Antiviral agent

Many antiviral drugs are antimetabolites that resemble the structure of naturally occurring purine and pyrimidine bases or their nucleoside forms. Antimetabolites are usually pro-drugs requiring metabolic activation by host-cell or viral enzymes—commonly, such bioactivation involves phosphorylation reactions catalyzed by kinases. 

Monophosphorylated by viral thymidine kinase (TK), then further bioactivated by host-cell kinases to the triphosphate. Acyclovir-triphosphate is both a substrate for and inhibitor of viral DNA polymerase when incorporated into the DNA molecule, it acts as a chain terminator because it lacks the ribosyl 3 hydroxyl group. 

Dose-limiting nephrotoxicity with acute tubular necrosis, electrolyte imbalance with hypocalcemia — tremors and seizures. Avoid pentamidine (IV) - T nephrotoxicity and hypocalcemia. 

The original inhibitors of reverse transcriptases of HIV are nucleoside antimetabolites (e.g., zidovudine, the prototype) that are converted to active forms via phosphorylation reactions. 

Nucleoside reverse-transcriptase inhibitors (NRTIs) are components of most combination drug regimens used in HIV infection. Commonly, two NRTIs are used together with a protease [ inhibitor (PI). During the past 5 or 6 years, such highly active antiretroviral therapy (HAART) 

Inhibit viral DNA polymerases Acyclovir, foscarnet, ganciclovir 

Inhibit viral reverse transcriptase Zidovudine, didanosine, zalcitabine, lamivudine, stavudine, nevirapine, delavirdine, efavirenz 

Inhibit viral aspartate protease Indinavir, ritonavir, saquinavir, nelfinavir 

1 Zidovudine, AZT i 1 i 1 Hematotoxicity (major and dose-hmiting) Headache, asthenia, myalgia, myopathy, and peripheral neuropathy 

The most pervasive and well-known antiviral agent is, of course, the immune system, in terms of the immune response. Certain types of white blood cells, collectively called lymphocytes, leave the blood vessels and patrol the intercellular regions looking for foreign invaders (Voet and Voet, 1995, p. 1207). The lymphocytes arise from precursor cells in the bone marrow, as do all blood cells. The lymphocytes eventually return to the blood by way of the lymphatic vessels after interacting with such lymphoid tissues as the thymus, lymph nodes, and the spleen. 

Another action of the immune system is to raise the body temperature, another way of killing off the invader s body. 

Vitamin C (ascorbic acid), besides its other purposes — for example, in preventing scurvy — is a suspected antiviral agent, though the point is controversial and not settled. In other words, the effectiveness of vitamin C as a cure or preventive for the common cold is still argued (see the woik of Linus Pauling), though recognition has come about that vitamin C at least alleviates its symptoms (Chaney, in Devlin, 1986, p. 1227). To which may be added, that the common cold is caused by a virus, and if vitamin C is not always effective, neither is the immune system, or we would never get sick in the first place. 

Vitamin C enhances the utilization of folic acid, either by aiding the conversion of folate to tetrahydrofolate or the formation of polyglutamate derivatives of tet-rahydrofolate (Chaney, in Devlin, 1986, p. 1226). Inasmuch as folic acid has a number of roles in body chemistry, including that of an anticancer agent, there may be further connections with the benefits of vitamin C that are yet to be spelled out. 

Another characteristic of ascorbic acid, CgHgOg, is that it is closely related chemically to glucose, C6Hi20g (Chaney, in Devlin, 1986, p. 1225). Whether or not this chemical resemblance has a desirable effect on some of its properties is fuel for speculation. For the record, its main biochemical role is said to be that of a reducing agent in certain important hydroxylation reactions, for example, of lysine and proline in protocollagen. It is therefore important in maintaining normal connective tissue. 

Since 2000, seven such agents have been approved for antiviral treatments covering anti-HIV, hepatitis B and cytomegalovirus (CMV). Rather than give details of each, we discuss below the importance of just two compounds of this class that would not have been synthesised without the historical perspective. 

In 2001, tenofovir disoproxil fumarate 61, a prodrug of tenofovir was approved for treatment of HIV, subsequently being preregistered in the USA for treatment of hepatitis B. Emtricitabine 62, a reverse transcriptase inhibitor, was approved in 2003 for HIV. What is of import is that these compounds are now part of fixed dose combination therapies for treatment of HIV, either two drug (tenofovir disoproxil fumarate/emtricitabine) or three drug Atripla (tenofovir disoproxil fumarate/emtricitabine/efavirenz) formulations. Thus, even 50 + years after Bergmann s discovery of bioactive arabinose nucleosides, small molecules synthesised as result of his discoveries are still in clinical use and others are in clinical trials for treatment of viral diseases. 

There has been much recent anxious speculation that the bird flu virus will mutate to a form that will spread from person to person. A worldwide influenza epidemic, at worst comparable to that which followed the Great War, could well be the net result of such an event. The efficacy of the first carbocychc neuraminidase inhibitor, oseltamivir (34), known famiharly 

Vimses are one of the smallest biological entities (except viroids and prions) that carry all the iaformation necessary for thek own reproduction. They are unique, differing from procaryotes and eucaryotes ia that they carry only one type of nucleic acid as genetic material, which can be transported by the vims from one cell to another. Vimses are composed of a shell of proteki enclosing a core of nucleic acid, either ribonucleic acid (RNA) or deoxyribonucleic acid (DNA), that codes for vkal reproduction. The outer shell serves as a protective coat to keep the nucleic acid kitact and safe from enzymatic destmction. In addition to thek proteki coat, some vimses contain an outer covering known as an outer envelope. This outer envelope consists of a Hpid or polysaccharide material. 

Once kiside the host ceU, the vims must repHcate its own nucleic acid. To do this, it often uses part of the normal synthesizing machinery of the host ceU. If the vims is to continue its growth cycle, vkal nucleic acid and vkal proteki must be properly transported within the ceU, assembled kito the kifective vims particle, and ultimately released from the ceU. AH of these fundamental processes kivolve an intimate utilization of both ceUular and vkal enzymes. Certain enzymes that ate kivolved ki this process ate specificaHy suppHed by the invading vims. It is this type of specificity that can provide the best basis for antivkal chemotherapy Thus an effective antivkal agent should specificaHy inhibit the vkal-encoded or vims-kiduced enzymes without inhibition of the normal enzymes involved in the biochemical process of the host ceH. Vims-associated enzymes have been reviewed (2,3) (Table 1). 

RNA-dependent RNA polymerase influenza vims, patamyxovims, vesiculovims 

RNA-dependent DNA polymerase (reverse transcriptase) oncomavims, human immunodeficiency vims (HIV) 

Vimses contain either RNA or DNA, and this nucleic acid composition forms the basis for thek classification. Although vimses ate known to infect bactetia, insects, plants, animals, and humans, this discussion is restticted to the important vimses of vertebrates. The relevant vimses ate summarized in Table 2, using the nomenclature and taxonomy recommended by the International Committee on Taxonomy of Vimses (4,5). 

The following lists some virus types together with diseases that they cause  

It has been e.slimatcd that viruses cause more than 60% of the infectious diseases that occur in the developing countries. Bacterial infections account for only 15%. Table 11-2 provides a synopsis of virus types with their possible therapeutic modalities. 

B) Positive sense but icquires RNA to be converted to DNA via a vlrion-associated emyme (reverse tnuncriptase) 

C) Ncgativc sense RNA (opposite polarity locellular mRNA. requires a virion associalcd enzyme to begin the replication cycle) I) Enveloped 

TABLE 11-Z Classification of Viruses Causing Disease in Humans 

The principal obstacle encountered by a vims is gaining entry into the cell. The cells are protected by a cell wall of a thickness comparable to the size of the vims. The vims must first become attached to the cell surface. Much of the specificity of a vims for a certain type of cell lies in its ability to attach to the surface of that specific cell. Durable contact is thus important if the vims is to infect the host cell. The ability of the vims and the cell surface to interact is a property of both the vims and the host cell. The fusion of viral and host-cell membranes, based on unique chemical recognition factors at the cellular surface, allows the intact viral particle or, in certain cases, only its infectious nucleic acid to enter the cell. This process also may involve a type of enzymatic digestion or breakdown of the host plasma membrane at the site of attachment. It is not only during initial infection of a cell that viruses have to cross cell membranes, however. Although the phenomenon of syncitia formation (for HIV infection) and lysing (for picomavims infection) are observed, cell-to-cell transfer must also occur if the vims is to effectively multiply and cause a substantial infection. 

Apraclouidiue (lopidiue) is a relatively selective tt2-receptor agouist that is used topically to reduce intraocular pressure. It can reduce elevated as well as normal intraocular pressure, whether accompanied by glaucoma or not. The reduction in intraocular pressure occurs with minimal or no effects on systemic cardiovascular parameters thus, apraclonidine is more useful than clonidine for ophthalmic therapy. Apparently, apraclonidine does not cross the blood-brain barrier. The mechanism of action of apraclonidine is related to oc2-receptor-mediated reduction in the formation of aqueous humor. 

The clinical utility of apraclonidine is most apparent as a short-term adjunctive therapy in glaucoma patients whose intraocular pressure is not well controlled by other pharmacological agents such as p-receptor antagonists, parasym-pathomimetics, or carbonic anhydrase inhibitors. The drug 

Aprepitant is supplied in 80- and 125-mg capsules and is administered for 3 days in conjunction with highly emetogenic chemotherapy along with a 5-HT3-receptor antagonist and a corticosteroid. The recommended adult dosage of aprepitant is 125 mg administered 1 hour before chemotherapy on day one, followed by 80 mg once daily in the morning on days two and three of the treatment regimen. 

Aprobarbital, a barbiturate sedative-hypnotic (40 to 80 mg p.o. h.s.), is indicated in the management of mild to severe insomnia (see also Barbiturates). 

Aripiprazole, a quinoUnone derivative, is a partial agonist at dopamine D2 and serotonin 5-HTlA receptors, and antagonist at serotonin 5-HT2A receptor. Aripiprazole is indicated in the treatment of schizophrenia and treatment of acute manic and mixed episodes associated with bipolar disorder. 

---

Anti tussive Antitussives Antiulcer therapy Antivert Antiviral agents... 

---