Successful treatment of naturally occurring influenza A/USSR/77 H1N1. Comparison of amantadine and rimantadine for prevention of type A (Russian) influenza. A controlled trial of amantadine and rimantadine in the prophylaxis of influenza A infection. Comparative toxicity of amantadine hydrochloride and rimantadine hydrochloride in healthy adults. Evaluation of amantadine hydrochloride in the treatment of A2 influenzal disease. Administration of amantadine for the prevention of Hong Kong influenza. Amantadine therapy of epidemic influenza a(2) (Hong Kong). Reduction in fever and symptoms in young adults with influenza A/Brazil/78 H1N1 infection after treatment with aspirin or amantadine. Safety and prophylactic efficacy of low-dose rimantadine in adults during an influenza A epidemic.
Forty-five university students with proved influenza A/USSR/77 H1N1 infection were randomly treated with either amantadine hydrochloride (14 students), rimantadine hydrochloride (19 students), or placebo (12 students). By 48 hours after initiation of therapy, amantadine and rimantadine recipients had significantly less fever and greater improvement compared with subjects given the placebo. Minor reversible CNS side effects at the end of the five-day course of therapy were observed in one third of the amantadine-treated subjects. However, both amantadine and rimantadine recipients returned to classes earlier and shed smaller amounts of virus than placebo recipients. Thus, both drugs exerted a notable therapeutic effect. Hence, during an influenza outbreak, five days of empirical therapy with amantadine or rimantadine for persons with an influenza-like syndrome should ameliorate clinical symptoms and might decrease spread of virus. The efficacies of 200 mg of daily doses of amantadine and of rimantadine for prevention of infection and illness due to influenza A/USSR/77 (H1N1) virus were compared in a double-blind, placebo-controlled study on a college campus. Frequencies of symptoms that might have been side effects of the drugs were not significantly different from those in placebo recipients. Analyses indicated that the trial was initiated late in the epidemic and that an age-related protective effect against A/USSR virus existed; seroconversion frequencies were 52/139 (37%) among 18-19-year-olds, 33/130 (25%) among 20-21-year-olds, and 5/39 (12.8%) among 22-24-year-olds. Among initially antibody-negative (less than 1 : 4 in complement fixing and neutralizing tests and less than 1 : 8 in hemagglutination inhibition tests) 18-19-year-old students, amantadine was associated with significantly fewer seroconversions (P = 0.01) and both less infection and milder illness than occurred in placebo recipients (P less than 0.05). Although rimantadine was not accompanied by reduction in frequency of seroconversions in the same age group, illness frequency and severity among seroconverters were significantly reduced when compared to placebo recipients (P less than 0.01). Amantadine and rimantadine appear suitable for use in young adults. Although other studies have suggested greater effectiveness of rimantadine than of amantadine against influenza, no evidence for this was seen in the present study which used both drugs at the same dose. Four hundred fifty volunteers participated in a placebo-controlled, double-blind, randomized trial of the prophylactic effects of rimantadine and amantadine during an outbreak of influenza A. The subjects received drugs orally at a dose of 100 mg twice a day for six weeks. Influenza-like illness occurred in 41 per cent of the subjects receiving placebo but in only 14 per cent of those receiving rimantadine and 9 per cent of these receiving amantadine (P less than 0.001 for either drug vs. placebo). Laboratory-documented influenza occurred in 21 per cent of placebo recipients, 3 per cent of rimantadine recipients, and 2 per cent of amantadine recipients (P less than 0.001). These findings represent efficacy rates of 85 per cent for rimantadine and 91 per cent for amantadine, as compared with placebo. More recipients of amantadine (13 per cent) than recipients of rimantadine (6 per cent; P less than 0.05) or placebo (4 per cent; P less than 0.01) withdrew from the study because of central-nervous-system side effects. On the basis of this study, rimantadine appears to be the drug of choice for the prophylaxis of influenza A. The relative toxicities of amantadine and rimantadine were compared in a double-blind, placebo-controlled study involving healthy adults. In separate studies, drugs were administered at a dosage of 200 mg/day (52 volunteers) or 300 mg/day (196 volunteers) for 4.5 days. Both drugs were well tolerated at the lower dosage. At 300 mg/day amantadine recipients had a greater frequency and severity of central nervous system (nervousness, lightheadedness, difficulty concentrating) and sleep (insomnia, fatigue) complaints compared with rimantadine or placebo recipients. Amantadine recipients also performed less well on an objective test measuring sustained attention and problem-solving ability. Both amantadine and rimantadine recipients reported adverse gastrointestinal symptoms more often than placebo recipients. Because of better tolerance at higher dosage, rimantadine offers more promise than amantadine for treatment of influenza A virus infections. Amantadine hydrochloride is the first drug to show promise as a practical anti-influenza agent. Several studies demonstrating a prophylactic effect in volunteers with induced A2 disease as well as in patients during A2 outbreaks have created the impetus for therapeutic trials. The widespread A2 influenza epidemic that occurred early in 1968 provided the opportunity for therapeutic evaluation in the USA.A total of 197 prison inmates with proven influenza agreed to participate in the 10-day double-blind evaluation of amantadine (100 mg, twice daily). Onset of therapy was approximately 20 hours after first subjective awareness of illness.Assessment of drug effectiveness was based on rapidity of resolution of illness. There was a significant increase in the number of drug-treated as against placebo patients in the "rapid resolver" group whereas individuals receiving placebo dominated the "slow resolver" group. Analysis of febrile responses indicated that amantadine-treated patients had significantly more rapid defervescence. Virus isolation studies revealed etiologically related virus in 90% of all volunteers during the first 5 days of therapy. It was apparent that clinical improvement was not correlated with disappearance of the virus. Nevertheless, the trials conducted during the influenza season of early 1968 indicated the therapeutic effect of amantadine hydrochloride. Administration of 100 mg, twice daily, for 10 days did not cause any adverse effects. The prophylactic effectiveness of amantadine against A2/Hong Kong influenza was investigated in the course of a double-blind trial in Braşov, Romania, during an epidemic due to the Hong Kong virus that started there in March 1969.Altogether 215 subjects were included in the trial; 112 received 100 mg of amantadine twice daily for 20 days and the remaining 103 received inert placebo tablets. Of the amantadine-treated group, 2 had clinical symptoms diagnosed as influenza (1 of these was a doubtful diagnosis), whereas 20 (1 doubtful) of the placebo group had such symptoms. No case with both clinical symptoms and serologically confirmed influenza (>/=4-fold increase in haemagglutination-inhibition titre) occurred among 77 amantadine-treated subjects for whom paired sera were available but there were 13 such cases among the 74 placebo subjects with paired sera. These differences are statistically highly significant. No serious side-effects were recorded.The authors conclude that amantadine was highly effective in preventing overt disease and discuss indications that suggest that it did not interfere with the development of immunity in persons treated during the incubation period. In a double-blind comparison of the therapeutic effect of amantadine in a natural outbreak of Hong Kong influenza in January 1969 near Houston, Texas, the decrease in titers of virus in throat swabs from 12 treated patients during the first 10 hr of treatment was appreciably greater than similar titers of virus from 16 untreated patients (P = 0.06). The titer of shed virus decreased significantly more rapidly (P < 0.05) among amantadine-treated patients ill more than 48 hr before treatment than among five control patients who had been ill more than 48 hr. Cough, sore throat, and nasal obstruction cleared more rapidly in treated patients (P < 0.05), and decline of fever in 6 treated patients sick for less than 48 hr before treatment was more rapid than among 13 untreated patients who had been ill for less than 48 hr. These findings are considered to be consistent with a limited therapeutic effect of the drug. During an outbreak of influenza A/Brazil/78 H1N1 infection, 47 volunteers with clinical and virological influenza of less than 2 days duration were treated in a randomized double-blind fashion for 5 days with 100 or 200 mg of amantadine daily or with 3.25 g of aspirin daily. The aspirin treatment group defervesced more rapidly (10.3 h versus 21.5 h and 23.6 h; P less than 0.01), but by the second daily follow-up visit, both groups of amantadine recipients exhibited greater symptomatic improvement. Bothersome side effects resulted in discontinuation of therapy by 35% of the aspirin treatment group but only 3% of the amantadine treatment group (P less than 0.05). Individuals who present to a physician during an influenza A epidemic with characteristic symptoms will experience symptomatic benefit from amantadine treatment, with negligible toxicity. A placebo-controlled, double-blind study to evaluate the safety and prophylactic efficacy of a low dose (100 mg) of rimantadine hydrochloride against naturally occurring influenza in adults was conducted at two sites. After the onset of the influenza season, volunteers (ages, 18 to 55 years) were assigned randomly to receive rimantadine or placebo daily. Subjects were monitored for adverse effects and evidence of influenza virus infection weekly for six weeks. Only 10 (8.7%) of 114 rimantadine recipients and 5 (4.4%) of 114 placebo control recipients reported one or more mild to moderate adverse symptoms, most of which were related to the gastrointestinal or central nervous system. Compared with placebo, low-dose rimantadine was highly effective in the prevention of influenza A virus infection (20 of 110 versus 7 of 112 participants; P less than 0.01) and influenza illness (7 of 110 versus 1 of 112 participants; P = 0.04). Influenza A/Leningrad/87-like (H3N2) virus was recovered from the nasopharynxes of only five placebo recipients. These findings indicate that low-dose rimantadine is well tolerated and highly effective for the prevention of influenza A illness in healthy adults.
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. Resistance of influenza viruses to amantadine is a serious worldwide problem as shown by recent virological surveillances. Both drugs have adverse gastrointestinal (stomach and gut) effects, but amantadine can also have serious effects on the nervous system. They should only be used in an emergency when all other measures fail.