Disease relevance of Flumadine

• Emergence and apparent transmission of rimantadine-resistant influenza A virus in families [1].
• Rimantadine inhibits reproduction of influenza virus A/USSR/77 [2].
• METHODS: Ten influenza A (H3N2) viruses isolated during the outbreaks were examined for resistance to amantadine and rimantadine by means of an enzyme immunoassay and by sequencing of the viral nucleic acid that encodes the transmembrane domain of the M2 protein [3].
• Influence of membrane (M) protein on influenza A virus virion transcriptase activity in vitro and its susceptibility to rimantadine [4].
• These findings suggest that rimantadine dosage may need to be reduced in patients with end-stage renal disease but supplemental doses on dialysis days are not required [5].

High impact information on Flumadine

• 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 [1].
• No significant differences were observed in the proportion of patients shedding virus by treatment day 3 (57% ZNV plus rimantadine, 67% placebo plus rimantadine), or in the durations of hospitalization and supplemental oxygen use [6].
• Our objective was to assess the adverse reaction rate in elderly nursing home patients receiving sequential amantadine and rimantadine for influenza A prophylaxis [7].
• Oral amantadine and rimantadine are useful for prophylaxis and treatment of influenza A virus infections, but their efficacy, particularly in treatment of severe disease, has not been rigorously established in immunocompromised hosts [8].
• BACKGROUND: Amantadine hydrochloride and rimantadine hydrochloride have been used for treatment and prevention of influenza A infection in nursing home residents [3].

Chemical compound and disease context of Flumadine

• The single-dose (two 100 mg doses) pharmacokinetics of rimantadine hydrochloride were compared in eight patients with end-stage renal disease who were on hemodialysis and seven age-matched healthy subjects [5].
• We tested combinations that paired a neuraminidase (NA) inhibitor (zanamivir, oseltamivir carboxylate, or peramivir) with rimantadine against infection of MDCK cells with H1N1 and H3N2 subtypes of influenza A virus and characterized their mode of interaction [9].
• The sialidase (neuraminidase) inhibitor 4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid (4-guanidino-Neu5Ac2en) has been examined for the ability to inhibit the growth of a wide range of influenza A and B viruses in vitro in comparison with amantadine, rimantadine, and ribavirin [10].
• Rimantadine and oseltamivir demonstrate synergistic combination effect in an experimental infection with type A (H3N2) influenza virus in mice [11].
• In an independent, rimantadine-resistant function, M2, interacting with the M1 protein, controls the shape of virus particles [12].

Biological context of Flumadine

• Rimantadine pharmacokinetics in healthy subjects and patients with end-stage renal failure [5].
• These data provide further evidence that rimantadine-resistant viruses that emerge during treatment of patients with the drug are unaltered both in their growth characteristics and virulence [13].
• The risk of adverse drug effects, particularly central nervous system side effects, which occur more often with amantadine than rimantadine, and potential drug interactions are additional concerns [14].
• The infectivity titer and the 50% inhibitory concentration of rimantadine were calculated for each virus [15].
• Therefore, the depression in CTL and antibody responses associated with rimantadine treatment appears to be due to a decrease in the amount of viral antigen available or interference with viral antigen processing and not to nonspecific immunosuppressive effects [16].

Anatomical context of Flumadine

• 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 [17].
• However, at concentrations of 16 and 32 micrograms/ml, rimantadine was toxic to the ciliated epithelium after 10 to 21 days of continuous exposure [18].
• Virus-neutralizing-antibody titers were reduced only by rimantadine treatment, which included prophylaxis, whereas the cytotoxic T lymphocyte (CTL) response was depressed by treatment given with or without prophylaxis [16].
• Both patients are receiving rimantadine therapy and performing well, with functioning kidney and pancreas grafts and no evidence of recurrent PV interstitial nephritis 22 and 37 months after retransplantation [19].
• 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) [20].

Associations of Flumadine with other chemical compounds

• Ribavirin in combination with high (50 micrograms/ml), but not low (1.56 to 25 micrograms/ml), concentrations of rimantadine showed an enhanced antiviral effect against B/Hong Kong/72 virus [21].
• We compared rimantadine to acetaminophen therapy in a controlled, double-blind study of 91 children with influenza-like illness [22].
• 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) [20].
• Dansylcadaverine and rimantadine inhibition of phagocytosis, PAF-acether release, and phosphatidylcholine synthesis in human polymorphonuclear leukocytes [23].
• Interestingly, diamino compound 16 is a 4-fold more potent inhibitor than its parent monoamino heterocyclic rimantadine 4 propably because of additional hydrogen bonding interactions with the M2 protein receptor [24].

Gene context of Flumadine

• Compared with placebo, rimantadine treatment reduced viral shedding, systemic symptoms, and levels of IL-8 [25].
• The data show that M protein can influence the activity of influenza A virus virion transcriptase and that the susceptibility of influenza virus to rimantadine may be due to the peculiarities of M protein [4].
• Taken together, our results suggest that regimens that combine NA inhibitors and rimantadine exert synergistic anti-influenza effects in vitro [9].
• 2. The ion selectivity of the rimantadine-sensitive current through M2 was determined [26].
• A single amino acid substitution within the transmembrane domain of the human immunodeficiency virus type 1 Vpu protein renders simian-human immunodeficiency virus (SHIV(KU-1bMC33)) susceptible to rimantadine [27].

Analytical, diagnostic and therapeutic context of Flumadine

• A combination of antiviral drugs and immunotherapy may need to be considered for their potential additive effect as well as to prevent the emergence of resistant virus, as occurs during monotherapy for influenza with amantadine or rimantadine [28].
• Hemodialysis did not appreciably remove rimantadine [5].
• Elimination half-lives were similar after both aerosol and oral administration (24.1 and 25.2 h, respectively), and rimantadine urinary excretion was less than 1% per 24 h in both groups [29].
• Rimantadine appeared to provide an additional protective effect beyond vaccination in reducing the risk of clinical and laboratory-confirmed influenza-like illness; however, the efficacy estimates were never statistically significant [30].
• Susceptible adults (n = 105) were enrolled into a randomized double-blind study of rimantadine treatment of experimental influenza A infection [31].

References