Evaluation of the impact of sulfobutylether7 -ß-cyclodextrin on the liquid chromatography-mass spectrometry analysis of biological samples arising from in vivo pharmacokinetic studies.

The utility of cyclodextrin (CD) complexation in improving apparent solubility of drugs in parenteral formulations is well established. Administration of these formulations delivers CD directly into the systemic circulation, and it may be necessary to demonstrate unaltered in vivo disposition of a drug coadministered with a CD. Crucial to the undertaking of such a study is the need for bioanalytical assays in which CD presence does not impact drug quantitation. This is of particular importance when assessing the potential impact of in vivo CD complexation on the urinary excretion of a drug, as CDs are predominantly eliminated via glomerular filtration, and hence are present in urine at significantly higher concentration than would be present in blood and plasma. Of 23 publications (in the past 30 years) describing preclinical and clinical assessment of drug pharmacokinetics after i.v. administration of CD-enabled formulations, only two reports clearly stated that the presence of CD had no impact on assay performance. In this work, we describe the simple process involved in (1) predicting the maximum concentrations of a modified CD, sulfobutylether7 -ß-CD (SBE7 -ß-CD), in plasma and urine samples from preclinical studies, and (2) evaluating the impact of SBE7 -ß-CD on the quantitative liquid chromatography-mass spectrometry analysis of rimantadine.

The effect of intravenous sulfobutylether7 -ß-cyclodextrin on the pharmacokinetics of a series of adamantane-containing compounds.

Intravenously administered (i.v.) drug-cyclodextrin (CD) inclusion complexes are generally expected to dissociate rapidly and completely, such that the i.v. pharmacokinetic profile of a drug is unchanged in the presence of CD. The altered pharmacokinetics of a synthetic ozonide in rats has been attributed to an unusually high-binding affinity (2.3 × 10(6) M(-1) ) between the drug and sulfobutylether7 -ß-cyclodextrin (SBE7 -ß-CD) with further studies suggesting a significant binding contribution from the adamantane ring. This work investigated the binding affinity of three adamantane derivatives [amantadine (AMA), memantine (MEM) and rimantadine (RIM)] to SBE7 -ß-CD and the impact of complexation on their i.v. pharmacokinetics. In vitro studies defined the plasma protein binding, as well as the impact of SBE7 -ß-CD on erythrocyte partitioning of each compound. SBE7 -ß-CD binding constants for the compounds were within the typical range for drug-like molecules (10(2) -10(4) M(-1) ). The pharmacokinetics of AMA and MEM were unchanged; however, significant alteration of RIM plasma and urinary pharmacokinetics was observed when formulated with CD. In vitro studies suggested two factors contributing to the altered pharmacokinetics: (1) low plasma protein binding of RIM, and (2) decreased erythrocyte partitioning in the presence of high SBE7 -ß-CD concentrations. This work demonstrated the potential for typical drug-cyclodextrin interactions to alter drug plasma pharmacokinetics.

[The antiviral activity of the adamantane derivatives against the influenza virus A (H1N1) pdm2009 model in vivo].

For the first time in vivo, the model of the viral pneumonia in mice was used to study the antiviral activity against influenza A virus (H1N1) pdm09 synthetic derivatives of adamantane series including the amino acid residues and lipoid acid. It was found that the adamantane derivatives with histidine, serine, and lipoid acid could inhibit the rimantadine-resistant strain of the influenza A (H1N1) pdm09. As a result, the lifespan of the mice infected with the virus has increased by 1.6 times with respect to viral control. Thus, the possibility of restoration of antiviral properties of rimantadine both in vitro and in vivo by introducing into its molecular structure new functionally active groups was tested.

Rimantadine and 2-adamantanamine elicit local anesthesia to cutaneous nociceptive stimuli in a rat model.

The aim of this study was to investigate infiltrative cutaneous anesthesia of 2-adamantanamine and rimantadine. After subcutaneous injections of drugs in rats, the blockade of cutaneous trunci muscle reflex by 2-adamantanamine and rimantadine was evaluated. Lidocaine, a common local anesthetic, was used as control. We showed that rimantadine and 2-adamantanamine as well as the local anesthetic lidocaine produced infiltrative anesthesia of skin in a dose-dependent fashion. Saline (vehicle) group displayed no cutaneous anesthesia. The relative potency of these drugs was rimantadine [23.8 (21.1-26.8)] = lidocaine [26.4 (22.7-30.6)] > 2-adamantanamine [64.6 (55.0-75.9)] (P < 0.01). On an equianesthetic basis [25% effective dose (ED25 ), ED50 , and ED75 ], rimantadine and 2-adamantanamine had longer duration of action than lidocaine (P < 0.05). Neither local injection of saline nor intraperitoneal administration of a large dose of drugs elicited cutaneous anesthesia (data not shown). These data demonstrated for the first time that rimantadine had a similar potent and longer duration of skin infiltrative anesthesia than did lidocaine, whereas 2-adamantanamine had a less potency but longer duration of cutaneous anesthesia than did lidocaine.

Conjugation to polymeric chains of influenza drugs targeting M2 ion channels partially restores inhibition of drug-resistant mutants.

By attaching multiple copies of the influenza M2 ion channel inhibitors amantadine (1) and rimantadine (2) to polymeric chains, we endeavored to recover their potency in inhibiting drug-resistant influenza viruses. Depending on loading densities, as well as the nature of the drug, the polymer, and the spacer arm, polymer-conjugated drugs were up to 30-fold more potent inhibitors of drug-resistant strains than their monomeric parents. In particular, a 20% loading density and a short linker group on the negatively charged poly-l-glutamate resulted in one of the most potent inhibitors for 2's conjugates against drug-resistant influenza strains. Although full recovery of the inhibitory action against drug-resistant strains was not achieved, this study may be a step toward salvaging anti-influenza drugs that are no longer effective.

[Effect of a combination of glutamyl-tryptophan and glycyrrhizic acid on the course of acute infection caused by influenza (H3H2) virus in mice].

The purpose of the study was to evaluate the modulating effect of glutamyl-tryptophan (EW), glycyrrhizic acid (GA), and their combination on the course of experimental infection caused by influenza A (H3N2) virus in mice. The animals were infected with influenza A/Aichi/2/68 (H3N2) virus in a dose of 1 or 10 LD50. GA (10 mg/kg body weight) and EW (0.1, 10, and 1000 microg/kg) alone or in combination were intraperitoneally injected for 5 days, starting on day 1 of virus infection. Rimantadine 50 mg/kg/day was used as a comparison drug. The combination of EW (1000 microg/kg) and GA (10 mg/kg) was ascertained to exert the maximum protective effect manifesting itself in reducing the death of infected animals (by 75-79% compared to the control depending on the viral dose) and the titers of viruses accumulated in the lung (5-6 log EID50) and in preventing lung tissue edema and inflammation. The noted effect was comparable with that seen in the use of rimantadine. The agents used alone had a lower efficacy than rimantadine. The findings permit the combination of GA and EW to be considered to be a promising agent for the treatment of influenza.

[The specific features of the cocirculation of influenza viruses in the 2010-2011 postpandemic period according to the results of activities of the D. I. Ivanovsky Research Institute of Virology, Ministry of Health and Social Development of Russia].

The paper gives the results of monitoring the circulation of influenza viruses in the 2010-2011 season, that covers the second year of circulation of pandemic A(H1N1)v virus strains, and their interaction with seasonal A (H3N2) and B strains. Unlike the previous season, the beginning of an increase in morbidity was recorded in January 2011; its peak in the most of contiguous areas was noted at 5-7 weeks of 2011, with its further decline to threshold levels at week 11 of 2011. Preschool and school children were most involved in the epidemic process. Three influenza virus strains (A(H1N1)v, A(H3N2), and B) were found to circulate. Differences were found in the level of participation of the isolated strains in individual areas of the Russian Federation. Detailed typing of the isolated strains determined the compliance of the vast majority of them with vaccine viruses. The pandemic influenza A(H1N1)v virus strains retained their susceptibility to oseltamivir and were resistant to rimantadine. The participation of non-influenza acute respiratory viral infection pathogens was estimated as follows: 11.9% for parainfluenza viruses, 5.9% for adenoviruses, and 3.5% for PC viruses, and 0.7% for pneumonia Mycoplasma, which was comparable with the previous epidemic seasons.

Prophylactic and therapeutic combination effects of rimantadine and oseltamivir against influenza virus A (H3N2) infection in mice.

The combined effect of rimantadine and oseltamivir in a prophylactic context (therapy beginning 4 h pre-virus infection) and therapeutic context (therapy started at 24 h post-viral inoculation) course on influenza H3N2 virus infection in mice was studied. In the prophylactic course 5 and 10 mg/kg/day rimantadine with 0.2 and 0.4 mg/kg/day (25:1 dose ratio) oseltamivir showed a protection index (PI) of 79.6% and 75%, respectively and a mean survival time (MST) of 13.1 and 12.9 days. The individual effects of the same doses ranged from 0% to 33.3% PI and 8.2 to 10.3 days MST, respectively. Lung virus titers were decreased 630-fold in the combination-treated groups as compared to monotherapy and placebo groups. The reduction of surface lung pathology in combination-treated groups demonstrated a protective effect for the combination of both antivirals. In the therapeutic course 5 and 10 mg/kg rimantadine combined with 0.2 and 0.4 mg/kg oseltamivir showed no beneficial effect. At higher dosage (0.8, 1.6, 3.2 mg/kg oseltamivir and 20, 40, 80 mg/kg rimantadine) preserving the 25:1 ratio, the resultant PI ranged from 57.6% to 80.5% and the MST was 12.8-13.4 days. Used alone at the same doses the compounds' protection varied between 10.7% and 71.8% PI, MST 9.8-12.8 days (8.7 days in PBS control). Compared to vehicle and individual treatment, a decrease in infectious viral titers of up to 1000-fold and other viral pneumonia parameters were also recorded. The therapeutic effect of the drugs' optimal effective doses combinations was characterized as synergistic. Survival of animals was 81.2-100% and MST was extended by 5-7 days compared to placebos. Monotherapy protection was from 9.1% to a maximum of 56.5%, MST being prolonged only by 1.3-4.2 days compared to 7.5 days in the PBS control group. Lung viral titers were decreased 1445-fold for the most efficacious combination groups and a significant reduction in lung parameters was observed. These data emphasize that prophylactic and therapeutic courses using a combination of oseltamivir and rimantadine have a significant protective effect in mice experimentally infected with drug-sensitive influenza virus A (H3N2).

Absence of pharmacokinetic interaction between intravenous peramivir and oral oseltamivir or rimantadine in humans.

Peramivir, an intravenously administered neuraminidase inhibitor, may be used concomitantly with other influenza antivirals. Two studies were conducted to assess the potential for pharmacokinetic interactions of peramivir when coadministered with oseltamivir or rimantadine. Twenty-one healthy subjects were enrolled in each randomized, open-label, crossover study, and they received 1 intravenous dose of peramivir (600 mg), 1 oral dose of oseltamivir (75 mg) or rimantadine (100 mg), or a combination of peramivir with oseltamivir or rimantadine. Assessment of the 90% confidence interval for the geometric mean ratio of peramivir and oseltamivir carboxylate or rimantadine pharmacokinetic parameters showed no effect of oseltamivir or rimantadine on the pharmacokinetics of peramivir and no effect of peramivir on the pharmacokinetics of oseltamivir carboxylate or rimantadine. The drugs were well tolerated. These results suggest no reason to expect an effect of concomitant administration of oseltamivir or rimantadine on the safety profile of peramivir in patients with influenza.

Pharmacokinetics and safety of coadministered oseltamivir and rimantadine in healthy volunteers: an open-label, multiple-dose, randomized, crossover study.

Preclinical data suggest increased antiviral activity and less viral resistance when neuraminidase inhibitors and adamantanes are used in combination to harness the complementary effects of their different mechanisms of action. Healthy volunteers were randomized to 5-day oral treatment with oseltamivir 75 mg or rimantadine 100 mg twice daily as monotherapy or to combination treatment. Each participant received all 3 regimens in 1 of 6 treatment sequences, with a minimum of 7 days' washout between periods. Final follow-up was 10 to 14 days after the final dose. Drug exposure, elimination, safety, and tolerability were assessed. There were no clinically relevant differences in 12-hour areas under the concentration-time curves of drug in plasma or peak plasma drug concentrations with combination versus monotherapy. Elimination half-life was unaffected by coadministration. There were no safety/tolerability concerns. One case of vomiting and 1 of paresthesia were considered remotely related to combination treatment, and 1 episode of toothache and 1 of acne were considered unrelated. There were no serious adverse events and no deaths. Combination therapy with oseltamivir and rimantadine at recommended dosages in adults had no discernible effect on the pharmacokinetics of either drug and raised no tolerability issues.

[Comparative pharmacokinetics of antigrippin-maximum administered in capsules and powder for preparing solutions].

Comparative pharmacokinetics of anti-influenza drug composition Antigrippin-maximum administered in capsules and a powder for preparing solutions has been studied after single administraton in a group of 18 healthy volunteers. Both preparations [manufactured by the Antiviral Research and Production Corporation (St Petersbutg) contain 6 active components, including paracetamol, rimantadine, loratadine, ascorbic acid, calcium gluconate, and rutoside in equal amounts. The concentrations of unchanged paracetamol, rimantadine, and loratadine in the blood plasma were degtermined by HPLC with mass-spectrometric and UV detection. The pharmacokinetic parameters of allindicated active components exhibited no detectable distinctions, except for the time to attaining maximum concentration ofparacetamol and the value of the maximum concentration of loratadine.

[In vitro and in vivo efficacy of Ingavirin against strains of pandemic influenza virus A(H1N1/09)v].

AIM: To study efficacy of Ingavirin in vitro and in vivo against strains of pandemic influenza virus A(H1N1/09)v and influenza virus A(H5N1) and A(H3N2). MATERIALS AND METHODS: Changes in hemagglutinating and cytopathic activity of influenza virus strains A(H1N1/09)v, A(H5N1) and A(H3N2) during their incubation in the presence of Ingavirin or Remantadin on MDCK cell culture were studied. In mice infected by influenza strains A(H1N1/09)v and A(H3N2) and orally treated with Ingavirin, Tamiflu or Remantadin virus titers in lungs were measured. RESULTS: There was decrease in hemagglutinating and cytopathic activity of influenza virus strains after incubation with Ingavirin in vitro. Ingavirin effectively inhibited reproduction of influenza virus strains A(H1N1/09)v and A(H3N2) in lungs of infected mice. Titers of these strains in lung homogenates decreased when Ingavirin was orally administered to infected mice. CONCLUSION: Strains of influenza virus A(H1N1/09)v were susceptible to Ingavirin and Tamiflu but resistant to Remantadin. Reference strains of A(H5N1) and A(H3N2) were susceptible to Ingavirin, Tamiflu and Remantadin.

[Study of the antiviral activity of Russian anti-influenza agents in cell culture and animal models].

The study of the antiviral activity of Russian anti-influenza agents in the cultured MDCK cells demonstrated that arbidol and ribavirin inhibited the reproduction of various influenza A virus strains, including rimantadine- and ozeltamivir-resistant variants, as well as influenza B viruses (IC50 2-8.5 microg/ml). Rimantadine at concentrations of 1-5 microg/ml completely inhibited the reproduction of reference and ozeltamivir-resistant influenza A virus strains, and it had no effect on the reproduction of influenza B viruses and rimantadine-resistant influenza A viruses. Arbidol and ribavirin also inhibited the reproduction of pandemic influenza A/California/04/2009(H1N1), A/California/07/2009(H1N1), and A/Moscow/01/2009(H1N1)swl viruses in the cultured MDCK cells (IC50 = 1.5-4.0 microg/ml) while rimantadine had no effect on their reproduction. The cultured cells showed no significant antiviral activity of ingavirin at nontoxic concentrations (up to 200 microg/ml) against all study strains of influenza A and B viruses, including pandemic A(H1N1) influenza virus strains. The activity of rimantadine, arbidol, and ingavirin was found on a model of Influenza pneumonia in mice infected with their adopted influenza A/Aichi/2/69(H3N2) virus. The preventive efficacy of the three test agents was similar and most pronounced when they were used 96 hours before infection, by preventing 40-50% death in the animals and their body weight loss and by increasing their survival by 1.3-1.5 times. Arbidol and rimantadine were more effective when used for treatment and prophylaxis in doses of 30 and 10 mg/kg/day, respectively, by protecting the infected animals from 60-80% death, increasing their survival by 1.7-2 times, and preventing their body weight loss as compared with the control. The same experiments with ingavirin showed that this agent was less effective than arbidol and rimantadine. Thus, arbidol and rimantadine have a pronounced antiviral infection in both cell culture and a model of influenza pneumonia. The found efficacy of ingavirin on an integral model of murine influenza pneumonia without its activity in the cultured cells is likely to be due to other pharmacological properties of the drug rather than its direct virus-specific action.

WHO Guidelines for pharmacological management of pandemic influenza A(H1N1) 2009 and other influenza viruses: part II review of evidence

This revised guidance is published in two parts. Part II documents the procedures followed in developing this guidance, together with a review of evidence and other new information on the pharmacological agents considered.

Influenza guideline for South Africa--update 2008.

OBJECTIVE: The South African Thoracic Society, in conjunction with interested stakeholders, published a Guideline for Influenza Management in Adults in 1999. This year the South African Thoracic Society (SATS) identified the need to revise that guideline for the following reasons: * To indicate the viral strains that are to be incorporated into the vaccine for the 2008 season * To add important new data regarding treatment of influenza * To add a section on influenza in children * To clarify issues in managing and preventing influenza in HIV-infected individuals. INFLUENZA VIRUS: The influenza virus genus belongs to the family orthomyxoviridae. The haemagglutinin (HA) protein is the outermost protein, responsible for attachment to the host receptor, and is critical in determining the host's immune response to the virus. Changes in the antigenic epitopes of HA therefore allow the virus to escape the host's specific immune response. The genus is classified into three types, A, B and C, on the basis of the antigenic epitopes of the nucleoprotein (NP). Type A, which is widespread in nature in birds and mammals, is the most important type clinically and epidemiologically. It is further divided into subtypes on the basis of the antigenic epitopes of the HA and neuraminidase (NA) proteins. Each of the human subtypes H1N1, H2N2 and H3N2 are further subdivided into strains on the basis of more subtle antigenic properties of the HA protein. INFLUENZA VACCINATION: Influenza vaccine is the mainstay of influenza prevention strategies. All persons who are at high risk of influenza and its complications because of underlying medical conditions or who are receiving regular medical care for conditions such as chronic pulmonary and cardiac disease, chronic renal diseases, neuromuscular diseases, diabetes mellitus and similar metabolic disorders, and individuals who are immunosuppressed (including HIV-infected persons with CD4 counts above 100 cells/microl and HIV-infected children with CD4 counts >15%), should be vaccinated. Vaccines should be given from at least 2 months prior to the onset of autumn (March in South Africa). The recommended vaccine formulation for 2008 is: * A/Solomon Islands/3/2006 (H1N1) (IVR-145) * A/Brisbane/10/2007 (H3N2) (IVR-147) * B/Florida/4/2006 or B/Brisbane/3/2007. TREATMENT OF INFLUENZA: Influenza illness is characterised by the acute onset of systemic and respiratory signs occurring in autumn or winter. Recommendations for the Prevention and Control of Influenza have indicated that neither amantadine nor rimantadine should be used for the treatment or chemoprophylaxis of influenza A. NA inhibitors are an important adjunct to influenza vaccination, in both the prevention and treatment of influenza. Because of concerns about the possibility of the development of viral resistance with overuse of these agents, it is recommended that NA inhibitors in the treatment of influenza should be reserved for high-risk or sicker influenza patients.

Determination of rimantadine in rat plasma by liquid chromatography/electrospray mass spectrometry and its application in a pharmacokinetic study.

A rapid and sensitive liquid chromatography/mass spectrometry (LC/MS) method was developed and validated for the determination of rimantadine in rat plasma. Rimantadine was extracted by protein precipitation with methanol, and the chromatographic separation was performed on a C(18) column. The total analytical run time was relatively short (4.6 min), and the limit of assay quantification (LLOQ) was 2 ng/mL using 50 microL of rat plasma. Rimantadine and the internal standard (amantadine) were monitored in selected ion monitoring (SIM) mode at m/z 180.2 and 152.1, respectively. The standard curve was linear over a concentration range from 2 to 750 ng/mL, and the correlation coefficients were greater than 0.999. The mean intra- and inter-day assay accuracy ranged from 100.1-105.0% to 100.3-104.0%, respectively, and the mean intra- and inter-day precision was between 1.3-2.3% and 1.8-3.0%, respectively. The developed assay method was successfully applied to a pharmacokinetic study in rats after oral administration of rimantadine hydrochloride at the dose of 20 mg/kg.

Emergence of rimantadine-resistant virus within 6 days of starting rimantadine prophylaxis with oseltamivir treatment of symptomatic cases.

OBJECTIVES: To report on the detection of rimantadine resistance within 6 days of starting rimantadine prophylaxis. DESIGN: Observational prospective study. SETTING: Fifty-bed nursing unit during the 2004/05 influenza season. PARTICIPANTS: All residents. INTERVENTION: Clinical monitoring for new onset of respiratory illness followed by collection of nasopharyngeal swabs for Directigen AB testing and influenza culture. After outbreak identification, rimantadine was administered as prophylaxis, whereas oseltamivir was used to treat symptomatic cases. Laboratory monitoring for the emergence of rimantadine resistance was reinitiated on the fifth day of rimantadine prophylaxis. MEASUREMENTS: Tabulation of respiratory illnesses, rapid tests and cultures yielding influenza A, and rimantadine sensitivity determination in five index isolates. RESULTS: A total of 15 symptomatic cases were identified over 8 days. Amantadine sensitivity was determined in five cases. Three initial cases were sensitive to rimantadine, whereas two cases identified after 6 days of rimantadine prophylaxis were resistant to rimantadine. CONCLUSION: The Centers for Disease Control and Prevention reported that 91% of isolates collected early the following season (2005/06) were resistant to rimantadine. Rimantadine treatment is no longer recommended. This experience anticipated the new recommendations. If reemergence of sensitivity follows discontinuation of rimantadine use, using rimantadine as prophylaxis and oseltamivir for treatment of symptomatic cases might be efficacious and economical on a national scale.

Antiviral therapy and prophylaxis for influenza in children.

Antiviral agents are available that are safe and effective for the treatment and prophylaxis of influenza virus infections in children. The neuraminidase inhibitors (oseltamivir [Tamiflu] and zanamivir [Relenza]) are preferred agents because of current widespread resistance to the adamantanes (amantadine [Symmetrel] and rimantadine [Flumadine]). Therapy should be provided to children with influenza infection who are at high risk of severe infection and to children with moderate-to-severe influenza infection who may benefit from a decrease in the duration of symptoms. Prophylaxis should be provided (1) to high-risk children who have not yet received immunization and during the 2 weeks after immunization, (2) to unimmunized family members and health care professionals with close contact with high-risk unimmunized children or infants who are younger than 6 months, and (3) for control of influenza outbreaks in unimmunized staff and children in an institutional setting. Testing of current H5N1 avian influenza virus isolates, the potential agents of pandemic influenza, suggests susceptibility to oseltamivir and zanamivir. Because no prospective data exist on the efficacy of these agents in humans for H5N1 strains, the dosage and duration of therapy in adults and children may differ from those documented to be effective for epidemic influenza strains.

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.

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.