Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-08-11
2002-11-12
O'Sullivan, Peter (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S046000, C514S049000, C514S050000, C514S263230, C514S263320, C514S263400, C514S272000
Reexamination Certificate
active
06479466
ABSTRACT:
The present invention relates generally to the fields of medicine and virology. More particularly, it concerns methods and combination compositions for the treatment of viral infections, especially retroviral infections, for treatment of individuals who are treatment experienced and resistant to current protocols, and for post-exposure prophylaxis.
BACKGROUND OF THE INVENTION
Antiviral agents are generally modeled to inhibit viral replication within an infected cell. Effective antiviral agents specifically target steps within the viral replication pathway thereby inhibiting or hindering viral replication within infected host cells while having a minimal cytotoxic effect on the host. Thus, many antiviral agents are specific inhibitors to virus-specific enzymes or proteins, such as viral DNA or RNA polymerases, or cleavage enzymes for viral capsid protein. Nucleoside analogues, for example, have been developed that target particular enzymes in the viral replication pathway by mimicking a natural substrate of the enzyme.
Adverse toxicity effects exist with the administration of most antiviral agents, particularly at the dosage levels required to attain effective antiviral chemotherapy, due to a lack of viral specificity. Presently, there are very few antiviral agents that are considered to be efficacious, i.e. agents having a high level of viral toxicity and a low level of cytotoxicity. Such agents include iododeoxyuridine, adenine arabinoside and trifluorothymidine, all used to treat herpetic keratitis, acyclovir which is used in the treatment of genital herpes and mucosal and cutaneous herpes infections in the immunocompromised patient, and amantadine which is used to treat influenza A. These antiviral agents have a relatively low level of cytotoxicity in comparison to other antiviral agents. Adverse toxicity effects associated with acyclovir, for example, include transient impairment of renal function, nausea and vomiting, reversible neurological reactions, raised liver enzymes, rashes and increased hematological indexes.
Human immunodeficiency virus (HIV) is a prototype for pathogenic retroviruses, i.e., viruses that use reverse transcription to replicate. Reverse transcription mechanisms are required by those viruses having an RNA genome wherein the RNA is copied by a polymerase into DNA for subsequent replication. Certain DNA viruses use, in part, reverse transcription mechanisms to replicate such as, for example, hepatitus B virus. Reverse transcriptase is the virally-encoded polymerase used by retroviruses for this purpose.
Two nucleoside analogue reverse transcriptase inhibitors in combination with a potent protease inhibitor are generally recommended to achieve suppression of viral replication in current treatment protocols for HIV-1 infected individuals. Nucleoside analogue reverse transcriptase inhibitors in current use are described infra (adapted from Scientific American Medicine, January 1999, Chapter 11 www.samed.com, Scientific American Inc.).
Azidothymidine (AZT, zidovudine) is administered at a dosage of 600 mg orally daily in two divided doses. The major dose-limiting toxicity of AZT is on bone marrow. Clinical trials demonstrate that therapy delays clinical evidence of disease progression in previously untreated persons with CD4+T cell counts below 500 cells/mm
3
. AZT is generally not used as a single agent.
Dideoxyinosine (ddI, didanosine) is administered orally as an inosine prodrug and is formulated with a buffer directed at gastric acid because of the acid lability of dideoxyadenosine. The major toxicities associated with ddI are pancreatitis and peripheral neuropathy. DdI was demonstrated to be superior to AZT in antiviral and immunomodulatory effects and to provide additional clinical benefits to patients who have used AZT.
Dideoxycytosine (ddC) is a nucleoside analogue reverse transcriptase inhibitor that exhibits potent antiretroviral activity in vitro. Dose escalation of ddC is limited by peripheral neuropathy, however, and ddC is therefore used only in combination regimens or for the treatment of patients who are intolerant of, or unresponsive to, other antiretrovirals. DdC is administered at a dosage of 0.75 mg three times daily and has been used extensively in combination regimens for persons with advanced AIDS who are intolerant of other antiretroviral chemotherapeutic agents.
D4T (stavudine), a thymidine analogue, has been investigated in patients with moderate to advanced HIV-1 infection, especially those with previous AZT experience. However, peripheral neuropathy is a major side effect.
Lamivudine (3TC) is well tolerated and results in acute reductions in plasma HIV-1 RNA levels. However, a single mutation in reverse transcriptase at position 184 results in a 100-fold to 1,000-fold decrease in susceptibility to lamivudine. Any measurable degree of viral replication in the presence of the drug results in the rapid emergence of resistant mutations. Lamivudine is associated with suppression of the erythroid and myeloid elements of bone marrow.
Abacavir is usually given as 600 mg, orally, daily in 2 divided doses. The drug is compromised by mutations in the reserve transcriptase (RT) gene. The efficacy of abacavir is compromised by the emergence of reverse transcriptase drug-resistant viral variants. In vitro studies have shown that the single mutations 65R, 74V, 184V, and 115F in the RT gene confer 2-3—fold decreases in susceptibility to abacavir. Mutants harboring 2 or 3 of these mutations exhibit approximately 10-fold resistance to the drug. In clinical studies, patients with more than 2 RT mutations showed a markedly inferior response to abacavir containing regimens.
F-ddA (lodenosine) is a fluoridated compound with similar structure and activity to ddI. F-ddA is not FDA-approved at the present time. Unlike ddI, stomach acids do not degrade F-ddA, so it can be administered without an antacid, thereby avoiding side effects attributable to the use of a buffer. Resistance to F-ddA is slow to emerge and the drug has shown in vitro activity against strains of HIV resistant to AZT, ddI, and ddC.
In light of rapid rates of viral replication, the highly error-prone HIV-1 reverse transcriptase, and the inability of currently available antiretroviral agents to completely inhibit HIV-1 replication, the development of resistance to antiretroviral drugs has been an inevitable consequence of drug exposure. Viral variants resistant to all antiretroviral agents in active use have been demonstrated (see the Scientific American Medicine, Chapter 11 cited herein, for a discussion of molecular mechanisms by which the virus may develop resistance to antiretroviral drugs).
The above-described protocols focus primarily on the interruption of the virus life cycle, through the inhibition of viral enzymes involved in viral replication. Though this has resulted in some control of the virus, over one-fourth of treatment naive individuals are infected with a virus with reduced susceptibility to one or more of the currently FDA-approved drugs. Moreover, up to 3% of newly diagnosed individuals are infected with a virus that is resistant to drugs in all types of currently approved therapies. Unfortunately, many of the current drugs in development are similar to currently existing therapies, and are likely to offer little to the current armamentarium of treatment.
Another approach to control HIV-1 replication is the targeting of cellular enzymes, a strategy based on the fact that the virus is dependent on the host cellular machinery for replication. Since host enzymes do not mutate at the same rate that viral proteins do, a cellular approach may result in controlling the emergence of drug-resistant viruses. Clinical trials using hydroxyurea and ddI have been reported in the treatment of HIV-1 infection (Lori, et al., JAMA, 277:1437-38, 1997; Vila, et al., Lancet, 348(9021:203-4, 1996). U.S. Pat. No. 5,736,527 relates to a method of treating HIV in humans by administration of ddI and hydroxycarbamide (hydroxyurea, (HU)), however, a mixture of hydroxycarbamide with AZT
Davis, Jr. Charles E.
Heredia Alonso
Redfield Robert R.
Fuierer Marianne
Hultquist Steven J.
O'Sullivan Peter
University of Maryland
Yang Yongzhi
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