Introduction: very well reported but the only clinical important



Oseltamivir is an effective inhibitor of
neuraminidase enzyme of the influenza viruses A and B. The enzyme plays an
vital role in the release and spread of progeny virions by cleaving the sialic
acid residues on the newly formed virions. The degree of infection is limited
within the mucosal secretion upon the exposure to oseltamivir as the influenza
virions aggregate on the surface of the host cell(McNicholl 2001) .

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Osletamivir is the first choice as a
preventive medicine in influenza patients with acute illness who are 1 year and
older and who are symptomatc not more than for 2 days. H5N1 strains  are sensitive against oseltamivir but lacks
the data on clinical efficacy.


The neuraminidase inhibitors can
decrease the duration of influenza related symptoms in 48hours of onset as
revealed by the clinical studies. If the treatment is stared within 48 hours
the clinical efficacy is about 60-70% for symptoms such as , fever, and
headache and were reduced by approximately 0.7 – 1.5 days (McNicholl 2001)..  In febrile individuals the treatment is
effective when initiated with 30 hours of symptom.  The inhibitor does not seem to negatively
affect the the primary in vivo cellular immune responses to influenza virus infection (Burger 2000).


The tolerance of oseltamivir is very
well reported but the only clinical important side effect being mild
gastrointestinal upset (Doucette 2001). Of late, the drug has been related to
vast cases of physiological disorders and two teenage sucides in Japan.
Although there is no evidence of relationship between oseltamivir intake and



of Oseltamivir and OC:


therapeutic concentration of OC must be attained at all sites of infection and
sustain for the period of dosing interval to limit the viral load and
replication.  For this rationale, the pharmacokinetic
profiles of oseltamivir and OC has been broadly studied in healthy individuals
and infected patients.  Inter- and
intra-subject variability across different geographic populations has also been


Absorption, distribution,
metabolism and elimination


Upon oral administration
of OP, oseltamivir is absorbed from the gastrointestinal tract and converted to
active metabolite OC by hepatic esterases and gives an absolute bioavailability
of 80%. OC is noticeable within 30 min of dosing, and its concentration reach
near maximal level in 3-4 hours and exceeds the oseltamivir concentration by 20
fold. The plasma concentration of OC exhibit minimal inter and intra subject
variability  and the associated food
intake has little effect on its bioavailability. The absorption rate of oseltamivir
is impassive under altered gastric pH and that induced by cimetdine and


The amount of circulation
of OC after intravenous administration in man is 23-26 L. This value is
comparable of extracellular volume of body water in humans, signifying that the
metabolite may penetrate infection site at volume similar to those in plasma.
In reality, oseltamivir and OC are relatively distributed with therapeutic
concentration reachin in lung, trachea and nasal mucosa, as well as the sinuses
and middle ear. OC reached the lung and was detected in bronchoalveolar lining
fluid with more or less exposure to that in plasma and a slower clearance  in rats as confirmed by Eisenberg


Oral administration of the
prodrug results in 75% conversion in to OC by first-pass metabolism and 5% is
recovered in urine as OP. In in-vitro, neither of the drug interacts with human
cytochrome P450 mixed function oxidases or glucuronyl transferases. The
elimination of OP and OC are mainly by renal excretion but small amounts are
also eliminated in faeces.  Upon oral
administration of oseltamivir, the plasma concentration

decrease rapidly (half
time of 1-3 h) , though OC concentrations remain for longer (half time of 6-10
h), permitting two-dose daily. Renal clearance of both the compounds go above
the glomerular filtration rate, signifying that renal tubular secretion
contributes to elimination; for OC, this has been shown to continue via the
anionic transport process.


A high safety margin for
Oseltamivir have been shown in acute, subacute and chronic toxicity studies4.  Dosing of oseltamivir till 500mg twice daily
results in pharmacokinetics which are linear and dose proportional. Before the
attainment of steady state, the accumulation of OC is noted to above 2 fold.  The pharmacokinetics of multiple dosing can be
envisage from single dosing and it provides no sign of temporal change in the character
of either oseltamivir or OC


Daily dosing of OC twice
results in a steady state plasma concentration with 2-3 days. An             latest research on pharmacokinetics of high
doses of oseltamivirs was studied in healthy Thai individuals. In a
dose-escalation study, 21 individuals got single doses of oseltamivir at
rangeof four increasing dose levels, giving a total of 125 individual series.
The tolerance limit was established at 675mg. Pharmacokinetics were dose linear,
with rapid absorption and conversion (median¼93%) into OC. Median 95%
confidence interval (CI) elimination half-lives were 1.0 (0.9–1.1) h for
oseltamivir and 5.1 (4.7–5.7) h for OC. One patient confirmed reduced
conversion of oseltamivir into OC due to impaired carboxylesterase activity.








Oseltamivir dosing is initiated at volumes of 75mg for 5 days, in individuals
who naturally acquired febrile influenza, within 36 hours of symptoms, the
duration of disease can be reduced up to 1.5 days and the severeness of illness
by 38%. Earlier commencement of therapy was linked with a faster resolution:  i.e. beginning of treatment within first 12 hr
after the beginning of fever results in reduction of total median illness
duration 3 days before than intervention at 48 hours. Early dosing of
oseltamivir results in reduction of length of fever, the seriousness of
symptoms and period to return to basline activity.


body temperature was more than 39C it was an indication of a brief period of
fever.  The result of oseltamivir may be
seen with 24 hours of commence of treatment. A research done by meta-analysis
of 10 placebo-controlled, double-blind trials propose that cure of influenza
with oeltamivir lessen the lower respiratory tract complications, use of anti-bacterial
and hospitalization in both healthy and susceptible individuals  



with underlining diseases such as chronic respiratory diseases or chronic
cardiac diseases, the efficiency of oseltamivir is not very well stated. In  an small randomised trial, oseltamivir
radically reduced the rate of complication(11 % vs. 45 %)  and antibiotic
use(37 % vs. 69 %) in the treated group as compared with control group.  The overall expenditure for treatment of
influenza and its complication was similar in the two groups.


The treatment of Influenza
B is less effective with Oseltamivir as compared to Influenza A. In one of the
studies which included the epidemiological data as well as data from clinical
trials of antivirals, it was concluded that oseltamivir treatments was
cost-effective during  the influenza
season  for un-vaccinated or high risk
vaccinated patients, while for other patients the start of treatment relies on
the diagnostic testing.