Tamiflu
New, azide-free transformation of epoxides into 1,2-diamino compounds: synthesis of the anti-influenza neuraminidase inhibitor oseltamivir phosphate (Tamiflu).

Karpf M, Trussardi R.

F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Non-Clinical Development, Chemical Process Research, Grenzacherstrasse 124, CH-4070, Basel, Switzerland. martin.karpf roche.com

A new, azide-free transformation of the key precursor epoxide 6 to the influenza neuraminidase inhibitor prodrug oseltamivir phosphate (1, Tamiflu) is described. This sequence represents a new and efficient transformation of an epoxide into a 1,2-diamino compound devoid of potentially toxic and hazardous azide reagents and intermediates and avoids reduction and hydrogenation conditions. Using catalytic MgBr(2).OEt(2) as a new, inexpensive Lewis acid, the introduction of the first amino function was accomplished by opening of the oxirane ring with allylamine followed by Pd/C-catalyzed deallylation to the amino alcohol 16. The introduction of the second amino group was then accomplished via an efficient reaction cascade involving a domino sequence preferably utilizing a transient imino protection. Selective acetylation of the resulting diamine 17 was achieved under acidic conditions providing the crystalline 4-acetamido-5-N-allylamino-derivative 18, which upon deallylation over Pd/C and phosphate salt formation afforded drug substance 1. The overall yield of this route from 6 of 35-38% exceeds the yield of the azide-based process (27-29%) and does not require any chromatographic purification.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11300898&dopt=Abstract oseltamivir Tamiflu



Tamiflu
Influenza pneumonia: a descriptive study.

Oliveira EC, Marik PE, Colice G.

Division of Critical Care Medicine, Washington Hospital Center, Washington, DC, USA.

OBJECTIVE: To describe the clinical features and complications of patients hospitalized with influenza during the 1999-2000 influenza season. METHODS: We reviewed all cases of patients with influenza admitted to a large metropolitan referral hospital during the 1999-2000 season. RESULTS: Thirty-five adult patients (15 men and 20 women) tested positive for influenza A by direct enzyme immunoassay. A fourfold to sevenfold increase in the number of influenza cases was observed over previous years. Most patients had serious comorbid illnesses (88%), such as diabetes and chronic respiratory and heart disease. Seventeen patients developed pneumonia; these patients tended to be older (mean +/- SD, 63 +/- 13 years vs 51 +/- 19 years, respectively; p = 0.04) and had a higher incidence of chronic lung disease (41% vs 6%, respectively; p = 0.02) than the patients without pneumonia. Shortness of breath was the only symptom that distinguished patients with pneumonia from those with an upper respiratory tract illness alone. Antiviral treatment was begun 4 +/- 3 days from initiation of symptoms in patients with pneumonia and consisted of oseltamivir (35.2%), rimantadine (5.8%), or a combination of both (17.6%). Respiratory and/or blood culture results were positive in five patients (29%), Staphylococcus aureus was isolated in five patients, and Streptococcus pneumoniae was isolated in one patient. Ten of the patients with pneumonia (58.8%) were admitted to the ICU, and 5 patients (29%) died. The length of ICU stay and mechanical ventilation were 28 +/- 26 days and 21.5 +/- 20.5 days, respectively. Death in most pneumonia patients was attributed to respiratory failure. CONCLUSION: The recognized number of hospital admissions for influenza increased fourfold to sevenfold over previous years, most likely due to the implementation of rapid diagnostic tests for influenza. Patients with signs and symptoms of influenza and shortness of breath should undergo chest radiography. Hospitalization of patients with influenza pneumonia occurred in both previously healthy and immunocompromised patients and had a high mortality. S aureus was the most common bacterial isolate in patients with influenza pneumonia. Empiric antibiotics with staphylococcal activity should be used pending culture results in patients with influenza pneumonia. The effectiveness of oseltamivir and rimantadine in treating patients with influenza pneumonia remains to be determined.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11399696&dopt=Abstract oseltamivir Tamiflu



Tamiflu
Comparison of efficacies of RWJ-270201, zanamivir, and oseltamivir against H5N1, H9N2, and other avian influenza viruses.

Govorkova EA, Leneva IA, Goloubeva OG, Bush K, Webster RG.

Department of Virology and Molecular Biology, St. Jude's Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA.

The orally administered neuraminidase (NA) inhibitor RWJ-270201 was tested in parallel with zanamivir and oseltamivir against a panel of avian influenza viruses for inhibition of NA activity and replication in tissue culture. The agents were then tested for protection of mice against lethal H5N1 and H9N2 virus infection. In vitro, RWJ-270201 was highly effective against all nine NA subtypes. NA inhibition by RWJ-270201 (50% inhibitory concentration, 0.9 to 4.3 nM) was superior to that by zanamivir and oseltamivir carboxylate. RWJ-270201 inhibited the replication of avian influenza viruses of both Eurasian and American lineages in MDCK cells (50% effective concentration, 0.5 to 11.8 microM). Mice given 10 mg of RWJ-270201 per kg of body weight per day were completely protected against lethal challenge with influenza A/Hong Kong/156/97 (H5N1) and A/quail/Hong Kong/G1/97 (H9N2) viruses. Both RWJ-270201 and oseltamivir significantly reduced virus titers in mouse lungs at daily dosages of 1.0 and 10 mg/kg and prevented the spread of virus to the brain. When treatment began 48 h after exposure to H5N1 virus, 10 mg of RWJ-270201/kg/day protected 50% of mice from death. These results suggest that RWJ-270201 is at least as effective as either zanamivir or oseltamivir against avian influenza viruses and may be of potential clinical use for treatment of emerging influenza viruses that may be transmitted from birds to humans.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11557461&dopt=Abstract oseltamivir Tamiflu



Tamiflu
Cost-effectiveness of vaccination versus treatment of influenza in healthy adolescents and adults.

Muennig PA, Khan K.

Program in Cost-Effectiveness and Outcomes, Robert J. Milano Graduate School, New School University, New York, NY 10011, USA. muennigp newschool.edu

At present time, there is uncertainty regarding whether influenza-like illness in healthy adults is best managed by preventive efforts that use the trivalent influenza vaccine, administration of neuraminidase inhibitors at the onset of illness, or recommendation of supportive care alone at the onset of illness. We conducted a cost-effectiveness analysis that examined these 3 strategies for managing influenza-like illness. Vaccination with inactivated trivalent vaccine would save approximately 25 dollars per person while resulting in a net gain of approximately 3.2 quality-adjusted hours relative to providing treatment with the neuraminidase inhibitor oseltamivir. A quality-adjusted hour is a fraction of a quality-adjusted life-year, which is the equivalent of 1 year lived in perfect health. Treatment with oseltamivir was associated with an incremental cost-effectiveness of approximately 27,619 dollars per quality-adjusted life-year gained relative to providing supportive care. Vaccination is cost-saving relative to providing either treatment with oseltamivir or providing supportive care alone.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11692300&dopt=Abstract oseltamivir Tamiflu



Tamiflu
Comparison of the activities of zanamivir, oseltamivir, and RWJ-270201 against clinical isolates of influenza virus and neuraminidase inhibitor-resistant variants.

Gubareva LV, Webster RG, Hayden FG.

Division of Epidemiology and Virology, Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA. lvg9b virginia.edu

RWJ-270201 is a novel cyclopentane inhibitor of influenza A and B virus neuraminidases (NAs). We compared the ability of RWJ-270201 to inhibit NA activity of clinical influenza isolates and viruses with defined resistance mutations with that of zanamivir and oseltamivir carboxylate. In NA inhibition assays with influenza A viruses, the median 50% inhibitory concentration (IC(50)) of RWJ-270201 (approximately 0.34 nM) was comparable to that of oseltamivir carboxylate (0.45 nM) but lower than that of zanamivir (0.95 nM). For influenza B virus isolates, the IC(50) of RWJ-270201 (1.36 nM) was comparable to that of zanamivir (2.7 nM) and less than that of oseltamivir carboxylate (8.5 nM). A zanamivir-resistant variant bearing a Glu119-to-Gly (Glu119-->Gly) or Glu119-->Ala substitution in an NA (N2) remained susceptible to RWJ-270201 and oseltamivir carboxylate. However, a zanamivir-selected variant with an Arg292-->Lys substitution in an NA (N2) showed a moderate level of resistance to RWJ-270201 (IC(50) = 30 nM) and zanamivir (IC(50) = 20 nM) and a high level of resistance to oseltamivir carboxylate (IC(50) > 3,000 nM). The zanamivir-resistant influenza B virus variant bearing an Arg152-->Lys substitution was resistant to each NA inhibitor (IC(50) = 100 to 750 nM). The oseltamivir-selected variant (N1) with the His274-->Tyr substitution exhibited resistance to oseltamivir carboxylate (IC(50) = 400 nM) and to RWJ-270201 (IC(50) = 40 nM) but retained full susceptibility to zanamivir (IC(50) = 1.5 nM). Thus, drug-resistant variants with substitutions in framework residues 119 or 274 can retain susceptibility to other NA inhibitors, whereas replacement of functional residue 152 or 292 leads to variable levels of cross-resistance. We conclude that RWJ-270201 is a potent inhibitor of NAs of wild-type and some zanamivir-resistant or oseltamivir-resistant influenza A and B virus variants.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11709315&dopt=Abstract oseltamivir Tamiflu