This report updates the 2002 recommendations by the Advisory Committee on Immunization Practices (ACIP) on the use of influenza vaccine and antiviral agents (CDC. Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2002;51 [No. RR-3]:1-31). The 2003 recommendations include new or updated information regarding 1) the timing of influenza vaccination by age and risk group; 2) influenza vaccine for children aged 6-23 months; 3) the 2003-2004 trivalent inactivated vaccine virus strains: A/Moscow/10/99 (H3N2)-like, A/New Caledonia/20/99 (H1N1)-like, and B/Hong Kong/330/2001-like antigens (for the A/Moscow/10/99 [H3N2]-like antigen, manufacturers will use the antigenically equivalent A/Panama/2007/99 [H3N2] virus, and for the B/Hong Kong/330/2001-like antigen, manufacturers will use either B/Hong Kong/330/2001 or the antigenically equivalent B/Hong Kong/1434/2002); 4) availability of certain influenza vaccine doses with reduced thimerosal content, including single 0.25 mL-dose syringes; and 5) manufacturers of influenza vaccine for the U.S. market. Although the optimal time to vaccinate against influenza is October and November, vaccination in December and later continues to be strongly recommended A link to this report and other information regarding influenza can be accessed at http://www.cdc.gov/ncidod/diseases/flu/fluvirus.htm.

https://stacks.cdc.gov/view/cdc/6625/cdc_6625_DS1.pdf

Prevention and control of influenza : recommendations of the Advisory Committee on Immunization Practices (ACIP)

ContextPrevious studies have shown oseltamivir, a neuraminidase inhibitor,
to be effective in preventing influenza and treating experimental influenza.ObjectiveTo evaluate the efficacy and safety of oseltamivir in the treatment
of naturally acquired influenza infection.DesignRandomized, placebo-controlled, double-blind study conducted January
through March 1998.SettingSixty primary care and university health centers throughout the United
States.ParticipantsA total of 629 healthy nonimmunized adults aged 18 to 65 years with
febrile respiratory illness of no more than 36 hours' duration with temperature
of 38°C or more plus at least 1 respiratory symptom and 1 constitutional
symptom.InterventionsIndividuals were randomized to 1 of 3 treatment groups with identical
appearing pills: oral oseltamivir phosphate, 75 mg twice daily (n = 211) or
150 mg (n = 209) twice daily, or placebo (n = 209).Main Outcome MeasuresDuration and severity of illness in individuals infected with influenza.ResultsTwo individuals withdrew before receiving medication and were excluded
from further analyses. A total of 374 individuals (59.6%) were infected with
influenza. Their duration of illness was reduced by more than 30% with both
oseltamivir, 75 mg twice daily (median, 71.5 hours; P<.001),
and oseltamivir, 150 mg twice daily (median, 69.9 hours; P = .006), compared with placebo (median, 103.3 hours). Severity of
illness was reduced by 38% (median score, 597 score-hours; P<.001) with oseltamivir, 75 mg twice daily, and by 35% (median
score, 626 score-hours; P<.001) with oseltamivir,
150 mg twice daily, vs placebo (median score, 963 score-hours). Oseltamivir
treatment reduced the duration of fever and oseltamivir recipients returned
to usual activities 2 to 3 days earlier than placebo recipients (P≤.05). Secondary complications such as bronchitis and sinusitis
occurred in 15% of placebo recipients compared with 7% of combined oseltamivir
recipients (P = .03). Among all 629 subjects, oseltamivir
reduced illness duration (76.3 hours and 74.3 hours for 75 mg and 150 mg,
respectively, vs 97.0 hours for placebo; P = .004
for both comparisons) and illness severity (686 score-hours and 629 score-hours
for 75 mg and 150 mg, respectively, vs 887 score-hours for placebo; P<.001 for both comparisons). Nausea and vomiting occurred
more frequently in both oseltamivir groups (combined, 18.0% and 14.1%, respectively; P = .002) than in the placebo group (7.4% and 3.4%; P<.001).ConclusionsOur data suggest that oral oseltamivir treatment reduces the duration
and severity of acute influenza in healthy adults and may decrease the incidence
of secondary complications.

https://jamanetwork.com/journals/jama/articlepdf/192425/JOC91318.pdf

Efficacy and Safety of the Oral Neuraminidase Inhibitor Oseltamivir in Treating Acute Influenza

http://research.kaums.ac.ir/UploadedFiles/mirhosseini/Lancet%20-%20Efficacy%20and%20Safety%20of%20the%20Oseltamivir%20in%20Flu-kashan.pdf

Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial

About 40 years have passed since the classical glycosidase inhibitor nojirimycin was discovered from the cultured broth of the Streptomyces species. Since then, over 100 glycosidase inhibitors have been isolated from plants and microorganisms. Modifying or blocking biological processes by specific glycosidase inhibitors has revealed the vital functions of glycosidases in living systems. Because enzyme-catalyzed carbohydrate hydrolysis is a biologically widespread process, glycosidase inhibitors have many potential applications as agrochemicals and therapeutic agents. Glycosidases are involved in the biosynthesis of the oligosaccharide chains and quality control mechanisms in the endoplasmic reticulum of the N-linked glycoproteins. Inhibition of these glycosidases can have profound effects on quality control, maturation, transport, and secretion of glycoproteins and can alter cell-cell or cell-virus recognition processes. This principle is the basis for the potential use of glycosidase inhibitors in viral infection, cancer, and genetic disorders. In this review, the past and current applications of glycosidase inhibitors to agricultural and medical fields and the prospect for new therapeutic applications are reconsidered.

/pdf/glycosidase-inhibitors-update-and-perspectives-on-practical-34qajxdfww.pdf

Glycosidase inhibitors: update and perspectives on practical use.

Influenza remains an important disease in humans and animals. In contrast to measles, smallpox and poliomyelitis, influenza is caused by viruses that undergo continuous antigenic change and that possess an animal reservoir. Thus, new epidemics and pandemics are likely to occur in the future, and eradication of the disease will be difficult to achieve. Although it is not clear whether a new pandemic is imminent, it would be prudent to take into account the lessons we have learned from studying different human and animal influenza viruses. Specifically, reconstruction of the genes of the 1918 pandemic virus and studies on their contribution to virulence will be important steps toward understanding the biological capabilities of this lethal virus. Increasing the availability of new antiviral drugs and developing superior vaccines will provide us with better approaches to control influenza and to have a positive impact on disease load. A concern is that the imposition of new rules for working with infectious influenza viruses under high security and high containment conditions will stifle scientific progress. The complex questions of what makes an influenza virus transmissible from one human to another and from one species to another, as well as how the immune system interacts with the virus, will require the active collaboration and unencumbered work of many scientific groups.

/pdf/influenza-old-and-new-threats-aqaw6s1ywf.pdf

Influenza: old and new threats.

We have recently described GS 4071, a carbocyclic transition-state analog inhibitor of the influenza virus neuraminidase, which has potent inhibitory activity comparable to that of 4-guanidino-Neu5Ac2en (GG167; zanamivir) when tested against influenza A virus replication and neuraminidase activity in vitro. We now report that GS 4071 is active against several strains of influenza A and B viruses in vitro and that oral GS 4104, an ethyl ester prodrug which is converted to GS 4071 in vivo, is active in the mouse and ferret models of influenza virus infection. Oral administration of 10 mg of GS 4104 per kg of body weight per day caused a 100-fold reduction in lung homogenate viral titers and enhanced survival in mice infected with influenza A or B viruses. In ferrets, a 25-mg/kg dose of GS 4104 given twice daily reduced peak viral titers in nasal washings and eliminated constitutional responses to influenza virus infection including fever, increased nasal signs (sneezing, nasal discharge, mouth breathing), and decreased activity. Consistent with our demonstration that the parent compound is highly specific for influenza virus neuraminidases, no significant drug-related toxicity was observed after the administration of oral dosages of GS 4104 of up to 800 mg/kg/day for 14 days in nonclinical toxicology studies with rats. These results indicate that GS 4104 is a novel, orally active antiviral agent with the potential to be used for the prophylaxis and treatment of influenza A and B virus infections.

https://aac.asm.org/content/aac/42/3/640.full.pdf

Oral Administration of a Prodrug of the Influenza Virus Neuraminidase Inhibitor GS 4071 Protects Mice and Ferrets against Influenza Infection

GS 4071 is a potent carbocyclic transition-state analog inhibitor of influenza virus neuraminidase with activity against both influenza A and B viruses in vitro. GS 4116, the guanidino analog of GS 4071, is a 10-fold more potent inhibitor of influenza virus replication in tissue culture than GS 4071. In this study we determined the oral bioavailabilities of GS 4071, GS 4116, and their respective ethyl ester prodrugs in rats. Both parent compounds and the prodrug of the guanidino analog exhibited poor oral bioavailability (2 to 4%) and low peak concentrations in plasma (Cmaxs; Cmax <0.06 μg/ml). In contrast, GS 4104, the ethyl ester prodrug of GS 4071, exhibited good oral bioavailability (35%) as GS 4071 and high Cmaxs of GS 4071 (Cmax = 0.47 μg/ml) which are 150 times the concentration necessary to inhibit influenza virus neuraminidase activity by 90%. The bioavailability of GS 4104 as GS 4071 was also determined in mice (30%), ferrets (11%), and dogs (73%). The plasma of all four species exhibited high, sustained concentrations of GS 4071 such that at 12 h postdosing the concentrations of GS 4071 in plasma exceeded those necessary to inhibit influenza virus neuraminidase activity by 90%. These results demonstrate that GS 4104 is an orally bioavailable prodrug of GS 4071 in animals and that it has the potential to be an oral agent for the prevention and treatment of influenza A and B virus infections in humans.

Identification of GS 4104 as an Orally Bioavailable Prodrug of the Influenza Virus Neuraminidase Inhibitor GS 4071

Synthesis and evaluation of 3-deoxy-D-manno-2-octulosonate-8-phosphate (KDO8P) synthase inhibitors

Carbocyclic analogues as transition state mechanism based inhibitors of 3-deoxy-D-manno-2-octulosonate-8-phosphate synthase were designed, synthesized, and evaluated for their biological activity.

Weixing Li

Papers

Oral Administration of a Prodrug of the Influenza Virus Neuraminidase Inhibitor GS 4071 Protects Mice and Ferrets against Influenza Infection

Identification of GS 4104 as an Orally Bioavailable Prodrug of the Influenza Virus Neuraminidase Inhibitor GS 4071

Synthesis and evaluation of 3-deoxy-D-manno-2-octulosonate-8-phosphate (KDO8P) synthase inhibitors

Synthesis and Evaluation of 3-Deoxy-D-manno-2-octulosonate-8-phosphate (KDO8P) Synthase Inhibitors.