ANTIMICROBIALS FOR VIRUSES

Their use is essential against pluriserotipic viruses or against latent infections : anyway in acute viroses replication usually preceed symptoms and antimicrobials can't prevent infection. They can interfere with ...





pharmacokinetics
schedule for pre- and post-exposure prophylaxis
schedule for therapy
side effects
benefits
resistance (de novo never recognized; frequency of emergence is lower than with M2 inhibitors : reduced transmissibility of NAI-resistant variants leads to negligible community spread of such variantsref. Partial cross-resistance between oseltamivir and zanamivir has been reported)
storages (% of population)
[WTO regulations allow for drug patents to be violated in the event of medical emergencies, providing the patent holder is compensated at a later dateref]
zanamivir / GG167 / 4-guanidino-Neu5Ac2en (Relenza®; source : GlaxoSmithKline (complete product information, revised on June 2004)), manufactured from a readily available starting material, N-acetyl-neuraminic-acid (NANA), approved in 1999. The lactose dose (80 mg per dose) is insufficient to cause symptoms in lactase-deficient individuals.
guanidino group => a dry powder that is self-administered via oral inhalation by using a plastic device (DiskHaler®) included in the package with the medication. Investigational formulations include nebulised mist, nasal spray, intravenous.
After inhalation of 10 mg :
  •  70-87% deposits in the oropharynx
  • 7-21% reaches the lungs
  • 4-17% is systemically absorbed (levels not therapeutic => may not be useful if extrapulmonary dissemination has occurred)
  • plasma half-life of 2.5-5.1 hours => excreted unchanged in the urine
  • unabsorbed drug is excreted in the feces 
  • oral absorption < 5%; so cannot be used in distressed airways
  • total bioavailability : 12-17% (7.8% in ferrets, 43% in mice)
  • Tmax : 0.75-1.5 hours
  • Cmax : 30-50 ng/ml
  • V of distribution : 16 l
  • IC50 NA H1 : 0.5-2.5 nmol/l
  • interacts with acidic residues Glu119, Glu227, and Asp151 in a previously unoccupied area within the active cleft of influenza NA
  • not approved by FDA, but meta-analyses of clinical trials have shown that it is highly effective for postexposure prophylaxis or early treatment in compliant patients with no underlying pulmonary diseaseref1, ref2 for persons aged > 5-7 years (depending on the country) : 2 inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) twice daily (approximately 12 hours apart) for 5 days : take
    2 doses on the first day of treatment whenever possible if there are at least 2 hours
    between doses. No dose adjustment for patients with either mild to moderate or severe impairment in renal function 
    while there were reports of bronchospasm post-release,
    trials specifically targeting patients with mild-to-moderate asthma or COPD showed that zanamivir was an effbctive treatment and had a similar safety profile to the inhaled lactose placeboref. There were no adverse eff-ect on pulmonary function, however, the pack insert reports that it is not recommended for treatment for patients with underlying airway disease unless used with caution under conditions of appropriate monitoring and supportive care (including the availability of short-acting inhaled bronchodilators) due to reports of >20% decline in FEV1. Oropharyngeal or facial edema have also been reported; no increased incidence of other side effects
    2-3 days of symptom relief in high-risk patients, those presenting with severe influenza-related
    symptoms or those who had symptoms for <30 hours.
    Older patients, aged >50 years, presenting with severe symptoms
    derived up to 7 days of benefit, as in this group, untreated patients
    experienced up to 11.5 days of symptoms; reduced nasal pro-inflammatory cytokine levelsref
    no definitive evidence is available regarding the safety or efficacy of zanamivir for persons with underlying respiratory or cardiac disease or for persons with complications of acute influenza. Anyway studies with nebulized and intravenous preparations suggest that zanamivir has good safety and efficacy, even in patients with underlying respiratory diseaseref1, ref2, ref3
    NA :
    E119G (>100 fold reduction in NA sensitivity; isolated in the strain NWS:G70C, a reassortant containing the HA of A:NWS:33 and NA of A:Tern:Australia:G70C:75
    (H1N9)ref, A:Turkey:Minnesota:
    833:80 (A:Turkey:Minn, H4N2)ref1, ref2 (Gubareva, L.V., Bethell, R.C., Penn, C.R., Webster, R.G., 1996. In vitro characterization of 4-guanidino-Neu5Ac2en -resistant mutants of influenza A virus. In:
    Brown, L.E., Hampson, A.W., Webster, R.G. (Eds.), Options for the control of Influenza III, Elsevier, Amsterdam, pp. 753–760.), the B:HK:Lee strain, a reassortant with the HA of B:HK:8:73 and NA of B:Lee:40ref, and B:Beijing:1:87 (B:Beijing)ref
  • E119A (>100 fold reduction in NA sensitivity)
  • E119D (>1000 fold reduction in NA sensitivity), all 3 from in vitro selection against A/H1N9, A/H4N2 and B (<= reduction in infectivity for animals)ref1, ref2, ref3, ref4, ref5
  • R152K from an immunocompromised child infected with influenzavirus B (> 1000 fold reduction in NA sensitivity, 60-fold reduction in infectivity for animals)ref
  • R292K from in vitro selection against A/H4N2 (10-30 fold reduction in NA sensitivity, 400 fold reduction in infectivity for animals)ref1, ref2
  • no isolates with reduced susceptibility to zanamivir have been reported from clinical trials, although the number of posttreatment isolates tested is limitedref and the risk for emergence of zanamivir-resistant isolates cannot be quantified
  • only Germany and India are storing zanamivir up in large quantities, although other European countries and the USA have some stocks. Shorter shelf-life than oseltamivir
    oseltamivir phosphate / GS4104 (Tamiflu®; developed from a rare natural compound, shikimic acid, and patented by Gilead Sciences, South San Francisco, until 2016, described in 1997ref; in 1996 Roche Holding AG acquired the worldwide rights to develop and market the drug : Tamiflu was FDA approved in 1999 and launched in North America (US and Canada) and Switzerland during 1999/2000. In all key European markets, it was launched by 2002/2003. Chugai Pharmaceutical Co., Ltd. distributes it in Japan; complete product information, revised on June 2004. Available in blister packages of 10 capsules (enough for a 5-day bid course per person) (cost US$34-60, but up to US$190 on some websitesref) or in glass bottles containing 25 ml of suspension after constitution equivalent to 300 mg oseltamivir base. Seasonal flu prevention requires at least six weeks of treatment -- that is 84 pills or about $1,600 of Tamiflu based on current pricesref

    Gilead Sciences, the original developer, still receives a royalty from Roche equaling about 10% of sales. 
    US Defense Secretary Donald Rumsfeld served as Gilead (Research)'s chairman from 1997 until he joined the Bush administration in 2001, and he still holds a Gilead stake valued at between $5 million and $25 million, according to federal financial disclosures filed by Rumsfeld. The forms don't reveal the exact number of shares Rumsfeld owns. Gilead made a loss in 2003, the year before concern about bird flu started. Then revenues from Tamiflu almost quadrupled, from $35 to $44.6m, helping put the company well into the black. Sales almost quadrupled again, to $161.6m in 2005. Mr Rumsfeld sold some of his Gilead shares in 2004 reaping - according to the financial disclosure report he is required to make each year - capital gains of > $5m (£2.9 m)ref. The report showed that he still had up to $25m-worth of shares at the end of 2004. Rumsfeld isn't the only political heavyweight benefiting from demand for Tamiflu, which is manufactured and marketed by Swiss pharma giant Roche (Gilead receives a royalty from Roche equaling about 10% of sales). Former Secretary of State George Shultz, who is on Gilead's board, has sold more than $7 million worth of Gilead since the beginning of 2005. Another board member is the wife of former California Gov. Pete Wilson. In July, the Pentagon ordered $58 million worth of the treatment for U.S. troops around the world, and Congress is considering a multi-billion dollar purchase. Rumsfeld recused himself from any decisions involving Gilead when he left Gilead and became Secretary of Defense in early 2001ref.
    Tamiflu is currently at the center of attention in e-mail spammingref

    bulky hydrophobic group => orally administered ethyl ester prodrug (absolute bioavailability = 80%; 30-73% in rodents, ferrets, dogs, and marmosets) converted by liver and gut carboxyesterases to the active metabolite oseltamivir carboxylate / GS4071 / Ro 64-0802 / 4-guanidino-2,4- dideoxy-2,3-dehydro- N-acetylneuraminic acid (4-guanidino-Neu5Ac2en). Oseltamivir activation by HCE1 is inhibited by 90% by clopidogrelref. Oseltamivir carboxylate detectable in plasma within 30 minutes and reaches maximal concentrations after 3 to 4 hours (350 ng/ml)
  • 3% of carboxylate binds to human plasma proteins (vs. 43% of phosphate). The bioavailability of oseltamivir phosphate and oseltamivir carboxylate were assessed in healthy volunteers when delivered as a solution of the API compared with the commercial capsule formulation. The IC90 for the ratios of the 2 treatments (capsule vs. solution) were within the reference region [0.80-1.25] for AUC0-infinity (0.94-0.99) and Cmax (0.93-1.08). Thus, the 2 formulations were bioequivalent for oseltamivir carboxylateref.
  • Tmax : 2.5-5 hours
  • V of distribution : 23-26 l
  • reaches therapeutic levels in many tissues, including the upper and lower respiratory tract
  • apparent plasma half-life of 6 to 10 hours
  • eliminated primarily by glomerular filtration and renal tubular secretion of the active metabolite via the anionic pathway. Neither compound interacts with CYP450s or glucuronosyltransferases. The pharmacokinetic profile of the active metabolite is linear and dose-proportional, with less than 2-fold accumulation over a dosage range of 50 to 500 mg twice daily. Steady-state plasma concentrations are achieved within 3 days of twice daily administration, and at a dosage of 75 mg twice daily the steady-state plasma trough concentrations of active metabolite remain above the MIC for all influenza strains tested. The IC50 and IC90 are in the range of 0.0008 mM to > 35 mM and 0.004 mM to > 100 mM, respectively (1 mM = 0.284 mg/ml) : IC50 NA H1 : 0.3-1.0 nmol/l. It binds through an interaction between the lipophilic 3-pentyloxy side chain and a hydrophobic pocket in the region corresponding to the glycerol subsite of sialic acid. Exposure to the active metabolite at steady state is approximately 25% higher in elderly compared with young individuals; however, no dosage adjustment is necessary. Exposures (AUCinf) to both the parent drug and active metabolite were increased by more than 80% in the small number of very elderly subjects presented here. However, oseltamivir was well tolerated by these subjectsref
  • a dosage reduction to 75 mg once daily is recommended for patients with creatinine clearance <30 ml/min (1.8 L/h) because renal clearance averages 23 hours and a single dose appears adequate for haemodialysis patients. For those with clearance rates < 10 ml/min caution should be used even at the lower doseref. A 30 mg dose of oseltamivir given once weekly in CAPD or after alternate sessions in HD patients provides sufficient exposure to oseltamivir carboxylate to allow safe and effective anti-influenza treatment and prophylaxisref
  • pharmacokinetics in patients with influenza are qualitatively similar to those in healthy young adults. In vitro and in vivo studies indicate no clinically significant drug interactions other than probenecid (proposed by some to lengthen plasma half-life in cases of drug shortageref1, ref2, a technique invented during the Second World War to extend precious penicillin supplies and that is still widely used alongside antibiotics to treat gonorrhoea and syphilis, and in emergency rooms, where doctors need their patients to have high, sustained levels of antibiotics in their blood : giving oseltamivir together with probenecid doubles the oseltamivir plasma half-life and maximum blood concentration, and multiplies 2.5-fold the patient's total exposure to the drug)ref1, ref2
  • initially in patients > 13 years of age, but for all ages since 21 Dec 2005ref : 75 mg capsules once dailyfor at least 7 days. Therapy should begin within 2 days of exposure. Safety and efficacy have been demonstrated for up to 6 weeks, but the duration of protection last for as long as dosing is continued.
    In healthy unvaccinated adults (aged 13 to 65 years), oseltamivir 75 mg once daily taken for 42 days during a community outbreak reduced the incidence of laboratory confirmed clinical influenza from 4.8% for the placebo group to 1.2% (>70% protective efficacy) and from 4.4% to 0.4% (92% protective efficacy) in vaccinated (80%) high-risk (14% had COPD, and 43% had cardiac disorders) elderly residents of skilled nursing homes. In a study of post-exposure prophylaxis in household contacts (aged 13 years) of an index case, oseltamivir 75 mg once daily administered within 2 days of onset of symptoms in the index case and continued for 7 days 
    reduced the incidence of laboratory confirmed clinical influenza from 12% in the placebo group to 1% for the oseltamivir group. Index cases did not receive oseltamivir in the studyref
    for people aged >= 1 year recommended treatment dosages for children vary by the weight of the child: 
  • <15 kg : 30 mg twice a day
  • 15-23 kg : 45 mg twice a day
  • 23-40 kg : 60 mg twice a day
  • >40 kg : 75 mg twice a day. 

  • The treatment dosage for persons aged >13 years is 75 mg capsules bid  for 5 days. It needs to be initiated within 2 days of symptom onset achieves and maintains plasma concentrations above the antiviral IC50 for laboratory strains of influenza A and B for 12 hours after a single 75 mg dose, but the relationship between the in vitro antiviral activity in cell culture and the inhibition of influenza virus replication in humans has not been establishedref.

    A liquid formulation of oseltamivir (2 mg/kg twice daily for 5 days) is effectiveref
    5 day courses of 150 mg twice daily for treatment and 6 week courses of 75 mg twice daily for prophylaxis are as well tolerated as the approved dose regimensref, giving a larger reduction in viral load in respiratory secretions, as well as a shorter duration of illness in human influenza infections. However, there is currently no evidence that this higher dose of oseltamivir equates with a significant clinical advantage over the standard dosageref1, ref2, ref3. In avian influenza a higher dose of oseltamivir should be considered in the group of patients with very severe disease and especially those having diarrhoea (which may impair drug absorption) or immunosuppressed patients (including the very young and very old) who may have a high initial viral load. Duration of treatment should be extended to 2 weeks since neutralising antibodies appear much later because most humans do not have prior exposure to H5N1

  • of the 75 case reports presented at the  FDA’s Pediatric Advisory Committee meeting of Nov 18, 2005, 92%, originated from Japanref 
  • 12 skin/hypersensitivity events discussed at the FDA’s Pediatric Advisory Committee meeting of Nov 18, 2005 
  • nausea (10% vs. 6% in placebo) and vomiting (9% vs. 3%; 14.3% vs. 8.5% in children) causing discontinuation in 1%, less likely when taken with a light snack (which doesn't significantly affect peak plasma levels or bioavailability), and resolve in 1–2 days despite continued drug administration in most people
  • slight increase in headache frequency was observed in one prophylaxis study in older people
  • worldwide : 42 people died in Japan after they took Tamiflu since 2000, but only 2 of the deaths -- a man in his 50's and another in his 80's -- resulted from using Tamifluref. The 14 children aged 1-16 years died because of suicide (1, one 1 hour after taking Tamifluref), sudden deaths (4), cardiac arrest (4) and pneumonia, asphyxiation and acute pancreatitis (3) (1 death per million Japanese children treated) and 32 suffered "neuropsychiatric events" (hallucinations, delirium, convulsions, and encephalitis. For 8 cases causal relation ruled out : 5 died of influenza-related encephalopathy (first reported by Japanese paediatricians in the 1990s, before oseltamivir was approved). Relationship was difficult to assess because of the use of other medications and/or presence of other diseasesref. A 12- and a 13-yrs old males jumped out of the second floor window of their homes after receiving 2 doses of Tamiflu, and a third 8-year old boy ran into the street because of frightening hallucinations 3 hours after receiving his first dose of Tamiflu and  was rescued by his family

  • from potential traffic injuryref. Tatsuo Kurokawa (2nd L), the health ministry official in charge of pharmaceutical matters, announces at a predawn news conference in Tokyo on March 21 2007 that the government has recommended against the use of Tamiflu among teenagers. After taking Tamiflu, 2 12-year-old boys apparently jumped off the 2nd floor of their houses and broke their legs in February and March. In February, a 14-year-old boy fell to his death at his condominium in Miyagi after apparently taking the drug while a 14-year-old girl died in similar circumstances in Aichiref. Separately, the EMEA’s Committee for Medicinal Products for Human Use requested at its Nov. 14-17 meeting that Roche provide a “cumulative safety review of all available data on serious psychiatric disorders, including all case reports with a fatal outcome where Tamiflu was involved,” after 2 cases of alleged suicides in adolescents reported to the EMEA. In Japan, oseltamivir is often dispensed as a powder in Japan, and mixed at the pharmacy, possibly contributing to higher dosing. The length of dosing may also be different, with Japanese patients possibly stopping administration before the recommended period, contributing to recrudescenceref. Roche commissioned Ingenix to investigate the safety of Tamiflu in 63,000 children (1-12 years old) and concluded that there “was no indication of an increased risk of neuropsychiatric events for children aged 1-12 over that already posed by influenza illness alone. A case report was published about the 22-yo Cape Coral resident Lianne Espositoref. In Dec 2005 2 new cases in Japan. A man in his 50s was hospitalized due to a rash he developed 2 days after starting Tamiflu. He died 10 days from toxic epidermal necrosis, which produced fever and MOF. He had also been taking antibiotics, cold medicine and herbal medicine. A man in his 80s was hospitalized for fatigue on the 5th day on Tamiflu and died 3 weeks later from kidney failure. He had been taking 2 types of medicines to treat high blood pressure and stomach problemsref.
    A single-dose of 1000 mg/kg of oseltamivir phosphate to 7-day-old rats causes 10-fold higher plasma levels and 1500-fold higher brain levels (3-fold for oseltamivir carboxylate) those found in adults because of blood-brain barrier immaturity, and results in deaths, while 2000 mg/kg do not cause effects in 14-day-old rats. No adverse effect occurred at 500 mg/kg/day administered to 7- and 21-day-old rats, at which exposure to prodrug is 800-fold that expected in a 1-year old child. 
  • haemorrhagic colitisref1, ref2
  • subcutaneous hemorrhagesref
  • from Jan. 1, 1999, to Oct. 31, 2005, Health Canada received 19 reports of increased INR (3.2 to 10.9) suspected of being associated with  oseltamivir, including patients aged 46 to 92 years (median age 84 years) with onset ranging from the day treatment was started to 11 days after starting oseltamivir. 11 of the reports were submitted by the same source and described a suspected interaction between oseltamivir and warfarin. Creatinine clearances were provided in these cases; dosage adjustments of oseltamivir were necessary in 3 cases, as recommended in patients with a creatinine clearance rate of 10-30 mL/min. 6 patients required treatment with vitamin K. At the time of reporting, 12 patients had recovered, 2 patients had not yet recovered, and the outcome was unknown for the remaining 5 patients. In 3 cases, the warfarin dose was increased after the introduction of oseltamivir; the increases in INR occurred following these dose changes. In 3 other cases, decreases in INR occurred during the course of oseltamivir therapy without a reported change in warfarin dose. In 2 cases, clarithromycin and levofloxacin respectively were reported as co-suspect medications; these drugs are known to interact with warfarin and may cause increases in INR. Available data indicate that the potential for drug interactions with oseltamivir is minimalref.
  • arrhythmiasref
  • anasarcaref
  • single doses of up to 1000 mg associated with nausea and/or vomiting
  • pneumoniaref
  • anaphylaxisref
  • reduces the median time to alleviation of all symptoms by 30% (3 vs. 4.3 days) and the median time to become afebrile by 38% (42.3 vs. 69.3 hours) compared with placebo (earlier initiation of therapy associated with faster resolution), reduces lower respiratory tract complications  resulting in antibiotic therapy, overall antibiotic use, and hospitalization in both healthy adolescents and adults (4.6% vs 10.3% with placebo, and 14.0% vs 19.1% with placebo, respectively) and "at-risk" adults (12.2% vs. 18.5% with placebo, and 0.7% vs. 1.7% with placebo, respectively) with a proven influenza illnessref, and flu-related death rates (-60-90% in children). >103 infectious units/mL of virus were detected in some of the patients who did not shed drug-resistant viruses, even after 5 days of treatmentref. Anyways zeroing of median virus titers occurs in 60 hrs vs. 108 hrs for influenzavirus A and in 24 vs. 72 hrs or influenzavirus B (Hayden F, et al. Efficacy of oral oseltamivir in experimental human influenza B virus infection. Poster presented at: 37th Annual Meeting of the Infectious Diseases Society of America; November 18-21, 1999; Philadelphia, Pa.). The durations of virus shedding from children treated with neuraminidase inhibitors were not significantly shorter than those of untreated patientsref.
    For later-stage intervention in severe influenza
    illness, please contact WHOinfluenza @who.int for information on clinical trial protocols. In studies of naturally acquired and experimental influenza, oseltamivir did not impair normal humoral antibody response to infection. Initiation of therapy within the first 12 h after fever onset reduced the total median illness duration by 74.6 h (3.1 days; 41%) >  intervention at 48 h. Intermediate interventions reduced the illness proportionately compared with 48 h. In addition, the earlier administration of oseltamivir further reduced the duration of fever, severity of symptoms and the times to return to baseline activity and health scoresref; reduced nasal pro-inflammatory cytokine levelsref. Effective and well tolerated in high-risk patients with chronic respiratory or cardiac diseasesref
    develops within day 4 in 8-12% of aged < 12 yrs, 1-4% in aged > 12 yrs, but viruses that develop resistance appear to be less virulent in laboratory animals and to replicate less efficiently than parent strainsref. Mutants detected in vitro by passage of virus in the presence of increasing concentrations (underlined mutants have been found also in clinical specimens : no drug-induced HA variants have been recognised to date)
    HAref1, ref2 :
  • H3N2 :
  • A28T 
  • R124M
  • reassortant human/avian virus H1N9 :
  • H154Q
  • NA [N2 numbering of aminoacid residues] :
  • N1
  • H274Y (104-105-fold more resistant, but replicative ability in cell culture was reduced up to 3 logs, as was infectivity in animal models)ref1, ref2
  • Asn294Ser (intermediate resistance)
  • I222T 
  • A/H3N2 :
  • Glu119Val (E119V) against A:Wuhan:359:95 (H3N2) (20-300-fold reduction in NA sensitivity, 100-1000 fold reduction in infectivity for animals) [Covington E, Mendel DB, Escarpe PA, Tai CY, Soderbarg K, Roberts NA. Phenotypic and genotypic assay of influenza virus neuraminidase indicates a low incidence of viral drug resistance during treatment with oseltamivir. II International Symposium on Influenza and other Respiratory Viruses (Dec 10–12, 1999, Grand Cayman); abstr]
  • I222T
  • Arg292Lys (R292K) (10,000 fold reduction in NA sensitivity, 100-1000 fold reduction in infectivity for animals)ref [Ives J, Caar J, Roberts N, et al. An oseltamivir-treatment selected influenza A/N2 virus with an R292K mutation in the neuraminidase gene has reduced infectivity in vivo. II International Symposium on Influenza and Other Respiratory Viruses (Dec 10–12, 1999, Grand Cayman); abstr; Covington E, Mendel DB, Escarpe PA, Tai CY, Soderbarg K, Roberts NA. Phenotypic and genotypic assay of influenza virus neuraminidase indicates a low incidence of viral drug resistance during treatment with oseltamivir. II International Symposium on Influenza and other Respiratory Viruses (Dec 10–12, 1999, Grand Cayman); abstr.]
  • N9 :
    • Glu119Val (E119V) (300-fold more resistant) 
    • R292K
    • R305Q 
    Tamiflu can relieve symptoms of human flu within 2 days, causing people to stop taking the drug early; this could encourage the growth of resistant viruses
  • 5-year shelf life for pills. Although buying the drug in bulk form as a powder would have been cheaper and would have extended the shelf life of the government stockpile, large containers of powder can't easily be converted into pills or capsules
  • WHO suggests countries should stockpile enough for > 25% of their population (a global stockpile of 3 million coursesref), but although Roche quadrupled its production capacity since 2003, the current supply is thought to cover just 2% of the world population and the most optimistic estimate of production in the next 5 years (300 million treatments a year by the end of 2006) gives enough to treat just 7%. Roche's discount for governments stockpiling Tamiflu is 50%ref. The API (Active pharmaceutical ingredient) is available at a significantly reduced price

  • (developed world: € 7.70 per 1 treatment course; developing world: € 7.00 per 1 treatment course) and Tamiflu caps purchased by governments for pandemic use are at a significant discount  (developed world: € 15.00 (US$18) per 1 treatment course; developing world: € 12.00 (US$ 15) per 1 treatment course) compared to the seasonal price (seasonal ex-factory price
    ranges between € 20 and € 51 in Europe)ref. 7 of the 13 sites involved in making Tamiflu are controlled by subcontractors : on Dec 9 Roche reached agreements with 2 US generic drugmakers (Teva Pharmaceuticals and Mylan Laboratories, Inc.), as well as 13 other drug producers. Roche donated the WHO's stockpile 125,000 packs in 2004 and, 3 million treatment courses in Aug 2005 (enough to delay spread in an affected nation according to models), and 2 million treatment courses in Jan 2006
  • worldwide : 33 million people already used it in countries including USA, Japan, Canada, Australia, the EU, Switzerland and Latin America.ref 
  • 23 developed countries stockpiled itref

  • USA : 5.5 million people (872, 386 pediatrics)  treated since 2001, 2.3 million 10-dose courses stockpiled, enough to treat < 1% of Americans, with plans to acquire another 2 million courses by the end of  2005, and projects for 80 million courses to cover about 25% of the population, but  Roche could provide only 13 million courses in 2006, followed by 70 million in 2007. On July 19, 2006, < 2 weeks before a federal deadline for states to announce their plans, at least 16 say they're undecided how much Tamiflu and Relenza they'll buy. 13 others — including California, the biggest state — say they plan to buy their full allotments. The federal government plans to buy 44 million antiviral treatment courses for the states this fiscal year and next, enough to cover 17% of their populations. It wants states to buy 31 million more courses, to reach 25%. Even at a discount — about $15 for Tamiflu, about 20% of the Internet retail rate — cost is a concern. Arizona plans to spend $1 million for 70,000 courses. The state's full allotment of 585,780 courses would cost about $8 million, draining funds needed to prepare hospitals. Colorado plans to buy 5,400 courses — not the 477,470 allotted to it. Arizona and Nebraska are trying to get local entities to pay for more anti-virals. So is Oklahoma, which now plans to buy 9% of its allotment but may increase it. Montana and North Dakota also don't plan to buy full allotments. Other states didn't respond. The Aug. 1 deadline will help drugmakers plan, but states can change orders through Dec. 31. Businesses cannot buy the drugs at the federal discountref.
  • Canada : 16 million pills, enough for 1.2 million people
  • China : Shanghai Pharmaceutical Co., Ltd. reached a sublicensing deal with Roche on Dec 11
  • Hong Kong : 3.7 million caps (for 6.8 million people), wants to buy 16.8 million more
  • Viet Nam : 25 million tablets,  600,000 donated by Taiwan in July 2004, 420,000 allocated to hospitals; sale to privates banned to prevent overuse; local production permitted by Roche;
  • Romania : 20,000 (2,400 packs) doses donated by Roche in Oct 2005
  • Brazil : 90 million doses
  • Georgia will reserve Tamiflu for 4000 people within end of January 2006ref
  • Slovenia : for 25% of population
  • Turkey : 500,000 boxes requested, 5,000 donated by Roche in Oct 2005
  • Greece : enough to supply 5% of the country's 11 million people
  • Italy : 170,000 courses available; 50,000 more at March 2006. 4 million couses ordered on Feb 11, enough for 7 million people (4 million (60%) as treatment and 3 millions for PEP)
  • Taiwan : 1 million treatments available, 1.3 millions to be delivered in 2006, covering 10% of  population
  • Japan : 24.5 million patients (11.6 mil pediatrics) treated since 2001 with 8-10 million patients prescribed the medicine each year (about 70% of the world demand). Domestic sales totaled 35.2 billion yen in 2005. Chugai Pharmaceutical is securing enough Tamiflu for the October 2005- March 2006 flu season to treat 12 million people for 5 days. Of that amount, about one-third is in syrup form. Stockpiles to provide a 3 day course for 25 million people. Currently, Chugai imports ingredients from Germany for inspections, sends them to Switzerland for syrup production and imports them for packaging and sales. Domestic production will be less expensive. Chugai Pharmaceutical has been increasing its supply of Tamiflu since a shortage occurred in the winter season from 2002 to 2003ref
  • India : Cipla Ltd offered to pay Roche and Gilead a 4% royalty on the sale of oseltamivir but after denial she launched a generic on Feb 2006, priced at about Rs 1,000 per strip (650/pack to the wholesaler, exclusive of taxesref) of 10 tablets, in 49 countries where the patent is not applicableref. Cipla will sell Antiflu® for about $12ref. The company has the capacity to produce 100,000 packs of the medicine. Ranbaxy Laboratories Ltd. (RLL) could provide the generic to USA, but on Dec 22 Hyderabad-based  Hetero Drugs Ltd. bag the sub-license granted by Roche to make make 100,000 caps by the end of Dec 2005, 900,000 by the end of Jan 2006, and 20 million caps within Apr 2006 for exports. About 50,000 doses of Tamiflu have already been stockpiled, another 20,000 doses will be delivered at the end of Feb 2006, another 30,000 doses at the end of Marchref
  • Kenya : 2,000 dosesref
  • Korea : 5 companies, including Chongkeundang Corp., Hanmi Pharm Co. and Shinpoong Pharmaceutical Co., said they have successfully produced Tamifluref.
  • UK : 4 million courses on Jan 9 2006, growing by 800,000 doses a month. The 14.6 million target is likely to be reached in late summer 2006 at a cost of pounds 200 million
  • France : in 2005 13.8 million doses Tamiflu and Relenza (33 million in 2007) and 200 million professional-quality face masks (1 billion by the end of 2006) and 40 million doses reserved for vaccine against the transformed H5N1 virus
  • Algeria : 7 million dosesref. On Feb 15, 2006 Algerian state pharmaceuticals group Saidal will sign an agreement with India's Hetero Drugs to produce  6 million doses of Saiflu®ref
  • Jordan : 60,000 dosesref

  • Kuwait : 5 million dosesref; 10 million capsules, which are sufficient to treat about 40% of the 
    population of 3 millionref
  • Australia : coverage for almost 44%
  • Malaysia : 600,000 tablets 

  • Roche has no patents in :
  • Thailand : 1 million capsules for 100,000 treatments, but 120 million caps needed. Government Pharmaceutical Organization (GPO) has permission to produce 400,000 capsules a day of a generic that will cost 70 baht vs. 120 baht for a Tamiflu capref. The first 200,000 tablets were successfully manufactured on Feb 19 and will be available to the public in July 2006 at 70 baht per tablet, cheaper by 50 baht per unit, compared to the 120 baht per capsule of imported Oseltamivir. GPO is capable of producing about 1 million tablets of the anti-bird flu drug, sufficient for treating up to 100,000 patients, within 15 daysref.
  • Philippine received a donation from the Unilab enough to treat about 50,000 people, and 75,000 capsules from Roche, with another 25,000 to 35,000 expected in Jan 2006
  • Indonesia bought 400,000 tablets, enough to treat 40,000 people; 800,000 tablets provided by Australia, Japan and Singapore. Kimia Farma or Indofarma will produce 20 million tablets for domestic market (to cover 10% of population) starting from shikimic acid derived via fermentation or from the pod of the star-shaped anise fruit exported from Guangzhou, Chinaref. 5 of the 12 stages in the sseltamivir manufacturing process would be carried out by the private South Korean pharmaceutical company, Daewoong Chemical and 7 in Indonesia
  • Roche asked the European Medicines Agency, which regulates the use of drugs in Europe, to approve 2 smaller capsules - 30 mg and 45 mg - and planned a similar filing soon with the Food and Drug Administration in the USA. Roche has been granted an accelerated review and is optimistic that EMEA will complete their evaluation by mid 2007. The new capsules would be in addition to the 75 mg dosages already approved and will be easier to use than the liquid suspension already available for children. The capsules also will have a longer shelf life than the liquidref.
    The anti-influenza drug oseltamivir is an ester prodrug activated by hepatic carboxylesterases. Plasma esterases also convert up to 31.8% of the parent compound to the active metabolite after 4 h ex vivo, with wide interindividual variation. This source of error is removed by adding the esterase inhibitor dichlorvos to blood collection tubesref.
    Ferrets were protected from lethal infection with the A/Vietnam/1203/04 (H5N1) virus by oseltamivir 5 mg/kg/day given 4 h after virus inoculation, but higher daily doses (25 mg/kg) were required for treatment when initiated 24 h after virus inoculation. For the treatment of ferrets inoculated with the less pathogenic A/Turkey/15/06 (H5N1) virus, 10 mg/kg/day of oseltamivir was sufficient to reduce the lethargy of the animals, significantly inhibit inflammation in the upper respiratory tract, and block virus spread to the internal organs. Importantly, all ferrets that survived the initial infection were re-challenged with homologous virus after 21 days and were completely protected from infection. Direct sequencing of the NA or HA1 gene segments in viruses isolated from ferret after treatment showed no amino acid substitutions known to cause drug resistance in conserved residues. Thus, early oseltamivir treatment is crucial for protection against highly pathogenic H5N1 viruses and that higher dose may be needed for the treatment of more virulent virusesref.
    An influenza B virus from an infant with no history of treatment or contact with neuraminidase inhibitors demonstrated a significant reduction in sensitivity to these drugs. A mixed viral population was isolated that contained a novel D197E amino acid substitution that was responsible for this reductionref
    The impact of various NA mutations (E119A/G/V, H274Y, R292K and N294S) on the susceptibility profiles to different NAIs (oseltamivir, zanamivir and peramivir) was evaluated using recombinant NA proteins of influenza A/WSN/33 (H1N1) and A/Sydney/5/97-like (H3N2) viruses. In the Nl subtype, the E119V mutation conferred cross-resistance to oseltamivir, zanamivir and peramivir [1,727-2,144 and 5,050-fold increase in IC50 values compared with wild-type (WT)] whereas only oseltamivir-resistance (1,028-fold increase in IC50) was conferred by the same mutation in the N2 subtype. The N294S mutation conferred resistance to oseltamivir in both the NI and N2 subtypes (197- and 1,879-fold increase in IC50 values, respectively) whereas the H274Y mutation conferred resistance to oseltamivir (754-fold increase) and peramivir (260-fold increase) in the N1 subtype only. The virulence of reverse genetics-rescued A/WSN/33 viruses harbouring H274Y and N294S NA mutations was investigated in Balb/c mice. The WT and H274Y recombinants had identical LD50 values (103 PFUs) and generated similar viral lung titres, whereas a higher LD50 (10 PFUs) and a 1-log decrease in viral lung titres were obtained with the N294S mutant. This study shows that some NA mutations at framework residues may confer resistance to 1 or 3 NAIs depending on the viral subtype. It suggests that certain drug-resistant NA mutants may still be virulent although additional studies using clinical isolates are needed to confirm these resultsref.
    Desensitization therapyref1, ref2, ref3.
    During the lytic form of infection, 2 virally encoded kinases, the HHV-4 / EBVthymidine kinase (EBV-TK) and the BGLF4 gene product, which phosphorylate the prodrug GCV and convert it into its active cytotoxic form, are expressed. Phosphorylated GCV inhibits not only the virally encoded DNA polymerase but also the cellular DNA polymerase, leading to premature termination of the nascent DNA and cell deathref1, ref2, ref3. In addition, phosphorylated GCV can be transferred to adjacent cells, thus inducing "bystander" killingref. Lytic EBV infection also confers sensitivity to the cytotoxic effects of zidovudine (AZT), possibly by inducing AZT phosphorylationref1, ref2, ref3, ref4.
    Side effects : myelosuppression, urticaria
    Desensitization therapyref
    Side effects : Fanconi syndromeref
    Web resources : Bibliography :
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