Clinical Application

Chemo Secrets From a Breast Cancer Survivor

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Methods of Delivery

The route of administration of an antiviral agent is a prime consideration in assessing its general acceptability. The oral route is naturally by far the most convenient for the patient. Nasal drops or sprays may be acceptable for upper respiratory infections but can be irritating, whereas continuous delivery of aerosols through a face mask or oxygen tent is generally appropriate only for very sick hospitalized patients. Topical preparations (creams, ointments, etc.) are satisfactory for superficial infections of skin, genitalia, or eye, provided they are relatively localized; penetration of drugs through the skin can be enhanced by mixing with substances such as polyethylene glycol. Parenteral administration is the only option in the case of some drugs and may, in any case, be required for serious systemic infections; intravenous infusion of course necessitates hospitalization.

Currently, many experimental drugs have to be used in very high, potentially toxic concentrations because of poor solubility or poor penetration into cells. Delivery of antiviral concentrations of compounds into cells can sometimes be achieved by incorporating the drug into liposomes or by conjugating it to a hydrophobic membrane anchor. Sophisticated chemistry may also be required to modify potential antivirals, such as synthetic peptides or oligonucleotides, which are otherwise rapidly degraded intra- or extracellularly. In the future we may also see antiviral drugs conjugated to antiviral antibody, or incorporated into liposomes coated with such antibody, to direct them to virus-infected cells.

Strategies to Minimize Emergence of Drug-Resistant Mutants

It is already clear that mutants resistant to many of the available antiviral drugs readily emerge in vitro and in vwo, especially during long-term therapy of chronic infections and in immunocompromised patients. Often, resistance is the result of a single point mutation in the gene encoding the particular viral protein that is the target of the drug. Stepwise increases in Ihe degree of resistance may occur as further nucleotide substitutions accumulate, often in a particular order. Clinical isolates may be tested for drug sensitivity by growth in cultured cells in the presence of serial dilutions of the agent. For virus/drug combinations where resistance is regularly associated with particular mutations, it may be feasible to develop a PCR that differentiates resistant from sensitive isolates without the need for culture; for example, in cases of HIV infections treated with zidovudine (AZT), only the critical region of the reverse transcriptase gene needs to be sequenced.

To minimize the emergence of drug-resistant viral mutants we need to capitalize on the lessons learned in handling the problem of antibiotic resistance in bacteria. Antiviral agents should be used only when absolutely necessary, but administered in adequate dosage. Certain Iifesaving drugs may need to be retained for designated diseases only, and/or as replacement therapy following the emergence of resistance to the standard drug. Combined therapy, preferably using agents with distinct modes of action, minimizes the probability of emergence of resistant mutants. Furthermore, by allowing one or both drugs to be given in lower dosage, combined therapy can reduce the incidence of toxic side effects. In certain instances, particular drug combinations display synergism, as has been observed when interferon a is combined with acyclovir or zidovudine, for example.

Clinical Priorities

Diseases against which no satisfactory vaccine is available, including those with a large number of different etiologic agents, are prime targets for antiviral chemotherapy. The common cold is an admirable example on both counts, but there are so many serotypes that chemotherapeutic agents, to be sufficiently broad spectrum, will need to be directed at molecules (or ligands) that are conserved across the genus Rhinovirus. Other respiratory infections, gastroenteritis, hepatitis, and infectious mononucleosis must also be high on the list of priorities. Effective chemotherapy is also needed to treat reactivation of latent infections such as herpes simplex and zoster, even though the latent infection itself will not be eliminated. Reactivation of herpesvirus infections is a particular problem in immunocompromised individuals, such as AIDS patients or transplant recipients. Chronic infections, for example, hepatitis B and C, AIDS, congenital rubella, or cytomegalovirus infections, may be particularly amenable to antiviral chemotherapy, as might some other long drawn out diseases of currently unknown etiology such as certain cancers, autoimmune diseases, and degenerative conditions of the brain, should any of these turn out to be of viral causation. Finally, we must not forget less common but lethal viral diseases, such as encephalitis, rabies, and the hemorrhagic fevers, for which successful chemotherapy would be Iifesaving.

Chemoprophylaxis may also have a role, not only in the prevention of complications, such as orchitis or meningoencephalitis in mumps, but also in limiting the spread of diseases like hepatitis, mononucleosis, influenza, mea sles, or rubella to unimmunized family contacts. A special case is AIDS, which has such a long incubation period that development of the disease might be delayed, or conceivably prevented, by long-term chemoprophylnxis in individuals found to have seroconverted to HIV.

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