Jinay Patel Shubham Garg Ishita Rupapra

PROJECT ON SWINE FLU DRUGS

Contents:- What is swine flu, Tamiflu, Relenza and the drug properties.

What is Swine Flu? Swine Influenza also known as H1N1 flu, Swine flu, Pig and Hog flu is a respiratory disease caused by virus commonly found in pigs throughout the world. Most commonly it is due to H1N1 influenza subtype but sometimes H1N2, H3N1, and H3N2 can also be responsible. The major difference is that the current virus has strains of bird and pig viruses in it, and humans have very low or negligible immunity to it. That is what has made it more likely to become a pandemic virus (that can cause a global outbreak) as it could easily spread from human to human. Swine flu can look like a normal fever as its symptoms are similar to normal human influenza like cold and cough, sore throat, body aches, headaches, chills and fatigue. If diagnosed, earlier treatment can be done to avoid further complications. For confirmed case of Swine flu Oseltamivir (Tamiflu) or zanamivir (Relenza) are administered for treatment of virus infection.

Types: The Influenza viruses causing sickness in humans are classified into three types - A, B and C. Type A is most common in pigs and C is rare. Influenza B has not been reported in pigs. Swine influenza is commonly of the H1N1 influenza subtype, but sometimes they can come from other types, such as H1N2, H3N1, and H3N2.The recent outbreak of swine flu in humans is of the H1N1 type which is not as dangerous as some other types. It is caused by a new virus that has changed in ways that allow it to spread from person to person and its happening among people who havent had any contact with pigs. Normally swine flu virus does not transmit from pigs to human and do not cause swine flu, although if it happens, antibodies are produced in human blood. Its official name or scientific name is H1N1 influenza A. The H means hemagglutinin and the N means neuraminidase and the 1s refer to their antibody type. Influenza A is a genus of the Orthomyxoviridae family of viruses, and refers to the fact that the virus
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is first identified in an animal, usually a pig or a bird. When put together, they describe the 2009-2010 swine flu virus.

History of H1N1(swine flu) Virus Swine influenza is not a new disease. It was first diagnosed in the year 1918. It was not clear then that whether human contracted the virus from pigs or pigs contracted it from humans. Somewhere between 20-40 million people died from Spanish Flu or La Grippe which were the two names for it. To this day it is still unclear whether the strain was swine influenza or not. In the year 1976 on Feb06 ,4 comrades were hospitalized and their fellow army recruit died. The cause of his death came out to be a new strain of influenza with was a variant of H1N1 and was known as A/New Jersey/1976 as told by the health officials 2 weeks later. In between a new strain was discovered which was A/Victoria/75 (H3N2). President Gerald Ford made every person gets vaccinated against the disease to prevent people from another epidemic.This all came to a halt by Gullain-Barre

Syndrome which was a side effect result from a modern influenza vaccine. Initially 25 people had died of the vaccine, which lead to the death of more people and which over a period of time spread over to a large population base. Again later in the year 1998, this virus was found in pigs across four US States and within a year it had spread through pig populations across the US. Now, the current outbreak of the virus is in year 2009. This outbreak is due to a new strain of subtype H1N1 which was not previously reported in pigs. It appears as if this outbreak was transmitted from humans to pigs and then back to us as the same as the 1918 pandemic.

H1N1 Symptoms *fever, which is usually high, but unlike seasonal influenza, is sometimes absent. * cough. * runny nose or stuffy nose. * sore throat. * body aches.
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* headache. * chills. * fatigue or tiredness, which can be extreme. * Neurological problems . * diarrhea and vomiting, sometimes, but more commonly seen than with seasonal flu.

In Children * Fast and hard breathing * Skin color turning blueish. * Not drinking enough fluids and unable to eat * Not interacting properly * Being so irritable that the child does not want to be held * Flu-like symptoms that improve and return with fever and cough * Fever with a rash * Having no tears when crying

In Adults:

* Difficult and short of breath * Pain in the chest or abdomen * Sudden and regular dizziness * Severe or persistent vomiting or vomiting sensation. * Low temperature

THE HISTORY OF Oseltamivir (Tamiflu) Tamiflu was the first orally active neuraminidase inhibitor developed commercially. Gilead Sciences developed the drug, but Roche marketed it under its current trade name. In 1999, the FDA approved Tamiflu for the treatment of the flu in people ages one and older, and for the prevention of the flu in adolescents and adults. At first, the drug's sales were unimpressive. However, fears of an avian flu pandemic and the subsequent international stockpile of Tamiflu led to a spike in Roche's profits. The company went from $76 million in sales of the drug in 2001 to $700 million in 2005.
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What is Tamiflu? Tamiflu (oseltamivir) is an antiviral medication that blocks the actions of influenza virus types A and B in your body. Tamiflu is used to treat flu symptoms caused by influenza virus in patients who have had symptoms for less than 2 days. Tamiflu may also be given to prevent influenza in people who may be exposed but do not yet have symptoms. This medicine will not treat the common cold. Tamiflu, is an antiviral drug, which may slow the spread of influenza (flu) virus between cells in the body by stopping the virus from chemically cutting ties with its host cell. Oseltamivir is a prodrug, a (relatively) inactive chemical, which is converted into its active form by metabolic process after it is taken into the body.

Methods of synthesis of Tamiflu and their Merits Hoffmann-La Roche process (Starting from Shikimic Acid or Quinic Acid) Current commercial synthesis method Karpf / Trussardi synthesis (Azide free synthesis)

Corey synthesis (From butadiene and acrylic acid) Shibasaki synthesis (From Shikimic Acid) Fukuyama synthesis (From pyridine and acrolein)

Trost synthesis (Shortest route of synthesis up till date)

TAMIFLU is a prescription medicine used to:

treat the flu (influenza) in people 2 weeks of age and older who have had flu symptoms for no more than two days. prevent the flu in people who are 1 year of age and older.

It is not known if TAMIFLU is:

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effective in people who start treatment after 2 days of developing flu symptoms. effective for the treatment of the flu in people with long-time (chronic) heart problems or breathing problems. effective for the treatment or prevention of flu in people who have weakened immune systems (immunocompromised). safe and effective for the treatment of the flu in children less than 2 weeks of age. safe and effective in the prevention of the flu in children less than 1 year of age. TAMIFLU does not treat or prevent illness that is caused by infections other than the influenza virus. TAMIFLU does not prevent bacterial infections that may happen with the flu.

Tamiflu side effects

Stop using this medicine and get emergency medical help if you have any of these signs of an allergic reaction to Tamiflu: hives; difficulty breathing; swelling of your face, lips, tongue, or throat; a red and blistering or peeling skin rash. Some people using Tamiflu have had rare side effects of sudden confusion, delirium, hallucinations, unusual behavior, or self-injury. These symptoms have occurred most often in children. It is not known whether oseltamivir was the exact cause of these symptoms. However, anyone using this medicine should be watched closely for signs of confusion or unusual behavior. Call a doctor at once if you or the child using Tamiflu has any of these symptoms. Less serious Tamiflu side effects may include:

nausea, vomiting, diarrhea; dizziness, headache; nosebleed; eye redness or discomfort; sleep problems (insomnia); or cough or other respiratory symptoms.

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Chemical properties IUPAC Name: ethyl (3R,4R,5S)-4-acetamido-5-amino3-pentan-3-yloxycyclohexene-1-carboxylate

TAMIFLU (oseltamivir phosphate) is available as capsules containing 30 mg, 45 mg, or 75 mg oseltamivir for oral use, in the form of oseltamivir phosphate, and as a powder for oral suspension

Dissociation Constants: pKa = 7.7 at 25 deg C (primary amine) Solubility: In water, 1.6X10+3 mg/L at 25 deg C (est) Vapor Pressure: 1.3X10-8 mm Hg at 25 deg C (est) Mol wt: 410.40. White crystalline solid H-Bond Donor:- 2 H Bond Acceptor:- 5 Exact Mass 312.204907 g/mol

DRUG DESCRIPTION

TAMIFLU (oseltamivir phosphate) is available as capsules containing 30 mg, 45 mg, or 75 mg oseltamivir for oral use, in the form of oseltamivir phosphate, and as a powder for oral suspension, which when constituted with water as directed contains 6 mg/mL oseltamivir base. In addition to the active ingredient, each capsule contains pregelatinized starch, talc, povidone K30, croscarmellose sodium, and sodium stearyl fumarate. The 30 mg capsule shell contains gelatin, titanium dioxide, yellow iron oxide, and red iron oxide. The 45 mg capsule shell contains gelatin, titanium dioxide, and black iron oxide. The 75 mg capsule shell contains gelatin, titanium dioxide, yellow iron oxide, black iron oxide, and red iron oxide. Each capsule is printed with blue ink, which includes FD&C Blue No. 2 as the colorant. In addition to the active ingredient, the powder for oral suspension contains sorbitol, monosodium citrate, xanthan gum, titanium dioxide, tutti-frutti flavoring, sodium benzoate, and saccharin sodium.

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Oseltamivir phosphate is a white crystalline solid with the chemical name (3R,4R,5S)-4-acetylamino-5amino3(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid, ethyl ester, phosphate (1:1). The chemical formula is C16H28N2O4 (free base). The molecular weight is 312.4 for oseltamivir free base and 410.4 for oseltamivir phosphate salt. The structural formula is as follows:

Quality Control of Tamiflu:-

HOW SUPPLIED Dosage Forms And Strengths Capsules: 30 mg, 45 mg, 75 mg 30-mg capsules (30 mg free base equivalent of the phosphate salt): light yellow hard gelatin capsules. ROCHE is printed in blue ink on the light yellow body and 30 mg is printed in blue ink on the light yellow cap. 45-mg capsules (45 mg free base equivalent of the phosphate salt): grey hard gelatin capsules. ROCHE is printed in blue ink on the grey body and 45 mg is printed in blue ink on the grey cap. 75-mg capsules (75 mg free base equivalent of the phosphate salt): grey/light yellow hard gelatin
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capsules. ROCHE is printed in blue ink on the grey body and 75 mg is printed in blue ink on the light yellow cap. For Oral Suspension: 6 mg/mL (final concentration when constituted) White powder blend for constitution to a white tuttifruttiflavored suspension. After constitution, each bottle delivers a usable volume of 60 mL of oral suspension equivalent to 360 mg oseltamivir base (6 mg/mL).

Storage And Handling TAMIFLU Capsules 30-mg capsules (30 mg free base equivalent of the phosphate salt): light yellow hard gelatin capsules. ROCHE is printed in blue ink on the light yellow body and 30 mg is printed in blue ink on the light yellow cap. 45-mg capsules (45 mg free base equivalent of the phosphate salt): grey hard gelatin capsules. ROCHE is printed in blue ink on the grey body and 45 mg is printed in blue ink on the grey cap. 75-mg capsules (75 mg free base equivalent of the phosphate salt): grey/light yellow hard gelatin capsules. ROCHE is printed in blue ink

on the grey body and 75 mg is printed in blue ink on the light yellow cap. Storage Store the capsules at 25C (77F); excursions permitted to 15 to 30C (59 to 86F)

Indications and Limitations of Use TAMIFLU is indicated for the treatment of acute, uncomplicated illness due to influenza infection in patients 2 weeks of age and older who have been symptomatic for no more than 2 days. TAMIFLU is also indicated for the prophylaxis of influenza in patients 1 year and older. Efficacy of TAMIFLU in patients who begin treatment after 48 hours of symptoms has not been established. TAMIFLU is not a substitute for early and annual vaccination as recommended by the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices. There is no evidence for efficacy of TAMIFLU in any illness caused by agents other than influenza virus types A and B.
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Influenza viruses change over time. Emergence of resistant mutations could decrease drug effectiveness. Other factors (for example, changes in viral virulence) might also diminish clinical benefit of antiviral drugs. Prescribers should consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use TAMIFLU.

Limitations of populations studied Efficacy of TAMIFLU in the treatment of influenza in patients with chronic cardiac disease and/or respiratory disease has not been established. No difference in the incidence of complications was observed between the treatment and placebo groups in this population. No information is available regarding treatment of influenza in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring hospitalization. Efficacy of TAMIFLU for treatment or prophylaxis of influenza has not been established in immunocompromised patients.

Safety and efficacy of TAMIFLU for treatment of influenza in pediatric patients less than 2 weeks of age have not been established. Safety and efficacy of TAMIFLU for prophylaxis of influenza have not been established for pediatric patients less than 1 year of age. Concurrent use with live attenuated influenza vaccine The concurrent use of TAMIFLU with live attenuated influenza vaccine (LAIV) intranasal has not been evaluated. However, because of the potential for interference between these products, LAIV should not be administered within 2 weeks before or 48 hours after administration of TAMIFLU, unless medically indicated. Most common adverse reactions The safety profile observed in pediatric patients 2 weeks to less than 1 year of age was consistent with the established safety profile of pediatric subjects aged 1 year and above, with vomiting, diarrhea, and diaper rash being the most frequently reported adverse reactions. Patients who may benefit from Tamiflu
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The CDC recommends initiation of antiviral treatment as early as possible (within the first 2 days of symptom onset) for any patient who: Is at higher risk of influenza complications, including children <2 years of age. Is not at high risk but presents with confirmed or suspected influenza.

Antiviral therapies such as Tamiflu may: Reduce the severity of illness. Shorten the duration of illness. Encourage swift action for patients who may benefit from Tamiflu. To be effective at treating and reducing the duration of influenza symptoms, Tamiflu treatment should be initiated within 48 hours of the onset of flu symptoms.

ZANAMIVIR (RELENZA)

IUPAC Name: (2R,3R,4S)-3-acetamido-4(diaminomethylideneamino)-2-[(1R,2R)-1,2,3-

trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylic acid The active component of RELENZA is zanamivir Color/Form:- White to off-white powder Melting Point:- 256 deg C Solubility:- In water, 18,000 mg/L at 25 deg C Vapor Pressure:- 4.4X10-18 mm Hg at 25 deg C (est)

Conclusion (Drug Resistance)

Influenza virus is a constantly mutating virus. Because of its high frequency of mutations, leading
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to change of its structure, it escapes immunity that humans develop against the virus. Recently, it has also been reported to have developed resistance to anti-viral drugs. So far, cases of viral resistance have been reported only against Tamiflu, whereas no viral resistance has been observed against Relenza, a finding that can have very significant implications in favor of Relenza in the long run.

Recently, both the Center for Disease Control and Prevention (CDC) and the World Health Organization (WHO) have acknowledged in their reports that there is widespread resistance to Tamiflu in treating the H1N1 virus, the strain that caused the 2009 flu pandemic, with almost 99.6 % samples being resistant, against only 12% resistance an year earlier. The high incidence of viral resistance in the case of Tamiflu will make it less useful for treating influenza, a fact that can tilt the priorities in favor of Relenza, which has so far been free of the viral resistance problem.