Drugs anti-viral

Successful anti-viral drugs must have the ability to pass through cell walls and to remain reasonably stable in their physiological environment. In addition, undesirable side effects need to be minimal. 

Compounds investigated to date include modified versions of bases, nucleotides, nucleotide dimers and oligonucleotides, and also saccharide and phospholipid derivatives (Chapter 10). Many of these compounds, although found to be active, remain experimental and have yet to be proved suitable for large-scale use. 

Much-Studied Ribavirin (12.131a), known since 1972, and the later described Difficidin (12.131b) are broad-spectrum antibiotics, while 5-fluor-2-deoxyuridine-5 -phosphate (12.131c) is an anti-cancer drug. High-level anti-cancer activity has been found for compounds (12.131d-f) [17,17a,22,23], 

Antivirals in successful use are acylclovir (12.132a), ganciclovir (12.132b) and azidothymidine (AZT) (12.132c), which are metabohsed as their triphosphates, and are believed to act both as viral polymerase inhibitors and as chain terminators. 

Acylclovir and ganciclovir are outstandingly active against herpes simplex virus (HSV) and AZT is well known to be effective in alleviating some of the symptoms caused by the AIDS virus (HIV). 

The recent advances in nanotechnology that have enabled us to utilize particles on a nanoscale basis have also created new therapeutic horizons. In the case of 

1 Russell, A.D. and Hugo, W.B. (1994) Antimicrobial activity and action of silver. Progress in Medicinal Chemistry, 31, 351 70. 

2 Van de Voorde, K., Nijsten, T., Schelfhout, K., Moorkens, G. and Lambert, J. (2005) Long-term use of silver containing nose-drops resulting in systemic argyria. Acta Clinica Belgica, 60(1), 33-5. 

3 Spencer, W.H., Garron, L,K, Contreras, F Hayes, T.L and Lai, C, (1980) Endogenous and exogenous ocular and systemic silver deposition. Transactions of the Ophthalmological Societies of the United Kingdom, 100(Pt 1), 171-8, 

4 Wied, U., Andersen, K, Schultz, A, Rasmussen, E. and Watt-Boolsen, S, (1981) Silver nitrate pleurodesis in spontaneous pneumothorax, Scandinavian Journal of Thoracic and Cardiovascular Surgery, 15(3), 305-7, 

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Drugs Available No specific anti-viral drugs are available, but supportive therapy might call for analgesics and anticonvulsants. 

Trifluoromethyl-2 -deoxyuridine, trifluridine (Viroptic ), is an anti-viral drug acting on TS via another mechanism. It is a mechanism-based inactivator of thy-midylate synthase (Figs. 27 and 28). Trifluridine is marketed for the topical treatment of Herpes simplex virus infection in eyes. 

The enzymes that manipulate nucleotides, nucleic acids, etc. are the points of therapeutic intervention for a number of diseases involving cell replication disorders such as cancers and viral infections. For instance, AZT 10.10, an inhibitor of the enzyme reverse transcriptase, is an anti-viral drug currently used in the treatment of AIDS. 

Anti-viral drugs use mechanisms that interfere with nucleic acid and protein synthesis, inhibiting their attachment to and penetration of host cells. Because the viruses frequently adapt their structures, their elimination is difficult. A research team in Cambridge19 are looking at what they call a mutator protein . This protein is made by our own cells and is released to sneak inside certain viruses and cause chaos and mutations in their genome. Unfortunately the AIDS virus has evolved a defence against this process, but it is useful for other viruses. 

The only division in CDER with an established policy regarding pre-IND consultation meetings is the Division of Anti-Viral Drug Products (DAVDP). Established in 1988, the DAVDP pre-IND Consultation Program is a proactive strategy designed to facilitate informal early communications between DAVDP and potential sponsors of new therapeutics for the treatment of AIDS and life-threatening opportunistic infections, other viral infections, and soft tissue trans-... 

The traditional method for determining anti-viral drug activity involves conducting a plaque assay. A preliminary mass based screening can be helpful in reducing the number of drug candidates that need to be screened by more... 

In situ methods involve the external perfusion of an isolated segment of intestinal tissne." The rat has been shown to be an excellent model for human intestinal permeability." One of the principle advantages of the in situ method is that the intact rat intestinal tissne maintains a normal complement of influx and efQux transporters. Cephalosporins and beta-lactam antibiotics are known to be absorbed by oligopeptide transporters in the GI tract. The rat in situ permeability method was used to determine the saturable Michaelis-Menten-type kinetics for this class of drug molecules. In like fashion, the permeabilities of thymidine anti-viral drugs, like AZT, involving the nncleoside transporter were determined in situ. ... 

Structures of poliovirus complexes with anti-viral drugs Implications for viral stability and drug design. Curr. Biol. 4, 784-797. 

Some fatty acids, especially unsaturated fatty acids, are well-known skin penetration enhancers. It is also known that many fatty acids possess antimicrobial activity. The topical activity of the anti-viral drug acyclovir is hampered by its inadequate permeability through the skin barrier. Some reports have shown that fatty acid extract of cod liver oil as well as the extract in the form of an ointment show effective antiviral properties against herpes simplex virus (HSV-1) (37). 

Like many other polyoxometalates (POMs), vanadium-containing POM systems can also be potent anti-viral drugs. A vanadium-substituted polyoxotungstate has anti-viral in vitro activity against viruses causing influenza, parainfluenza. Dengue fever, HIV-1 and A possible mechanism of action is the (inhibitory) interference with... 

Cyclisation of the intermediate 241 in the same pot closes the five-membered ring 243 leading to 244, an intermediate in the synthesis of the anti-viral drug carbovir. Both stereo- and regioselectivity are controlled by the short tether.55... 

One synthesis of the important anti-viral drug AZT 163 (Azidothymidine, used in the treatment of HIV) shows this. The doubly silylated thymine 161 combines with the azido-sugar 162 under Lewis acid catalysis to give AZT after work-up. Only 33% of the required diastereoisomer 163 can be isolated and about the same amount of the other is formed.18... 

The rest of this chapter will show how the most successful treatment modalities have developed. These include vaccination (for smallpox, polio, measles, etc.), and chemotherapy using anti-viral drugs. A large number of viral diseases still lack an effective means of treatment, and the chapter will also cover the attempts to treat the common cold and influenza the struggles with HIV and the emergence of viruses (Marburg, Ebola, Lassa) that cause haemorrhagic fever. 

Zanamivir (8)is an inhaled anti-viral drug for the treatment of uncomplicated types A and B influenza, the two types most responsible for flu epidemics (14). Patients need to start treatment within 2 days of the onset of symptoms, and the drug is less effective in patients whose symptoms do not include a fever. Zanamivir (8)is a powder that is inhaled twice... 

In contrast to zanamivir (8), oseltamivir (9) is an oral anti-viral drug for the treatment cf uncomplicated influenza in patients whose flu symptoms have not lasted more than 2 days (15, 16). This product treats types A and B influenza however, the majority of patients in the United States are infected with type A. FTTit ay of oseltamivir (9) in the treatment of influenza in subjects with chronic cardiac disease and/or respiratory disease has not been established. Oseltamivir (9) is also approved for the prevention of influenza in adults and adolescents older than 13 years. Efficacy of oseltamivir (9) for the prevention of influenza has not been established in immune-compromisedpatients. 

Lithium and anti-viral drug toxicity. I. Further studies on the ability of lithium to modulate the hematopoietic toxicity associated with the anti-viral drug zidovudine (AZT). J Trace Microprobe Techn 13 1-9. 

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