Study of Rimantadine in the USSR: A Review of the Literature

Zlydnikov, D M; Kubar, Olga; Kovaleva, T. P.; Kamforin, L. E.

doi:10.1093/clinids/3.3.408

Cited by 67 publications

(24 citation statements)

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“…Blood was collected from the jugular vein at 0.5, 1, 2, 4, 6, 8, 10,12,16, and 24 h in sodium heparin-containing tubes. All samples from dogs were assayed separately.…”

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confidence: 99%

Pharmacokinetics and metabolism of rimantadine hydrochloride in mice and dogs

Hoffman

Gaylord

Blasecki

et al. 1988

Antimicrob Agents Chemother

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We studied the pharmacokinetics and metabolism of rimantadine hydrochloride (rimantadine) following single-dose oral and intravenous administration in mice and dogs. Absorption of the compound in mice was rapid. Maximum concentrations in plasma occurred at less than 0.5 h after oral administration, and the elimination half-life was 1.5 h. Peak concentrations in plasma following oral administration were markedly disproportional to the dose (274 ng/ml at 10 mg/kg, but 2,013 ng/ml at 40 mg/kg). The bioavailability after an oral dose of 40 mg/kg was 58.6%. Clearance was 4.3 liters/h per kg, and the volume of distribution was 7.6 liters/kg at 40 mg/kg. In contrast to the results observed in mice, absorption of the compound in dogs was slow. Maximum concentrations in plasma occurred at 1.7 h after oral administration, and the elimination half-life was 3.3 h. A further difference was that peak concentrations in plasma were approximately proportional to the dose. Following administration of a single oral dose of 5, 10, or 20 mg/kg, maximum concentrations in plasma were 275, 800, and 1,950 ng/ml, respectively. The bioavailability after an oral dose of 5 mg/kg was 99.4 o.The clearance was 3.7 liters/h per kg, and the volume of distribution was 13.8 liters/kg at 5 mg/kg. Mass balance studies in mice, using [methyl-'4CJrimantadine, indicated that 98.7% of the administered dose could be recovered in 96 h. Less than 5% of the dose was recovered as the parent drug in dog urine within 48 h. Finally, gas chromatography-mass spectrometry studies, done with mouse plasma, identified the presence of two rimantadine metabolites. These appeared to be ring-substituted isomers of hydroxyrimantadine.Rimantadine hydrochloride (rimantadine), which is chemically related to the anti-influenza A drug amantadine hydrochloride (amantadine, Symmetrel), has been reported to be effective against influenza A in human studies and in mouse model systems (2,7,11). It is being used in the USSR for both prophylaxis and therapy of influenza A infections (12).The pharmacokinetics and metabolism of rimantadine in humans have been reported (F. dine, which was then analyzed by gas chromatography (HP 5880A; Hewlett-Packard Co.) with an electron capture detector (6). PFB-amantadine was used as the internal standard and was prepared in house. The oven temperature was programmed for 240°C for 5 min, followed by a temperature gradient of 5°C/min for 6 min, to 270°C. The 6-ft (1.83-m) column was packed with 10% OV-1 (Ohio Valley Specialty Chemical, Inc.) on Chromasorb W (Hewlett-Packard Co.). The method was linear between 10 and 10,000 ng/ml in plasma-free solutions. The limit of detection was 5 ng/ml. However, linearity in biological solutions, such as plasma or tissue extracts, was restricted to a narrower range and was determined for each analysis. Samples were assayed only in the linear portion of the curve. Absolute recovery from plasma ranged from 54% at 50 ng/ml to 72% at 1,000 ng/ml. Reproducibility was 7% relative standard deviation. Rimantadine in plasma...

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“…Blood was collected from the jugular vein at 0.5, 1, 2, 4, 6, 8, 10,12,16, and 24 h in sodium heparin-containing tubes. All samples from dogs were assayed separately.…”

mentioning

confidence: 99%

Pharmacokinetics and metabolism of rimantadine hydrochloride in mice and dogs

Hoffman

Gaylord

Blasecki

et al. 1988

Antimicrob Agents Chemother

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“…The 100-mg regimen reduced the rate of influenza A virus illness in our study population (efficacy rate, 86%) and that of influenza A virus infection (efficacy rate, 67%) when compared with the placebo. Studies conducted in the USSR have reported similar efficacies for the 100-mg regimen of rimantadine (17,24). These prophylactic efficacy rates are also comparable to those for the conventional 200-mg dose observed in placebo-controlled studies in adults given rimantadine for 4 to (1,6).…”

Section: Discussionmentioning

confidence: 61%

Safety and prophylactic efficacy of low-dose rimantadine in adults during an influenza A epidemic

Brady

Sears

Pacini

et al. 1990

Antimicrob Agents Chemother

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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 < 0.01) and influenza illness (7 of 110 versus 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.

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“…Rimantadine (Fig. 2B) is its methylated derivative registered a decade later and has the same mechanism of antiviral action (7,67,94). Both bind the M2 proton channel and prevent the influx of H+ ions into the virion, a process crucial for the uncoating stage of the virus replication cycle (37).…”

Section: Introductionmentioning

confidence: 99%