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PubMed2000

Amantadine and rimantadine for preventing and treating influenza A in adults.

OBJECTIVES: Amantadine hydrochloride and rimantadine hydrochloride have antiviral properties, but they are not widely used due to a lack of knowledge of their properties and concerns about possible adverse effects. The objective of this review was to assess the effects and safety of amantadine and rimantadine in healthy adults. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register, Medline, Embase and reference lists of articles. We also contacted manufacturers, researchers and authors. SELECTION CRITERIA: Randomised and quasi-randomised studies comparing amantadine and/or rimantadine with placebo, control antivirals or no intervention, or comparing doses or schedules of amantadine and/or rimantadine in healthy adults. DATA COLLECTION AND ANALYSIS: For prevention trials the numbers of participants with clinically defined influenza, with serologically confirmed clinical influenza A and adverse effects were analysed. Analysis for treatment trials was of the mean duration of fever and adverse effects. MAIN RESULTS: Amantadine prevented 23% of clinical influenza cases (95% confidence interval 11% to 34%), and 63% of serologically confirmed clinical influenza A cases (95% confidence interval 42% to 76%) Amantadine reduced duration of fever by one day (95% confidence interval 0.7 to 1.3). Rimantadine demonstrated comparable effectiveness, but there were fewer trials and the results for prevention were not statistically significant. Both amantadine and rimantadine induced significant gastrointestinal adverse effects. Adverse effects of the central nervous system adverse and study withdrawals were significantly more common with amantadine than rimantadine. REVIEWER'S CONCLUSIONS: Amantadine and rimantadine have comparable effectiveness in the prevention and treatment of influenza A in healthy adults, although rimantadine induces fewer adverse effects than amantadine.

Adult↗
PubMed1987

Virion transcriptase activity of rimantadine-sensitive and rimantadine-resistant variants of human influenza virus.

All rimantadine-resistant variants of influenza virus prepared by consecutive passages in the presence of rimantadine had increased virion transcriptase activity as compared to the original strains. The increased virion transcriptase activity of rimantadine-resistant strains was unrelated to the possible role of M1 protein, since RNPs isolated from the virions of these variants also revealed higher transcriptase activity as compared to RNPs isolated from rimantadine-sensitive virus. The study of rimantadine-resistant recombinant X-4 which inherited from the resistant fowl plague virus (FPV) only the gene 7 coding for M proteins provided additional evidence for the suggestion that the increased virion transcriptase activity of rimantadine-resistant influenza virus variants is coincidental rather than directly associated with such resistance.

Adamantane↗
PubMed1982

Uncoating of a rimantadine-resistant variant of influenza virus in the presence of rimantadine.

A rimantadine-resistant variant of the Texas strain of influenza virus (Tr) was obtained by serial passages in eggs in MDCK cells in the presence of the drug, and its uncoating in MDCK cells was compared to that of the sensitive variant (Ts). First and second steps of uncoating were defined respectively by the appearance of subviral particles (SVP) in nuclear-associated cytoplasm (NAC) and ribonucleoproteins (RNPs) in nucleoplasm. In cells infected with Ts, SVP and RNPs were revealed in NAC, while in the presence of rimantadine RNPs were neither found in NAC nor in the nucleoplasm. In cells infected with Tr, SVP but not RNPs were observed in NAC. The amount of RNPs in the nucleoplasm was almost unchanged in rimantadine-treated cells, demonstrating that rimantadine did not interfere with uncoating of the resistant variant. These findings confirm the suggestion that rimantadine blocks the second step of uncoating of sensitive influenza viruses, and are consistent with the idea that this event does account for the prevention of influenza virus infection by the drug.

Adamantane↗
PubMed1995

Rimantadine: a clinical perspective.

OBJECTIVE: To provide a review of rimantadine, including its antiviral activity, pharmacokinetics, efficacy, adverse effects, drug interactions, and dosage and administration. Information on influenza A virus and clinical features of influenza disease are presented. Comparative data on rimantadine and amantadine are described. DATA SOURCES: A MEDLINE search restricted to English-language literature published from 1966 through 1994 and an extensive review of journals was conducted. DATA EXTRACTION: The data on antiviral activity, pharmacokinetics, adverse effects, and drug interactions were obtained from various articles on rimantadine in open and controlled studies. Controlled double-blind studies were evaluated to assess the efficacy of rimantadine in prophylaxis and treatment of influenza A infection. DATA SYNTHESIS: Over 90% of a rimantadine dose was absorbed in 3-6 hours in healthy adults. Steady-state plasma concentrations have ranged from 0.10 to 2.60 micrograms/mL at doses of 3 mg/kg/d in infants to 100 mg twice daily in the elderly. Nasal fluid concentrations of rimantadine at steady-state were 1.5 times higher than plasma concentrations, which may explain the effectiveness of rimantadine despite a low plasma concentration. Over 75% of a rimantadine dose was metabolized in the liver, and the parent compound and metabolites were almost completely eliminated by the kidneys. The elimination half-life ranged from 24.8 to 36.5 hours, which allows once-daily dosing. Dosage adjustment is recommended for patients with severe renal impairment (creatinine clearance < or = 0.17 mL/s), severe hepatic dysfunction, or elderly nursing home patients. Drug-resistant strains of influenza A virus to rimantadine occurred in several studies with children and/or adults. Clinical significance of drug-resistant strains has not been established. Rimantadine appeared to be effective in 85-90% of individuals for prevention of influenza A illness and in 50-65% for prevention of influenza A infection. Rimantadine reduced the time to a 50% reduction in symptoms by 1-3 days versus placebo. Differences in symptom reduction between rimantadine and placebo after the first 3 days of treatment was not generally clinically significant. The most common adverse effects of rimantadine administration were associated with the central nervous system (CNS) and the gastrointestinal (GI) tract. CNS-related adverse effects occurred in 3.2% of children younger than 10 years of age and 8.4% of adults. In elderly patients, the incidence of CNS-related adverse effects ranged from 4.9% at 100 mg/d to 12.5% at 200 mg/d. GI adverse effects occurred in 8.4% of children younger than 10 years of age, 3.1% of adults, and 2.9% at 100 mg/d and 17.0% at 200 mg/d in the elderly. CONCLUSIONS: Rimantadine offers some desirable features for the treatment and prophylaxis of influenza A infection. It appears to be an attractive choice in elderly patients with a history of CNS adverse effects from amantadine and in patients with mild or moderate renal impairment. Although approved for twice-daily dosing, rimantadine has a pharmacokinetic profile that would allow once-daily dosing. It is effective for prophylaxis (not postexposure prophylaxis) and treatment of influenza A virus. It also has a low incidence of adverse effects.

Absorption↗
PubMed2003

A case for rimantadine to be marketed in Canada for prophylaxis of influenza A virus infection.

PURPOSE: To evaluate the efficacy and safety of amantadine and rimantadine, the first generation antivirals, for the prophylaxis of influenza virus. DATA SOURCES: A systematic search of the English language literature using MEDLINE, EMBASE, Current Contents and the Cochrane database from 1966 to April 2002, as well as a manual search of references from retrieved articles, were performed. STUDY SELECTION: Prospective, randomized, controlled clinical trials evaluating amantadine and rimantadine for prophylaxis of naturally occurring influenza A illness were considered. The control arm used either a placebo or an antiviral agent. DATA EXTRACTION: Each trial was assessed by two authors to determine the adequacy of randomization and description of withdrawals. Efficacy data were extracted according to a predefined protocol. Discrepancies in data extraction among the investigators were solved by consensus. Nine prophylaxis studies of amantadine and rimantadine met the criteria for this systematic review. DATA SYNTHESIS: Seven amantadine versus placebo trials (n=1797), three rimantadine versus placebo trials (n=688) and two amantadine versus rimantadine studies (n=455) were included for the meta-analysis on the prevention of influenza A illness. The summary of results for the relative odds of illness indicated a 64% reduction in the amantadine group compared with placebo (OR 0.36, 95% CI 0.23 to 0.55, P< or =0.001), a 75% reduction in illness for the rimantadine group compared with placebo (OR 0.25, 95% CI 0.07 to 0.97, P=0.05) and no significant differences in the odds of illness for the amantadine versus rimantadine groups (OR 1.15, 95% CI 0.57 to 2.32, P=0.32). The summary of results examining adverse events showed significantly higher odds of central nervous system adverse reactions and premature withdrawal from the clinical trials in the amantadine-treated group than in the placebo-treated group. Compared with the placebo-treated group, the rimantadine-treated group did not have a significantly higher rate of withdrawal or central nervous system events. However, there was a significant increase in the odds of gastrointestinal adverse events for those treated with rimantadine compared with those treated with placebo (OR 3.34, 95% CI 1.17 to 9.55, P=0.03). In the comparative trials of amantadine to rimantadine, rimantadine was associated with an 82% reduction in the odds of central nervous system events (OR 0.18, 95% CI 0.03 to 1.00, P=0.05) and a 60% reduction in the odds of discontinuing treatment (OR 0.40, 95% CI 0.20 to 0.79, P=0.009). CONCLUSION: This meta-analysis demonstrates that amantadine and rimantadine are superior to placebo in the prevention of influenza A illness. Both antiviral agents have an increased number of adverse events compared with placebo; however, the use of amantadine is associated with significantly higher numbers of central nervous system events and treatment withdrawals compared with rimantadine. Thus, rimantadine should be the preferred agent in this class for the prevention of influenza A virus infection and should be made available in Canada.

Amantadine↗
PubMed1987

Children with influenza A infection: treatment with rimantadine.

Treatment with rimantadine of influenza in children and the potential development of resistance in clinical isolates associated with therapy have not been previously studied. We compared rimantadine to acetaminophen therapy in a controlled, double-blind study of 91 children with influenza-like illness. Of 69 children with proven influenza A/H3N2 infection, 37 received rimantadine and 32 received acetaminophen for five days. Children receiving rimantadine showed significantly greater reduction in fever and improvement in daily scores for symptoms and severity of illness during the first three days. Viral shedding also diminished significantly during the first two days but subsequently increased such that by days 6 and 7 the proportion of children shedding virus, as well as the quantity of virus shed, was significantly greater in the rimantadine group. During the seven-day study, of the 22 children in the rimantadine group with serial isolates tested, ten (45.5%) had resistant isolates compared with two (12.5%) of those with serial isolates in the acetaminophen group (P less than .03). Thus, of the total 37 children in the rimantadine group, 27% were found to have resistant isolated compared with 6% in the total group receiving acetaminophen (P less than .04). Furthermore, the mean inhibitory concentration of rimantadine increased with time in the rimantadine group (r = .4, P = .002) but not in the acetaminophen group. Rimantadine therapy, thus, appears to be significantly more effective than acetaminophen in ameliorating the clinical signs and symptoms of influenza in children. Treatment with rimantadine was also associated with increased viral shedding after the medication was discontinued and with the development of resistance in the clinical isolates, the significance of which is unknown.

Acetaminophen↗
PubMed2000

Comparison of central nervous system adverse effects of amantadine and rimantadine used as sequential prophylaxis of influenza A in elderly nursing home patients.

BACKGROUND: Amantadine hydrochloride and rimantadine hydrochloride are recommended by the Centers for Disease Control and Prevention for prophylaxis of influenza A. While data suggest that rimantadine is better tolerated, there are no data examining the rate of adverse reactions in elderly patients who receive amantadine vs rimantadine. Our objective was to assess the adverse reaction rate in elderly nursing home patients receiving sequential amantadine and rimantadine for influenza A prophylaxis. METHODS: Data were collected in 156 nursing home patients (70% women; mean+/-SD age, 83.7+/-10.1 years) in a single care setting who received sequential therapy with amantadine and rimantadine during the 1997-1998 influenza season. Patients were assessed for central nervous system adverse effects and therapy discontinuation occurring with each agent. RESULTS: Twenty-nine (18.6%) of the 156 patients experienced an adverse effect when receiving amantadine compared with 3 patients (1.9%) when rimantadine was given (P<.01). Drug use was discontinued due to adverse events in 17.3% (n = 27) of the amantadine courses and 1.9% (n=3) of the rimantadine courses (P<.001). Confusion was the most frequently observed adverse event (amantadine, 10.6%; rimantadine, 0.6%; P<.001). Multivariate logistic regression analysis showed that significant risk factors for central nervous system adverse events included male sex (odds ratio, 3.65), reduced calculated creatinine clearance (odds ratio, 1.78), and use of amantadine (odds ratio, 12.73). CONCLUSIONS: Amantadine use was associated with a significantly higher incidence of central nervous system adverse events than rimantadine use in this elderly population receiving influenza prophylaxis. In addition, the discontinuation rate of amantadine was significantly higher than that with rimantadine.

Adverse Drug Reaction Reporting Systems↗
PubMed2004

Amantadine and rimantadine for preventing and treating influenza A in adults.

BACKGROUND: Amantadine hydrochloride and rimantadine hydrochloride have antiviral properties, but these drugs are not widely used due to a lack of knowledge of their potential value and concerns about possible adverse effects. OBJECTIVES: The objective of this review was to assess the effectiveness and safety ("effects") of amantadine and rimantadine in healthy adults. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2003), MEDLINE (January 1966 to November week 2, 2003), EMBASE (January 1990 to September 2003) and the reference lists of articles. We also contacted manufacturers, researchers and authors. SELECTION CRITERIA: Randomised and quasi-randomised studies comparing amantadine and/or rimantadine with placebo, control antivirals or no intervention, or comparing doses or schedules of amantadine and/or rimantadine in healthy adults. DATA COLLECTION AND ANALYSIS: For prevention trials the numbers of participants with clinical influenza (influenza-like-illness or ILI), i.e. confirmed influenza A, and adverse effects were analysed. Analysis for treatment trials included the mean duration of fever and length of hospital stay, and the number of adverse effects. MAIN RESULTS: Amantadine prevented 25% of ILI cases (95% confidence interval (CI) 13% to 36%), and 61% of influenza A cases (95% CI 35% to 76%). Amantadine reduced duration of fever by one day (95% CI 0.7 to 1.3). Rimantadine demonstrated comparable effectiveness, but there were fewer trials and the results for prevention were not statistically significant. Both amantadine and rimantadine induced significant gastrointestinal adverse effects. Adverse effects of the central nervous system and study withdrawals were significantly more common with amantadine than rimantadine. REVIEWERS' CONCLUSIONS: Amantadine and rimantadine have comparable effectiveness in the prevention and treatment of influenza A in healthy adults, although rimantadine causes fewer adverse effects than amantadine.

Adult↗
PubMed2006

Amantadine and rimantadine for influenza A in adults.

BACKGROUND: Amantadine hydrochloride and rimantadine hydrochloride have antiviral properties, but they are not widely used due to a lack of knowledge of their potential value and concerns about possible adverse effects. OBJECTIVES: The objective of this review was to assess the efficacy, effectiveness and safety ("effects") of amantadine and rimantadine in healthy adults. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2005), MEDLINE (2003 to August Week 4, 2005), EMBASE (October 2003 to July 2005) and reference lists of articles. SELECTION CRITERIA: Randomised and quasi-randomised studies comparing amantadine and/or rimantadine with placebo, control medication or no intervention, or comparing doses or schedules of amantadine and/or rimantadine in healthy adults. DATA COLLECTION AND ANALYSIS: For prophylaxis (prevention) trials the numbers of participants with clinical influenza (influenza-like-illness or ILI) or with confirmed influenza A and adverse effects were analysed. Analysis for treatment trials was of the mean duration of fever, length of hospital stay and adverse effects. MAIN RESULTS: Amantadine prevented 25% of ILI cases (95% confidence interval (CI) 13% to 36%), and 61% of influenza A cases (95% CI 35% to 76%). Amantadine reduced duration of fever by one day (95% CI 0.7 to 1.2). Rimantadine demonstrated comparable effectiveness, but there were fewer trials and the results for prophylaxis were not statistically significant. Both amantadine and rimantadine induced significant gastrointestinal adverse effects. Adverse effects of the central nervous system and study withdrawals were significantly more common with amantadine than rimantadine. Neither drug affected the rate of viral shedding from the nose and the course of asymptomatic influenza. AUTHORS' CONCLUSIONS: Amantadine and rimantadine have comparable efficacy and effectiveness in relieving or treating symptoms of influenza A in healthy adults, although rimantadine induces fewer adverse effects than amantadine. The effectiveness of both drugs in interrupting transmission is probably low. Routine use of both drugs should be discouraged and both drugs should only be used when all other measures fail.

Adult↗
PubMed1988

Transport of amantadine and rimantadine through the blood-brain barrier.

The unidirectional transport of amantadine and rimantadine across cerebral capillaries, the anatomical locus of the blood-brain barrier, was measured with an in situ rat brain perfusion technique. Both rimantadine and, to a lesser extent, amantadine were transported principally across the blood-brain barrier by a saturable transport system with a one-half saturation concentration of about 1.0 mM (either rimantadine or amantadine). The permeability surface area constants were 8.5 x 10(-2) sec-1 (rimantadine) and 1.1 x 10(-2) sec-1 (amantadine) with concentrations of less than 1.0 microM in the perfusate. The extraction of rimantadine and amantadine from the perfusate at low concentrations (less than 1.0 microM) was 88 and 26%, respectively, of the extraction of diazepam which is 100% extracted. Amantadine and rimantadine transport through the blood-brain barrier was significantly inhibited by weakly basic drugs (e.g., diphenhydramine) but not choline (10 mM), probenecid (1 mM) or leucine (1 mM). Inasmuch as both the pKa and percentage ionized at pH = 7.4 of rimantadine (10.4 and 99.9%, respectively) are much higher than that of amantadine (pKa = 9.0 and 97.5%, respectively), and inasmuch as rimantadine is transported into brain much more readily than amantadine, our results suggest that the carrier-mediated transport of the ionized moiety is the crucial process determining the penetration of amantadine and rimantadine through the blood-brain barrier.

Adamantane↗
PubMed1986

Effectiveness of rimantadine prophylaxis of children within families.

With recent studies suggesting that children are the main introducers of influenza infections into families, we conducted a placebo-controlled, double-blind, randomized trial to study the prophylactic effectiveness of rimantadine hydrochloride in children on the transmission of influenza A infections within families. One hundred forty-five volunteers from 35 families completed this study during a naturally occurring outbreak of influenza A (H1N1) infection. Influenza infections, defined as a positive viral throat culture or a fourfold increase in antibody titer, occurred in 31.7% of children in the placebo group and 2.9% of children in the rimantadine group. Clinical illness with laboratory evidence of influenza infection occurred in 17.0% of children in the placebo group and 0% of children in the rimantadine group. Rimantadine was well tolerated by the children, with no significant difference in reported side effects between the placebo and rimantadine groups. Influenza A infection occurred in 19.0% of adults whose children were receiving a placebo and 8.8% of adults whose children were receiving rimantadine. On the basis of our study, rimantadine prophylaxis of children appears to be an effective method to prevent influenza A infection in children. Additional studies are needed to demonstrate the effects of rimantadine prophylaxis of children on the incidence of influenza A infection in their parents.

Adamantane↗
PubMedDate not supplied

Inhaled zanamivir versus rimantadine for the control of influenza in a highly vaccinated long-term care population.

BACKGROUND: Despite vaccination, influenza commonly causes morbidity and mortality in institutional settings. Influenza control with rimantadine and amantadine is limited by emergence and transmission of drug-resistant influenza A variants, ineffectiveness against influenza B, and toxicity. This study evaluated the efficacy and tolerability of zanamivir versus rimantadine for influenza outbreak control in long-term care facilities. METHODS: This double-blind, randomized, controlled study prospectively enrolled nursing home residents for 3 influenza seasons (1997 to 2000). Vaccine was offered to all subjects. Following influenza outbreak declaration, subjects were randomized to inhaled zanamivir 10 mg or standard of care (rimantadine 100 mg for influenza A or placebo for influenza B) once daily for 14 days. The proportion of randomized subjects developing symptomatic, laboratory-confirmed influenza during prophylaxis was the primary endpoint. RESULTS: Of 482 randomizations (238 zanamivir, 231 rimantadine, 13 placebo), 96% of subjects were elderly or had high-risk conditions; over 90% were vaccinated. Symptomatic, laboratory-confirmed influenza occurred in 3% of zanamivir subjects and 8% of rimantadine subjects during chemoprophylaxis (P = .038; additional protective efficacy for zanamivir over rimantadine = 61%). Since only 25 subjects were randomized during 2 influenza B outbreaks and none developed influenza, the influenza B data were excluded from further analysis. Zanamivir was well tolerated and unassociated with emergence of resistant virus; rimantadine-resistant variants were common. CONCLUSIONS: This is the first prospective, controlled study demonstrating effectiveness of chemoprophylaxis for influenza outbreak control. Zanamivir prevents symptomatic, laboratory-confirmed influenza more effectively than rimantadine, is unassociated with resistant virus, and has a favorable safety profile. Zanamivir is an appropriate alternative for influenza outbreak control among institutionalized vaccinated elderly.

Administration, Inhalation↗
PubMed1989

Emergence and apparent transmission of rimantadine-resistant influenza A virus in families.

To determine whether rimantadine can protect family members from acquiring influenza A viral illness and to assess the possible selection of drug-resistant strains of virus, we conducted a randomized, double-blind, placebo-controlled study in three communities during two influenza seasons. When influenza A occurred in a family, the members (including the index patient) were given either rimantadine (adult oral dose, 200 mg per day) or placebo for 10 days. The presence of illness was monitored by daily recording of symptoms and temperature measurements; infection was determined by isolation of the virus and by serologic studies. Among households with documented influenza A infections, symptomatic illness occurred in one or more contacts in 10 of 28 families treated with rimantadine and in 10 of 209 families treated with placebo. Asymptomatic secondary influenza A infections were found in five families assigned to receive rimantadine and in four families assigned to receive placebo. Rimantadine-resistant strains of influenza A virus (H3N2 subtype) with mutations consisting of single amino acid changes in the M2 protein (residue 27, 30, or 31) were recovered from eight index patients and five contacts treated with rimantadine. There was apparent transmission of drug-resistant strains of virus in six contacts with secondary illnesses in five families. We conclude that when index patients are treated concurrently, rimantadine is ineffective in protecting household members from influenza A infection. If rimantadine is used for both treatment and postexposure prophylaxis in families, rapid selection and apparent transmission of drug-resistant influenza A viruses can occur.

Adamantane↗
PubMed2003

Are the 2-isomers of the drug rimantadine active anti-influenza A agents?

There is a lack of information in the medical chemistry literature concerning the anti-influenza A activity of the drug rimantadine's 2-isomer (2-rimantadine). We now present results showing that, although 2-adamantanamine (2-amantadine) 3 is only moderately active, some 2-rimantadine analogues are effective anti-influenza A virus agents in vitro. The 2-rimantadine analogues and their spirocyclobutane and spirocyclopentane congeners were synthesized through interesting routes. The 2-rimantadine analogues were 2-4 times more potent than rimantadine 2 against influenza virus A H2N2 strain; their spirocyclobutane congeners proved equally active to rimantadine 2. Two compounds exhibited a similar activity and one of the compounds was was fourfold more potent than rimantadine 2 against H3N2 strain.

Animals↗
PubMed2006

Rimantadine and oseltamivir demonstrate synergistic combination effect in an experimental infection with type A (H3N2) influenza virus in mice.

We studied the combination effect of rimantadine hydrochloride and oseltamivir phosphate on mice infected with influenza A/Aichi/2/68 (H3N2) virus. Compounds were simultaneously administered in a 5-day-treatment course, starting 4 h before intranasal infection with 10 or 20 viral 50% mouse lethal doses. Initially, we tested combinations of oseltamivir (0.05, 0.1 and 0.2 mg/kg/day) and rimantadine (2.5, 5.0 and 7.5 mg/kg/day). Significant differences were recorded between combination-treated groups, and groups with separately applied compounds and the placebo group, such as: protection index of oseltamivir with 5.0 or 7.5 mg/kg rimantadine varied between 34-41% and 43-87%, respectively, whereas the individual effects of oseltamivir, 5 mg/kg of rimantadine and 7.5 mg/kg of rimantadine were 0-10%, 0% and 18.7-29.6%, respectively; mean survival time in combination-treated groups was lengthened by 3.1-6.9 days, in oseltamivir groups by 0-1.9 days, and in rimantadine groups by 0.8-1.3 days at 5 mg/kg and 2.6-3.2 days at 7.5 mg/kg. The three-dimensional method of Prichard and Shipman characterized the combination effect as synergistic. Further, we studied the activity of 0.05 mg/kg/day of oseltamivir combined with 5 mg/kg of rimantadine. Lung virus titre in Madin Darby canine kidney cells, lung index and consolidation score proved the high effectiveness of the combination. When compared with the placebo group, a 2.8 log10 lower titre of 50% cell culture infectious dose (CCID50) was recorded in the combination-treated group at 48-60 h post-infection (the peak of lung virus growth). This is in contrast to the 0.1-1.0 log10 and 1.1-1.4 log10 reduction in CCID50 titre observed in the oseltamivir and rimantadine groups, respectively. These data emphasize the high anti-influenza A potential of the combination.

Administration, Oral↗
PubMed1999

Pharmacokinetics and therapeutic efficacy of rimantadine in horses experimentally infected with influenza virus A2.

OBJECTIVE: To determine pharmacokinetics of single and multiple doses of rimantadine hydrochloride in horses and to evaluate prophylactic efficacy of rimantadine in influenza virus-infected horses. ANIMALS: 5 clinically normal horses and 8 horses seronegative to influenza A. PROCEDURE: Horses were given rimantadine (7 mg/kg of body weight, i.v., once; 15 mg/kg, p.o., once; 30 mg/kg, p.o., once; and 30 mg/kg, p.o., q 12 h for 4 days) to determine disposition kinetics. Efficacy in induced infections was determined in horses seronegative to influenza virus A2. Rimantadine was administered (30 mg/kg, p.o., q 12 h for 7 days) beginning 12 hours before challenge-exposure to the virus. RESULTS: Estimated mean peak plasma concentration of rimantadine after i.v. administration was 2.0 micrograms/ml, volume of distribution (mean +/- SD) at steady-state (Vdss) was 7.1 +/- 1.7 L/kg, plasma clearance after i.v. administration was 51 +/- 7 ml/min/kg, and beta-phase half-life was 2.0 +/- 0.4 hours. Oral administration of 15 mg of rimantadine/kg yielded peak plasma concentrations of < 50 ng/ml after 3 hours; a single oral administration of 30 mg/kg yielded mean peak plasma concentrations of 500 ng/ml with mean bioavailability (F) of 25%, beta-phase half-life of 2.2 +/- 0.3 hours, and clearance of 340 +/- 255 ml/min/kg. Multiple doses of rimantadine provided steady-state concentrations in plasma with peak and trough concentrations (mean +/- SEM) of 811 +/- 97 and 161 +/- 12 ng/ml, respectively. Rimantadine used prophylactically for induced influenza virus A2 infection was associated with significant decreases in rectal temperature and lung sounds. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of rimantadine to horses can safely ameliorate clinical signs of influenza virus infection.

Administration, Oral↗
PubMed1991

Effect of rimantadine on the immune response to influenza A infections.

The effects of rimantadine on lymphocyte responses to mitogens CON-A and PHA, natural killer cell activity, and the development of serum and local antibodies were studied during an epidemic outbreak of influenza A (H3N2). Twenty-three families consisting of 38 adults and 46 children had a member who developed a flu-like illness and were randomly assigned to receive placebo or rimantadine either as treatment or post exposure prophylaxis. Nasal washings for virus isolation and IgG and IgA determination were collected on days 1, 5, and 10 of illness. Blood samples for immunologic studies were obtained on days 1 and 5 of clinical illness and on day 21. No differences in lymphocyte responses to CON-A and PHA or in natural-killer cell activity were noted between placebo and rimantadine groups. The development of neutralizing antibodies to influenza H3N2 was also not affected by rimantadine. However, the presence of IgA in nasal secretions was significantly diminished in the rimantadine group compared to the placebo group (0/9 vs. 6/9, P less than 0.005). The findings indicate that rimantadine had no adverse affect on the systemic immune system. However, local immune response was diminished in individuals taking rimantadine possibly due to the presence of less immunogen resulting from reduction of virus in secretions of individuals taking antivirals.

Antibody Formation↗