[Studying the effect of antioxidants and/or antihypoxants on cell cultures under conditions of cytotoxic action of rimantadine].

The effect of some preparations with antioxidant and/or antihypoxic properties was studied under the conditions of cytotoxic action of the antiviral drug rimantadine in an MDCK cell culture. The preparations under study were hypoxene, reduced and oxidized glutathione, metadoxil, trolox (water-soluble analog of vitamin E), dihydroquercetin, coenzyme Q, and recsod (superoxide dismutase enzyme preparation). The protective drug action on the model of cytotoxicity in vitro was observed for the preparations possessing a complex of antioxidant/antihypoxic and detoxicant properties: hypoxene, metadoxil, and reduced glutathione. The protective effect of preparations did not correlate with their direct antiradical activity with respect to the stable free radical DPPH. Some compounds of phenolic nature (trolox, coenzyme Q) and recsod enhanced the harmful effect of rimantadine on the culture cells under the conditions studied. A possible explanation of this fact could be the conversion, under certain conditions, of the effect of phenolic compounds from antioxidant to pro-oxidant, which is confirmed by some literature data. The results do not allow antioxidant preparations to be recommended for routine application as cytoprotectors during toxic stresses of different nature. The protective activity of such preparations should be estimated separately for each particular xenobiotic.

Neuraminidase inhibitor-rimantadine combinations exert additive and synergistic anti-influenza virus effects in MDCK cells.

There is insufficient information about combination therapy with approved anti-influenza agents. 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. When reduction of extracellular virus was analyzed by individual regression models and three-dimensional representations of the data, all three combinations showed additive and synergistic effects with no cytotoxicity. Maximum synergy against A/New Caledonia/20/99 (H1N1) virus infection was observed with <2.5 microM rimantadine paired with low concentrations of NA inhibitors. All combinations reduced the extracellular yield of A/Panama/2007/99 (H3N2) influenza virus synergistically. However, our findings were different for the cell-associated virus yield. At some drug concentrations, the yield of cell-associated virus was inhibited antagonistically. Therefore, the method of analysis can be a crucial factor in evaluating the interactions of drugs with different mechanisms. We hypothesize that assays based on cell-associated virus yield may underestimate the efficacies of drug combinations that include an NA inhibitor. Taken together, our results suggest that regimens that combine NA inhibitors and rimantadine exert synergistic anti-influenza effects in vitro. These findings provide baseline information for therapeutic testing of the drug combinations in vivo.

Heterocyclic rimantadine analogues with antiviral activity.

2-(1-Adamantyl)pyrrolidines 6, 7, 2-(1-adamantyl)piperidines 10, 12a-c, 15a,b and 2-(1-adamantyl)hexahydroazepines 19, 21, 22 were synthesized and tested for their antiviral activity against influenza A, B viruses and the human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2). The synthetic procedure followed for the preparation of the parent piperidine 10 represents a general method for the synthesis of 2-alkyl- or cycloalkyl-substituted piperidine alkaloids. Parent aminoadamantanes 6, 10 and 19 contain the 1-aminoethyl pharmacophore group of rimantadine drug 2, extended into a saturated nitrogen heterocycle: pyrrolidine, piperidine and hexahydroazepine, respectively. The ring size effect in anti-influenza A activity was investigated. Rimantadine analogues 6 and 10 were, respectively, 6- and 4-fold more active than the drug Rimantadine 2, whereas the hexahydroazepine derivative 19 was inactive. Thus, enlargement from a 5-(pyrrolidine)- or 6-(piperidine)- to a 7-(hexahydroazepine)- membered heterocyclic ring dramatically reduced the anti-influenza virus A activity. Substitution of piperidine 10 with a dialkyaminoethyl group led to the active compounds 15a and 15b: compound 15a was active against influenza A virus whereas both 15a and 15b were active against HIV-1.

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.

Anti-infective therapy for viral pneumonia.

The recognition of viruses as causes of pneumonia in both immunocompetent and immunocompromised hosts has expanded dramatically. The number of therapeutic agents available for treatment of these illness also has increased in the last decade. Each of these agents has demonstrated a limited therapeutic indication for treatment of viral pneumonia. Many of these agents inhibit viral DNA synthesis through actions as nucleoside analogs (such as acyclovir and ganciclovir). However, a variety of alternative mechanisms of inhibition of viral replication are used. Ribavirin, while being a nucleoside analogue, also appears to exert broad antiviral activity by a variety of enzymatic inhibitory mechanisms. Foscarnet, an inorganic pyrophosphate analogue, offers additional treatment options for herpesviruses by acting as a direct virus DNA polymerase inhibitor. The tricyclic amines amantadine and rimantadine inhibit influenza A replication by interfering with viral uncoating after cell penetration. Thus, these two agents are largely effective as prophylaxis. The search for novel antiviral drugs, such as neuraminadases inhibitors with selective influenza activity, is currently in progress.

[Index of the proliferative activity of a cell culture in assessing the cytotoxicity of antiviral chemical preparations]. / Pokazatel' proliferativnoi aktivnosti kul'tury kletok v otsenke tsitotoksichnosti protivovirusnykh khimiopreparatov.

The influence of cytotoxicity of a number of antiviral compounds on the cell culture functional activity was studied by evaluating the changes in the kinetic cell growth parameters. Significant differences between the values of cytotoxicity were found with ribamide in cell lines of different origins. The differences in the measured values of cytotoxicity of the four antiviral compounds under study were demonstrated using the proposed proliferation cytotoxicity criterion (PCT).

[Characteristics of the degree and spectrum of antiviral activity of 2-(1'-aminoethyl)-bicyclo[2.2.1]heptane hydrochloride]. / Kharakteristika stepeni spektra protivovirusnoi aktivnosti 2-(1'-aminoétil)-bitsiklo[2.2.1]geptan khlorgidrata.

A high activity of a bicycloheptane derivative against influenza viruses, poor activity against Venezuelan equine encephalomyelitis and parainfluenza type 3 viruses, and the lack of activity against herpes simplex, vaccinia, ECHO 6, adenovirus type 3 replicating in tissue cultures were demonstrated. The efficacy of the drug in orthomyxovirus infection of tissue culture includes the viruses with the antigenic formula A (H3N2) and A (H1N1), is poor with the A/PR8/34 (H0N1) virus, and lacking with influenza B virus. The characteristics of antiviral activity of the drug obtained in tissue culture, chick embryos, and white mice were not inferior to that of remantadine. Animal experiments demonstrated its lower toxicity as compared with remantadine allowing it to be used in higher doses, thereby exceeding the effect of remantadine.

Comparative toxicity of amantadine hydrochloride and rimantadine hydrochloride in healthy adults.

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.