Introduction: Oseltamivir is an effective inhibitor ofneuraminidase enzyme of the influenza viruses A and B. The enzyme plays anvital role in the release and spread of progeny virions by cleaving the sialicacid residues on the newly formed virions. The degree of infection is limitedwithin the mucosal secretion upon the exposure to oseltamivir as the influenzavirions aggregate on the surface of the host cell(McNicholl 2001) . Osletamivir is the first choice as apreventive medicine in influenza patients with acute illness who are 1 year andolder and who are symptomatc not more than for 2 days.
H5N1 strains are sensitive against oseltamivir but lacksthe data on clinical efficacy. The neuraminidase inhibitors candecrease the duration of influenza related symptoms in 48hours of onset asrevealed by the clinical studies. If the treatment is stared within 48 hoursthe clinical efficacy is about 60-70% for symptoms such as , fever, andheadache and were reduced by approximately 0.
7 – 1.5 days (McNicholl 2001).. In febrile individuals the treatment iseffective when initiated with 30 hours of symptom. The inhibitor does not seem to negativelyaffect the the primary in vivo cellular immune responses to influenza virus infection (Burger 2000). The tolerance of oseltamivir is verywell reported but the only clinical important side effect being mildgastrointestinal upset (Doucette 2001).
Of late, the drug has been related tovast cases of physiological disorders and two teenage sucides in Japan.Although there is no evidence of relationship between oseltamivir intake andsuicide. Pharmacokineticsof Oseltamivir and OC: Thetherapeutic concentration of OC must be attained at all sites of infection andsustain for the period of dosing interval to limit the viral load andreplication. For this rationale, the pharmacokineticprofiles of oseltamivir and OC has been broadly studied in healthy individualsand infected patients.
Inter- andintra-subject variability across different geographic populations has also beenstudied. Absorption, distribution,metabolism and elimination Upon oral administrationof OP, oseltamivir is absorbed from the gastrointestinal tract and converted toactive metabolite OC by hepatic esterases and gives an absolute bioavailabilityof 80%. OC is noticeable within 30 min of dosing, and its concentration reachnear maximal level in 3-4 hours and exceeds the oseltamivir concentration by 20fold. The plasma concentration of OC exhibit minimal inter and intra subjectvariability and the associated foodintake has little effect on its bioavailability. The absorption rate of oseltamiviris impassive under altered gastric pH and that induced by cimetdine andantacids. The amount of circulationof OC after intravenous administration in man is 23-26 L. This value iscomparable of extracellular volume of body water in humans, signifying that themetabolite may penetrate infection site at volume similar to those in plasma.
In reality, oseltamivir and OC are relatively distributed with therapeuticconcentration reachin in lung, trachea and nasal mucosa, as well as the sinusesand middle ear. OC reached the lung and was detected in bronchoalveolar liningfluid with more or less exposure to that in plasma and a slower clearance in rats as confirmed by Eisenberg Oral administration of theprodrug results in 75% conversion in to OC by first-pass metabolism and 5% isrecovered in urine as OP. In in-vitro, neither of the drug interacts with humancytochrome P450 mixed function oxidases or glucuronyl transferases. Theelimination of OP and OC are mainly by renal excretion but small amounts arealso eliminated in faeces. Upon oraladministration of oseltamivir, the plasma concentration decrease rapidly (halftime of 1-3 h) , though OC concentrations remain for longer (half time of 6-10h), permitting two-dose daily. Renal clearance of both the compounds go abovethe glomerular filtration rate, signifying that renal tubular secretioncontributes to elimination; for OC, this has been shown to continue via theanionic transport process.
A high safety margin forOseltamivir have been shown in acute, subacute and chronic toxicity studies4. Dosing of oseltamivir till 500mg twice dailyresults in pharmacokinetics which are linear and dose proportional. Before theattainment of steady state, the accumulation of OC is noted to above 2 fold. The pharmacokinetics of multiple dosing can beenvisage from single dosing and it provides no sign of temporal change in the characterof either oseltamivir or OC Daily dosing of OC twiceresults in a steady state plasma concentration with 2-3 days. An latest research on pharmacokinetics of highdoses of oseltamivirs was studied in healthy Thai individuals. In adose-escalation study, 21 individuals got single doses of oseltamivir atrangeof 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 foroseltamivir and 5.1 (4.7–5.7) h for OC. One patient confirmed reducedconversion of oseltamivir into OC due to impaired carboxylesterase activity. Efficacy: Treatment: WhenOseltamivir dosing is initiated at volumes of 75mg for 5 days, in individualswho naturally acquired febrile influenza, within 36 hours of symptoms, theduration of disease can be reduced up to 1.
5 days and the severeness of illnessby 38%. Earlier commencement of therapy was linked with a faster resolution: i.e. beginning of treatment within first 12 hrafter the beginning of fever results in reduction of total median illnessduration 3 days before than intervention at 48 hours. Early dosing ofoseltamivir results in reduction of length of fever, the seriousness ofsymptoms and period to return to basline activity. Ifbody temperature was more than 39C it was an indication of a brief period offever.
The result of oseltamivir may beseen with 24 hours of commence of treatment. A research done by meta-analysisof 10 placebo-controlled, double-blind trials propose that cure of influenzawith oeltamivir lessen the lower respiratory tract complications, use of anti-bacterialand hospitalization in both healthy and susceptible individuals Patientswith underlining diseases such as chronic respiratory diseases or chroniccardiac diseases, the efficiency of oseltamivir is not very well stated. In an small randomised trial, oseltamivirradically reduced the rate of complication(11 % vs. 45 %) and antibioticuse(37 % vs. 69 %) in the treated group as compared with control group. The overall expenditure for treatment ofinfluenza and its complication was similar in the two groups.
The treatment of InfluenzaB is less effective with Oseltamivir as compared to Influenza A. In one of thestudies which included the epidemiological data as well as data from clinicaltrials of antivirals, it was concluded that oseltamivir treatments wascost-effective during the influenzaseason for un-vaccinated or high riskvaccinated patients, while for other patients the start of treatment relies onthe diagnostic testing.