake of amantadine, a significant dose-dependent decrease of ICF was noticed as well as a significant increase of L-ICI as compared to placebo. The effect on ICF and L-ICI significantly correlated with amantadine serum levels. ICI was slightly increased after amantadine intake, but the effect failed to be significant. Furthermore, amantadine had no significant effects on motor thresholds, MEP recruitment curves, CSP, or peripheral excitability. In conclusion, a low dose of amantadine is sufficient in modulating human motor cortex excitability. The decrease of ICF and increase of L-ICI may reflect glutamatergic modulation or a polysynaptic interaction of glutamatergic and GABA-ergic circuits. Although amantadine has several mechanisms of action, the NMDA-receptor antagonism seems to be the most relevant effect on cortical excitability. As L-ICI can be influenced by this type of drug, it may be an interesting parameter for studies of motor learning and use-dependent plasticity.

Economic Evaluation of Oseltamivir Phosphate for Postexposure Prophylaxis of Influenza in Long‐Term Care Facilities

To compare the cost-effectiveness of oseltamivir postexposure prophylaxis during influenza A outbreaks with that of amantadine postexposure prophylaxis or no postexposure prophylaxis in long-term care facilities (LTCFs). Cost-effectiveness analysis based on decision analytic model from a government-payer perspective. A Canadian LTCF, with high staff vaccination, at the beginning of influenza season. Elderly, influenza-vaccinated patients living in a Canadian LTCF. Incremental costs (or savings) per influenza-like illness case avoided compared with usual care. From a government-payer perspective, this analysis showed that oseltamivir was a dominant strategy because it was associated with the fewest influenza-like illness cases, with cost savings of $1,249 per 100 patients in 2001 Canadian dollars compared with amantadine and $3,357 per 100 patients compared with no prophylaxis. Costs for amantadine dose calculation and hospitalization for adverse events contributed to amantadine being a more-expensive prophylaxis strategy than oseltamivir. Both prophylaxis strategies were more cost-effective than no prophylaxis. Despite high influenza vaccination rates, influenza outbreaks continue to emerge in LTCFs, necessitating cost-effective measures to further limit the spread of influenza and related complications. Although amantadine has a lower acquisition cost than oseltamivir, it is associated with more adverse events, lower efficacy, and individualized dosing requirements, leading to higher overall costs and more influenza-like illness cases than oseltamivir. Therefore the use of oseltamivir postexposure prophylaxis is more cost-effective than the current standard of care with amantadine prophylaxis or no prophylaxis.

Amantadine therapy for chronic hepatitis C: a dose escalation study.

Amantadine reduces liver transaminase levels in some patients with chronic hepatitis C at doses of 200 mg daily and may improve the sustained virological response (SVR) when given with interferon and ribavirin. The primary purpose of the present investigation was to study the safety and toxicity of higher doses of amantadine in subjects who previously failed or were intolerant to interferon. The secondary aim was to test the efficacy of higher dose of amantadine against hepatitis C. An open-labeled prospective study was conducted starting with amantadine 200 mg daily and increasing to 500 mg daily while monitoring for safety, toxicity, and efficacy. An amantadine blood level exceeding 1,600 ng/ml was considered toxic requiring dose reduction. The patient's symptoms, laboratory tests, and quality of life were monitored. One hundred patients enrolled in the study. Normalization of alanine aminotransferase (ALT) for each dose was as follows: 200 mg (35%), 300 mg (49%), 400 mg (53%), and 500 mg (56%). The incidence of toxic amantadine plasma levels increased with dose, i.e., 200 mg (0%), 300 mg (6%), 400 mg (27%), and 500 mg (49%). The frequency and severity of arthralgias and fatigue improved at all dosages administered. No changes in the occurrence or severity of headache, insomnia, or depression were reported. Serious adverse events included myocardial infarction and suicide attempt. Other side effects included impotence, confusion, alopecia, and hoarseness. Amantadine given at a dose of 300 mg daily is safe, and significantly lowers ALT blood levels more than 200 mg daily. The enzyme response rate does not significantly improve above 300 mg, but toxicity increases.

Double-Blind, Placebo-Controlled Study of Amantadine Hydrochloride in the Treatment of Children With Autistic Disorder

To test the hypothesis that amantadine hydrochloride is a safe and effective treatment for behavioral disturbances--for example, hyperactivity and irritability--in children with autism. Thirty-nine subjects (intent to treat; 5-19 years old; IQ > 35) had autism diagnosed according to DSM-IV and ICD-10 criteria using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule-Generic. The Aberrant Behavior Checklist-Community Version (ABC-CV) and Clinical Global Impressions (CGI) scale were used as outcome variables. After a 1-week, single-blind placebo run-in, patients received a single daily dose of amantadine (2.5 mg/kg per day) or placebo for the next week, and then bid dosing (5.0 mg/kg per day) for the subsequent 3 weeks. When assessed on the basis of parent-rated ABC-CV ratings of irritability and hyperactivity, the mean placebo response rate was 37% versus amantadine at 47% (not significant). However, in the amantadine-treated group there were statistically significant improvements in absolute changes in clinician-rated ABC-CVs for hyperactivity (amantadine -6.4 versus placebo -2.1; p = .046) and inappropriate speech (-1.9 versus 0.4; p = .008). CGI scale ratings were higher in the amantadine group: 53% improved versus 25% (p = .076). Amantadine was well tolerated. Parents did not report statistically significant behavioral change with amantadine. However, clinician-rated improvements in behavioral ratings following treatment with amantadine suggest that further studies with this or other drugs acting on the glutamatergic system are warranted. The design of these and similar drug trials in children with autistic disorder must take into account the possibility of a large placebo response.

A PET study with [11-C]raclopride in Parkinson's disease: preliminary results on the effect of amantadine on the dopaminergic system.

Amantadine has been proved to be beneficial in Parkinson's disease. Although it is still uncertain which neurochemical events are modified at therapeutic doses, an increase in dopaminergic tone secondary to NMDA receptor blockade and a direct inhibition of the glutamatergic overactivity have been suggested to be involved in its clinical effects. The aim of this study was to evaluate the effects of amantadine on the dopaminergic system by measuring the in vivo binding of [11-C]raclopride to D2 dopamine receptors in the basal ganglia of 6 patients with idiopathic Parkinson's disease. Each patient underwent a PET study, before and after 14 days of treatment with amantadine (200 mg/day). Repeated treatment with therapeutic doses of amantadine induced a moderate increase in the in vivo binding of [11C]raclopride in the putamen of PD patients. This observation indicates that in PD patients, 200 mg/day amantadine does not produce an increase in extracellular levels of dopamine sufficiently to inhibit raclopride binding or that, if present, is it masked by a concurrent increase in receptor availability, as recently reported in rat striatum.

Previous creatinine levels safely predict amantadine dose for influenza A outbreak control.

Amantadine, an antiviral agent, is the only drug currently approved in Canada for prophylaxis of influenza A virus infection. To minimize side effects, the amantadine dose is adjusted for age and estimated creatinine clearance (CrCl) based on plasma creatinine (Cr) levels. As amantadine is used more frequently for influenza A outbreak control in care facilities for elderly people, physicians are increasingly called on to prescribe it for residents and to consider the necessity of requesting plasma Cr levels. To determine whether previous Cr levels are predictive in estimating current CrCl and safe amantadine dose determination. Residents' charts were reviewed in two facilities in Vancouver, British Columbia. CrCl estimated using previous or current Cr results, current weight and age, as well as recommended amantadine doses based on Canadian National Advisory Committee on Immunization guidelines, were studied. 165 charts with Cr results in March 1998 were included; 122 had results before March 1998, and 103 had Cr results after March 1998. Pearson's correlation coefficient for CrCl estimated from current and previous Cr values was 0.929 for results less than six months previously, 0.974 for six to 12 months previously and 0.952 for 12 to 18 months previously. The same or a more conservative dose of amantadine was predicted in 92% of cases when using a Cr result taken within the previous year and in 76% of cases when using a Cr result taken 12 to 18 months previously. In long term care facilities, Cr levels measured up to 12 months previously can usually safely be used to estimate CrCl. Using previous Cr results permits advance preparation of doctor's orders for amantadine prophylaxis and avoids repeating Cr testing on every resident when an outbreak occurs, reducing related staff time and cost.

Influenza outbreak in a long-term-care facility: considerations for pharmacy.

The role played by a hospital pharmacy department in managing an influenza outbreak at an affiliated long-term-care facility is described. In February 1998 an outbreak of influenza A was confirmed in a 570-bed long-term-care facility. During the outbreak, a total of 48 cases of influenza-like illness (ILI) were reported to infection control, and 62 staff members missed work because of ILI. Infection control measures included a recommendation for prophylaxis with amantadine. Pharmacists assumed responsibility for educating patients and families about amantadine prophylaxis, providing individualized dosing, evaluating reported adverse effects, and drug distribution. Pharmacists developed an information sheet on amantadine for patients and met with patients and their families. The overall acceptance rate for chemoprophylaxis was 91%. Of the 349 patients receiving amantadine during the outbreak, 203 (58%) were given 100 mg daily, 136 (39%) were given 100 mg every other day, and 10 (3%) were prescribed 100 mg weekly. Pharmacists confirmed a total of 22 adverse effects; generally the problem was solved by reducing the dosage rather than discontinuing the drug. In all cases, the first dose of amantadine was provided to the nursing units within three hours of an order being written. Pharmacists played an active role in managing an influenza A outbreak at a long-term-care facility.

TREATMENT OF CHRONIC HEPATITIS C WITH AMANTADINE HYDROCHLORIDE IN CHILDREN

109 Background: Hepatitis C is the most common chronic viral hepatitis in the US today. Because treatment with alpha-interferon (IFN), has been disappointing and complicated by significant side effects, anti-viral therapy with a nucleoside analogue is logical. Aims: To test the efficacy and safety of the anti-viral drug, amantadine hydrochloride in patients with chronic hepatitis C. Methods: Prospective open-labeled uncontrolled study using amantadine-HCL 4mg/kg/d orally in 2 divided doses, for 6 mo in children with chronic hepatitis C. Diagnosis was confirmed by positive Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) in plasma & liver, detectable plasma hepatitis C RNA by Chiron branched chain DNA analysis (bDNA), and abnormal liver histology. Response was defined as complete (normalization of ALT), or partial (>50% reduction in ALT). Virological response was defined as undetectable HCV RNA in serum. Pre and post-treatment liver biopsies were scored using a modified Knodell histology activity index (HAI). Patients: Six patients (4M/2F, median age 12y, range 5-18y), entered the trial. Transmission was vertical in 2. Three pts were liver transplant recipients, 2 of them for chronic hepatitis C, and one for biliary atresia. Two had previously failed therapy with interferon, at least 1 year before starting the amantadine. Results: Amantadine dose was decreased by 50% in pt # 4 secondary to tremor. Four pts. completed the 6 mo course, with 1 achieving a partial response, 2 achieved 20-40% reduction in ALT, and 1 no response. Another pt completed 5 mo of therapy. Pre-treatment Chiron (bDNA) ranged from 3 to 262 × 10E+5/ml. Despite a partial enzyme response in pt # 3, 2.5 fold increase in the chiron bDNA titer, and an RT-PCR increase from 3+ to 4+ were seen. Chiron bDNA increased by 4.5 fold in pt # 6, who had ×3 episodes of rejection. Conclusions: In children with chronic hepatitis C: 1-Amantadine is a safe anti-viral drug. 2-Monotherapy with amantadine does not appear to lower Chiron bDNA values in this select population. Further studies of amantadine as monotherapy or combined with interferon are necessary.

Amantadine and equine influenza: pharmacology, pharmacokinetics and neurological effects in the horse.

Amantadine is an antiviral agent effective against influenza A viruses. We investigated 1) the antiviral efficacy, 2) analytical detection, 3) bioavailability and disposition, 4) pharmacokinetic modelling and 5) adverse reactions of amantadine in the horse. In vitro, amantadine and its derivative rimantadine suppressed the replication of recent isolates of equine-2 influenza virus with effective doses (EDs) of less than 30 ng/ml. Rimantadine was more effective than amantadine against most viral isolates; we suggest a minimum plasma concentration of 300 ng/ml of amantadine for therapeutic efficacy. In vivo an i.v. dose of amantadine 15 mg/kg bwt produced mild, transient CNS signs which were no longer apparent after 30 min. Amantadine administered at a dose of 15 mg/kg bwt was established as the maximum safe single i.v. dose. However, if repeated i.v. administration of amantadine is required no more than 10 mg/kg bwt t.i.d. should be used. The maximal safe plasma concentration of amantadine was not evaluated but is probably greater than 2000 ng/ml and possibly greater than 4000 ng/ml. On the other hand, horses with lower seizure thresholds, or those on medications that lower seizure thresholds, may be at increased risk of amantadine-induced seizures, which show few premonitory signs and are rapidly fatal. After i.v. administration of amantadine 10 mg/kg bwt, the disposition kinetics were well fitted by a 2-compartment open model. The estimated peak plasma concentration after this dose was about 4500 ng/ml, the volume of distribution at steady-state (Vdss) was (mean +/- s.d.) 4.9 +/- 1.9 l/kg bwt and the beta phase half-life was 1.83 +/- 0.87 h. Computer projections of plasma amantadine concentrations after i.v. administration of amantadine at a dose of 10 mg/kg bwt t.i.d. at 8 h intervals suggest peak plasma concentrations of 4000-5000 ng/ml and troughs of less than 300 ng/ml will be achieved. Amantadine administered orally at 10 mg/kg bwt and 20 mg/kg bwt showed mean oral bioavailability of about 40-60% and a plasma half life of 3.4 +/- 1.4 h; however, there was substantial inter-animal variation in bioavailability. Projections based on the kinetics observed in individual animals suggest that some animals readily maintain effective plasma concentrations of amantadine after oral administration of 20 mg/kg bwt t.i.d. On the other hand, animals in which amantadine is poorly bioavailable may require up to a 6-fold (120 mg/kg bwt) increase in the oral dose to achieve effective blood concentrations. Withholding food for 15 h did not reduce these inter-animal differences in bioavailability. Our results showed that simple dosing with oral amantadine will not yield effective plasma concentrations in all animals. While i.v. administration yielded more reproducible plasma concentrations, care should be taken to see that the seizure threshold is not exceeded. In acute situations, i.v. administration (5 mg/kg bwt) every 4 h should maintain safe and effective plasma and respiratory tract concentrations of amantadine.

Intermittent amantadine for fluoxetine-induced anorgasmia

Various drugs, including amantadine, have been reported in the successful treatment of antidepressant-induced sexual dysfunction. Only a regular daily dosing schedule of amantadine has been used for the treatment of sexual dysfunction so far. This case demonstrates that an intermittent dose of amantadine at 100 mg five to six hours prior to coitus could be useful in the treatment of fluoxetine-induced anorgasmia.

Amantadine does not reduce cocaine use or craving in cocaine-dependent methadone maintenance patients

We tested the efficacy of amantadine to reduce cocaine use or craving in cocaine-dependent methadone maintained patients. Two doses of amantadine (200 mg p.o. daily, n = 16, and 200 mg p.o. bid, n = 21) were tested against placebo, n = 22, in a random assignment, double-blind clinical trial lasting nine weeks. Amantadine was well tolerated. However, neither dose of amantadine was more effective than placebo in reducing cocaine use and craving.

Amantadine stimulates sexual behavior in male rats

The effects of amantadine on sexual behavior, penile erection, and seminal emission of male rats was studied. Amantadine significantly decreased latency of mounts in all doses (1.25 to 50 mg/kg), and decreased the number of mounts and intromission latency at the highest doses used. The lowest dose of amantadine significantly increased ejaculation latency and intromission frequency, while higher doses significantly reduced it, which indicates a biphasic response of the drug. Additionally, seminal emission, erections, and genital grooming were significantly induced by amantadine. Amantadine-induced seminal emissions were impaired by spinal cord transection, which suggests the involvement of supraspinal structures in the drug action. Haloperidol and atropine sulphate significantly reduced seminal emissions and penile erections induced by amantadine. These results demonstrate that amantadine stimulates sexual behavior and genital reflexes in male rats and suggest a facilitatory effect of the drug that probably involves different mechanisms of action.