Chemotherapy

Abstract

Retrospectively, the development of antiviral agents can be divided into three phases. Drugs that were originally employed as antitumour agents were examined in the early stages for inhibition of viral replication; these included compounds such as iodine deoxyuridine and cytosine arabinoside. The former was introduced in 1962 by Herbert E. Kaufman as one of the first antiviral drugs for the local treatment of keratoconjunctivitis, which is induced by herpes simplex virus. With increased knowledge of the molecular biology of the cell and that of viruses, the predominantly empirical strategies were superseded by approaches designed to improve poorly selective agents by chemical modifications. The results of that “targeted empiricism” were drugs such as adenosine arabinoside, bromovinyl deoxyuridine and acycloguanosine. Adenosine arabinoside was the first chemotherapeutic drug that showed a healing effect on herpes simplex virus induced encephalitis and herpes infection of neonates (herpes neonatorum) by systemic, i.e. intravenous, administration. The drug acycloguanosine, which was subsequently developed by Gertrude Elion in 1977, was a breakthrough in the treatment of herpesvirus infections (Sect. 19.5). The currently established methods for sequencing viral genetic information, structural analysis of viral enzymes and recent new insights in molecular genetics allow the specific investigation of the targets of antiviral agents, including the development of so-called designer drugs. The acquired knowledge and the new insights into the pathogenesis of viral infections constitute the basis for the development of targeted, optimally configured inhibitory antimetabolites, and thus for the design of virostatic drugs. Although a series of new antiviral compounds has been developed in recent years, not least under the pressure to find ways for AIDS therapy, there are only a few effective chemotherapeutic agents today (Table 9.1), in comparison with the large number of antibiotics available to treat bacterial infectious diseases. The production of new antiviral drugs is certainly limited by the strictly intracellular replication cycle of the virus, which complicates the selection of specific targets without generating cell damage. Besides the direct inhibition of the viral replication cycle, attempts have also been undertaken to influence therapeutically the inflammation processes triggered by viral infections, by combining chemotherapeutic drugs with cytokines, as it became clear that the pathogenesis of most viral diseases is linked to viral and immunological processes (Chap. 8).