Drugs for curing the flu -- avian, swine or otherwise

With the concern over "avian flu" increasing by the hour, an overview of the available drugs is in order. This overview will be rather sketchy. But as you will learn in the following, the subject-matter doesn’t merit an overly thorough treatment -- effective influenza drugs for the general population are all but absent.

Frightening, but strictly for the birds -- for the time being

Let me first emphasize that the avian influenza and its H5N1 virus is still nothing more than a true "bird flu", i.e. the infection can only be spread among birds. Humans who are in very close contact with infected domestic birds can sometimes become infected, with a frighteningly deadly result (human mortality rate of around 60%). However, an infected human can NOT infect another human, so there can never be an "avian flu" epidemic among humans.

Hence the current concern among health authorities the world over is not the current avian flu itself. Rather it is the possibility that this very aggressive "avian-only" H5N1 virus might mutate into a new form, with the ability to transmit the infection from one human to the next. Nobody knows when such a mutation will take place. It can be any time in the future, from 1 month to 20 years.

Nor can the experts predict whether the mutated virus will exhibit the same deadly aggressiveness as the present avian virus does, or whether it might fizzle down to a human influenza with rather ordinary symptoms. Because in the long run, a virus that kills 60 % of its host animals is not looking after its best interests. But what the epidemiologists are pretty sure of is that sooner or later a human-transmittable mutated strain of the present avian virus is almost certain to hit humanity.

The cures

Vaccine

The best way to fight off an outbreak of a new virus epidemic or pandemic is to have an effective vaccine ready. Unfortunately, this is a contradiction in terms. Because you can not prepare a vaccine unless you have full access to the specific new virus. And the concept "new virus" means that you are quite assured of NOT having access to it, not before the epidemic has already hit you. Nevertheless, the world’s vaccine manufacturing capacity should be prepared to mass produce vaccine as soon as possible after the first wave has hit, in order to counter the next wave, which is certain to arrive as well.

Drugs against the influenza virus

Mechanisms

A virus attacks a body cell in a cycle consisting of four steps: (1) attaching itself to the cell wall, (2) entering the cell through the cell wall, (3) ordering the cell to make a number of replicas of itself, and (4) letting the replicas pass through the cell wall to the outside (where they are ready to infect new body cells, creating the viral “chain reaction” that causes the symptoms of disease).

The working mechanism of all the influenza drugs depends on trying to interfere biochemically with one or more of these four steps of viral action.

Shortening the illness by 1 day

The problem with all of the drugs that exist now is that you have to take them before the viral chain reaction has started in earnest. Unfortunately this point in time is very difficult to recognise early enough. Because by the time that all other diagnoses have been ruled out and the patient is found to exhibit unequivocal influenza symptoms, then he viral chain reaction may already have proceeded too far for the drugs to make much difference. In general, when taken shortly after the onset of clear-cut symptoms, the drugs described below are proven to be able to reduce the period of illness by 1 (one) day only!

Not much of a match for a pandemic.

Most of the influenza drugs below are claimed to work relatively well as prophylactics (i.e. when administered before any infection has occurred). But their high cost and side effects make them impractical to use for protecting populations against pandemics. An effective pandemic protection would require the entire world’s population to take the drugs for extended periods of time. A more reasonable prophylactic use would be to protect medical personnel who are acutely involved with influenza patients during an epidemic.

All of the drugs below (except one, which is still in the development stage) have been shown to exhibit a rather disquieting property -- the influenza virus can mutate and become resistant to the drug in a fairly short period of time. This may limit the effectiveness of the drugs even when administered as mere prophylactics.

The drugs, grouped according to their working mechanism

M2 inhibitors -- amantadine, rimantadine

Both of these drugs interfere with step (3) of the viral mechanism, by inhibiting the action of a virus protein called M2. M2 forms channels in the cell membrane, enabling the virus to take over the cell’s chemical factory and to order it to start making replicas of the virus itself. By M2 inhibition amantadine and rimantadine inhibit virus replication.

Amantadine has been around since the 1970’s and rimantadine (a derivative of amantadine) since 1993. Both are only effective against influenza virus type A (fortunately, the avian flu virus H5N1 is of type A), not against type B. Amantadine and rimantadine are taken orally as pills.

Both have neurological side effects (rimantadine to a somewhat lesser degree), e.g. insomnia, anxiety, nausea, loss of appetite and in some cases even seizures. An advantage with these older drugs is that they are considerably cheaper than the new ones.

Neuraminidase inhibitors -- oseltamivir, zanamivir, peramivir

This group represents the newest influenza drugs. Oseltamivir (brand name Tamiflu) and zanamivir (brand name Relenza) started to be marketed in the 2000’s and peramivir is not even on the market yet (clinical testing on humans is scheduled to start in January).

These drugs work by inhibiting step (4) in the viral mechanism and are effective against both type A and type B influenza virus. Neuraminidase is the virus protein (enzyme) that enables the virus to penetrate through the cell wall. It is difficult to prevent the primary infecting virus from entering the cell, but if the cell contains a neuraminidase inhibitor (because you have taken your medicine), then the virus replicas within the cell can no longer penetrate the cell wall and escape to the outside. The viral chain reaction is thus broken.

Oseltamivir (Tamiflu)

Tamiflu is marketed by the Swiss pharmaceutical company Roche (Hoffman-La Roche), under an exclusive licence from the Gilead Sciences. Tamiflu is taken orally as pills. It has side effects, but to a markedly lesser extent than in the case of the M2 inhibitors. On the other hand it is several times more expensive. A more detailed description of Tamiflu is given in the writeup Tamiflu.

Zanamivir (Relenza)

Relenza is marketed by the British pharmaceutical company GlaxoSmithKline, but the drug was developed by an Australian research team at the Victorian College of Pharmacy (Monash University) in Parkville, Australia.

Relenza is taken by inhalation through a device called Diskhaler. This method of administering a drug against the influenza virus, which enters the body via the respiratory system, may seem sensible -- the drug is concentrated to the part of the body where the attack hits first. On the other hand, children and weak patients may have trouble using the Diskhaler, which requires certain low-level dexterity. Also, it increases the already high cost of the drug.

The general side effects of Relenza are on the same level as those of Tamiflu, i.e. much lower than for the older M2-inhibiting drugs. But there is one extremely serious exception -- a risk for severe respiratory problems, including bronchial collapse (i.e. you may suffocate to death). These side effects are rare in normal patients, but occur rather frequently among patients with asthma and with the smoking-caused chronic pulmonary disease COPD. Patients with COPD and asthma are dissuaded from using Relenza, thereby excluding two groups of patients who in all probability will be hardest hit by a future outbreak of a new strain of influenza.

Peramivir (no brand name yet)

The drug was originally developed at the University of Alabama, but final development and subsequent marketing is conducted by BioCryst Pharmaceuticals in Birmingham, Alabama.

BioCryst claims that peramivir can be administered by intramuscular injection. This would presumably make it work faster than if taken orally. There is no information regarding side effects of peramivir, as it has not yet been tested in humans.

Attachment inhibitors -- VIRA 38
VIRA 38

VIRA 38 is claimed by the developer (PRB Pharmaceuticals of Hong Kong and Cypress, California) to inhibit virus attachment to the cell wall (step (1) in the viral mechanism), as well as to attack the virus cycle at the viral uncoating (M2), replication and release stages. The development of VIRA 38 is still at the laboratory stage (work on chicken embryos).

VIRA 38 apparently consists of several components and the developers claim that the virus cannot develop resistance to the drug, like it does to amantadine, rimantadine, oseltamivir, zanamivir, and peramivir.

This claim, as well as all the other claims by PRB Pharmaceuticals, remain yet to be proven in clinical tests on humans. Nothing is known about the side effects of VIRA 38. The drug is in such an early stage of development that it can turn out to be almost anything, from being a wonder drug to becoming a pie in the sky.

Sticking to grandmother’s house cure

The outlook regarding effective drug cures for a new epidemic/pandemic strain of influenza (as well as for the present influenza strain, which regularly hits us every year) looks truly bleak indeed. An anti-viral drug even remotely resembling penicillin is not even behind the horizon. The only way in which the presently existing anti-viral drugs may help, is perhaps by preventing medical personnel becoming infected during the most acute stages of an epidemic.

For the rest of us it seems like a rather pointless exercise in theoretical biochemistry to try to lop off just 1 day from a normal one-week illness period, particularly when the exorbitant cost is reckoned with.

For the majority of the population the best preparation for an upcoming influenza epidemic is keeping physically and mentally fit, and following the advice of the epidemiological authorities and of grandmother. Warm milk with honey may not be such a bad idea after all, not in the face of today’s biochemical alternatives.

Reference:

http://www.fda.gov/cder/foi/label/2003/21036slr006_relenza_lbl.pdf
http://www.niaid.nih.gov/factsheets/fludrugs.htm
http://www.biocryst.com/pdf/peramivirfacts.pdf
http://www.tamiflu.com/

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