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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to the use of combinations of nucleoside derivatives for inhibiting human immunodeficiency virus (HIV) replication, thereby limiting the effects of HIV infection.
• the crux of the invention lies in the discovery that nucleoside derivatives used in combination have synergistic effects, such that the combined effective dose of these agents is lower than the sum of the therapeutic dosages of either drug used individually; increased anti-viral activity is not associated with a commensurate increase in cytotoxicity; in fact, combinations of nucleoside derivatives are less toxic to uninfected cells when compared to identical compounds administered separately.
• HIV Human immunodeficiency virus
• AIDS acquired immune deficiency syndrome
• ARC AIDS related complex
• the HIV virion or virus particle is a sphere that is roughly 1000 angstrom units across.
• the particle is covered by a lipid bilayer membrane derived from the outer membrane of the infected host cell. Studding the viral membrane is an envelope glycoprotein which is synthesized as a precursor of 160 Kd and subsequently processed into two glycoproteins: gp41 which spans the lipid bilayer, and gpl20 which extends beyond the lipid bilayer.
• the envelope covers a core made up of proteins designated p24 and pl8.
• the viral RNA is carried in the core, along with several copies of the enzyme, reverse transcriptase, which catalyzes the assembly of viral DNA.
• the HIV genome contains three genes that encode the components of retrovirus particles: env (which codes for the envelope proteins) , gag (which codes for the core proteins) , and pol (which codes for reverse transcriptase) . These three genes are flanked by stretches of nucleotides called long terminal repeats (LTRs) .
• LTRs include sequences that have a role in controlling the expression of viral genes.
• the genome of HIV includes at least five additional genes, three of which have known regulatory functions, and the expression of which is thought to have an impact on the pathogenic mechanisms exerted by the virus.
• the tat gene encodes a protein that functions as a potent trans-activator of HIV gene expression, and, therefore, plays an important role in the amplification of virus replication.
• the rev, or trs/art gene can upregulate HIV synthesis by a transacting antirepression mechanism; rev enables the integrated HIV virus to selectively produce either regulatory proteins or virion components.
• the nef, or 3 -orf, gene appears to down-regulate virus expression by producing a cytoplasmic protein which, presumably via a second messenger, inhibits transcription of the HIV genome.
• the vif, or sor gene is not essential for virion formation, but is critical to the efficient generation of infectious virions and influences virus transmission in vitro.
• the pr, or R gene encodes an immunogenic protein of unknown function.
• the critical basis for the immunopathogenesis of HIV infection is believed to be the depletion of the helper/inducer subset of T lymphocytes, which express the CD4 antigen, resulting in profound immunosuppression. Viral killing of these immune cells is thought to be a major factor contributing to the crippling effect HIV has on the immune system.
• the envelope glycoprotein plays an important role in the entry of HIV into CD4 positive host cells.
• the gpl20 portion has been shown to bind directly to the cellular CD4 receptor molecule, thereby producing HIV's tropism for host cells that express the CD4 receptor, e.g. , T helper cells (T4 cells) , macrophages, etc.
• the virus After HIV binds to the CD4 molecule, the virus is internalized and uncoated. Once internalized, the genomic RNA is transcribed into DNA by the enzyme reverse transcriptase. The proviral DNA is then integrated into the host chromosomal DNA and the infection may assume a "dormant" or latent phase. However, once activation occurs, the proviral DNA is transcribed. Translation and post translational processing results in virus assembly and budding of mature virions from the cell surface.
• a prominent feature in the cytopathology of HIV infection is the formation of multinucleated syncytia formed by the fusion of as many as 500 cells which appear to be induced by the gpl20/gp41 envelope proteins.
• HIV-infected macrophages may continue to produce HIV without cytopathi effects for long periods of time; it is believed that the macrophage is a major reservoir for HIV and may be responsible for transporting virus into the central nervous system (Gartner et al., 1986, Science 233:215- 219) .
• Intervention could potentially prevent virus binding to target cells, fusion with cell membranes, uncoating of viral nucleic acid, reverse transcription of the HIV RNA genome into DNA, transcription or translation of viral mRNA, processing of viral proteins, assembly into mature virions, or other events related to replication or infectivity.
• CD4 antigen can block HIV infectivity by binding to viral particles before they encounter CD4 molecules embedded in cell membranes.
• anti-idiotype antibodies directed toward anti-CD4 antibodies, have been shown to bind to HIV virus in vitro, presumably by possessing protein configurations similar to CD4 determinants (Dalgleish et al., 1989, UCLA Symposia on Molecular and Cellular Biology. J. Cell Biochem. Supp. 13B, p. 298) .
• CD4 determinants Dalgleish et al., 1989, UCLA Symposia on Molecular and Cellular Biology. J. Cell Biochem. Supp. 13B, p. 298) .
• several large, sulfated, negatively charged molecules including dextran sulfate, have been shown to inhibit HIV replication and syncytia formation jln vitro (Yarchoan et al., supra) .
• Anti-sense oligonucleotides have been found to inhibit virally induced syncytium formation and expression of viral p24 protein (Agrawal et al., 1988, Proc. Natl. Acad. Sci. U.S.A. ££5:7079-7083) .
• These synthetic nucleic acid polymers complementary to HIV mRNA, were designed to inhibit the translation of viral mRNA into protein; forming phosphoramidate and phosphorothioate derivatives of anti-sense oligonucleotides has produced compounds substantially resistant to endonuclease degradation.
• Ribavirin comprising a ribose moeity and a triazol ring, is believed to act as an analogue of the nucleoside guanosine. It has activity against several RNA viruses _in vitro, primarily, it is believed, by interfering with the guanylation step required for capping of viral mRNA. Ribavirin has been reported to suppress the replication of HIV in cultures of human T lymphocytes (McCormick et al., The Lancet, Dec. 15, 1984:1367-1369).
• post-translational processing of viral proteins can be disrupted; castanospermine, a plant glycosidase activity, has been shown to reduce synctium formation and HIV infectivity (Wall et al., 1988, Proc. Natl. Acad. Sci. U.S.A. 85:5644-5648) .
• the final steps in HIV replication involve its exit from the host cell and infection of new cellular targets.
• Alpha interferon has been found to suppress HIV replication in vitro (Ho et al., Lancet, March 16, 1985:602-604), may reduce viral budding, and has been shown to have direct antitumor activity against Kaposi's sarcoma, a malignancy associated with AIDS.
• a lipid compound, AL 721, composed of neutral glycerides, phosphatidylcholine, and phosphatidylethanolamine in a 7:2:1 ratio has a demonstrated ability to extract chloresterol from cellular membranes, and appears to decrease HIV infectivity (Sarin et al., 1985, N. Engl. J. Med. 313:1289-1290) .
• Nucleoside derivatives are modified forms of the purine (adenosine and guanosine) and pyrimidine (thymidine, uridine and cytidine) nucleosides which are the building blocks of RNA and DNA. Reverse transcriptase and DNA polymerase will bind and incorporate nucleoside derivatives into the nascent DNA chain provided that the 5' carbon of the derivative can bind to the 3' hydroxyl group of the previous nucleotide (i.e.
• nucleoside derivatives by forming a phosphodiester linkage) ; subsequent nucleotides can only be added if the nucleoside derivative contains a means for linking its 3' carbon to the 5' phosphate of another nucleotide.
• nucleoside derivatives under study as potential anti-HIV medications result in premature termination of viral DNA replication before the entire viral genome has been transcribed. These derivatives lack 3' substituents that can bind to subsequent nucleosides and result in chain termination.
• AZT (3'-azido-2',3'-dideoxythymidine, azidothymidine, zidovudine) is a nucleoside derivative which has been shown to be effective in the treatment of patients with AIDS and ARC; data indicates that AZT increases the median survival of AIDS patients (Fischl et al., 1987, N. Engl. J. Med. 317:185-191; Creagh-Kirk, et al., 1988, J.A.M.A. 260:3009-3015) .
• AZT may be efficacious in children with AIDS, HIV associated psoriasis (Bartlett et al., supra) , AIDS associated dementia (Sch itt et al., 1988, N. Engl. J. Med. 319:1573-1578) and HIV associated thrombocytopenia (Pottage et al., 1988, J.A.M.A. 260:3045-3048).
• AZT is phosphorylated by mammalian cells to form AZT triphosphate (an analogue of thymidine triphosphate) which is believed to inhibit the production of viral DNA by at least two mechanisms: competitive inhibition and chain termination (Yarchoan et al., supra) .
• Dideoxynucleosides are nucleoside derivatives which lack hydroxyl groups at both the 2 ' and 3' carbon residues, and therefore result in DNA chain termination.
• the 5' triphosphate products of 2', 3'-dideoxyadenosine, dideoxyguanosine, dideoxycytidine, and dideoxythymidine selectively inhibit viral reverse transcriptase and cellular ⁇ and DNA polymerase, but do not interfere with the function of DNA polymerase , the major DNA synthetic enzyme utilized during cell division (Edenberg et al., 1978, J. Biol. Chem. 253:3273-3280; Waqar et al., 1978, Nucl. Acids Res.
• European patent application 0273277 publication date July 6, 1988, relates to the use of 3'- deoxythymidin-2 '-ene (3 '-deoxy-2',3'-didehydrothymidine d4T) , which lacks 2 ' and 3'hydroxyl groups and has a double bond between 2 ' and 3' carbon atoms, in treating patients infected with a retrovirus.
• D4T also referred to as 2 ' ,3 / -didehydro-2 ,3 , -dideoxythy idine, or l-(2,3- dideoxy- ⁇ -D-glycero-pent-2-enofuranosyl)thymine, was found to inhibit HIV reverse transcriptase, and had anti-HIV activity comparable to AZT (Mansuri et al., J. Med. Chem. in press) . D4T may also have less toxic effects than AZT (Mansuri et al., supra; Ghazzouli et al., 1988, ICAAC, Abstract 1301, p. 344) .
• AZT therapy is associated with bone marrow toxicity (Richman et al., 1987, N. Engl. J. Med. 317:192-197) and consequently, decreased production of red blood cells (resulting in anemia) , platelets (resulting in thrombocytopenia) ,and white blood cells (resulting in leukopenia). According to Bartlett et al. (1988, J.A.M.A.
• AZT is being tested in combination with other antiviral agents, such as acyclovir sodium, foscarnet sodium, interferon- ⁇ , ⁇ , or , interleukin 2, or ampligen.
• other antiviral agents such as acyclovir sodium, foscarnet sodium, interferon- ⁇ , ⁇ , or , interleukin 2, or ampligen.
• ddC dideoxycytidine therapy
• the present invention relates to the use of synergistic combinations of nucleoside derivatives for inhibiting human immunodeficiency virus (HIV) replication and thereby limiting HIV infection.
• certain nucleoside derivatives used together exhibit greater anti-viral effects and less cytotoxicity at lower concentrations than either drug used separately. thus maximizing treatment of HIV infection and minimizing toxic side-effects.
• the purine nucleoside analogue dideoxyinosine (ddl) and the pyrimidine nucleoside analogue 2',3'- dideoxy-2',3'-didehydro hymidine (d4T) can be used to inhibit HIV replication. It is shown, by way of example, that ddl and d4T exhibit strong synergistic anti-HIV activity; the combination of ddl and d4T produced a greater anti-HIV effect but was associated with less cytoxicity than either compound used separately.
• combinations of fluoronucleoside analogs may be used with d4T to inhibit HIV replication.
• the purine nucleoside analog, 2 ',3 '-dideoxy-2 '-beta-fluoroinosine (F-ddl) may be used with d4T.
• Combination Index a numerical representation of the synergistic or antagonistic effects of drug combinations wherein a CI less than one represents synergy, greater than one represents antagonism, and equal to one represents additivism.
• the CI value is obtained using an isobologram equation and computer simulation according to Chou and Talalay (1984, Adv. Enz. Reg. 2 ⁇ :27-55 and 1987, in "New Avenues in Developmental Cancer Chemotherapy,'" Harrap and Connors, eds., Bristol-Myers Symposium Series, Academic Press, pp. 37-64; Hartshorn et al., 1987 Antimicrobial Agents and Chemotherapy 31:168-172).
• a combination index may be determined with the equation:
• ⁇ is 0 (i.e., CI is the sum of two terms) ; if the agents 0 are mutually nonexclusive, a is 1 (i.e., CI is the sum of three terms) .
• Synergy the action of two or more substances to achieve an effect greater than that of either substance used 5 individually. Synergism in antiviral activity should be construed to mean greater antiviral activity; synergism in cytotoxicity should be construed to mean greater cytotoxicity.
• Tissue Culture Inhibitory Dose i.e. TCID gQ
• TCID gQ Tissue Culture Inhibitory Dose
• Tissue Culture Toxic Dose i.e., TCTD..- the amount i.e. of ou drug required to reduce the number of tissue culture cells by a given percentge (i.e., 50 percent). 5 4. DESCRIPTION OF THE FIGURES
• the present invention relates to the use of synergistic combinations of nucleoside derivatives for inhibiting the replication of HIV, thereby limiting the effects of HIV infection.
• combinations of certain nucleoside derivatives exert stronger anti-HIV effects but are associated with less cytotoxicity than individual nucleoside derivatives at comparable total drug concentrations.
• nucleoside derivatives any one of which may substitute for naturally occurring nucleosides in viral reverse transcriptase activity, the likelihood that these derivatives will be incorporated into the viral DNA sequence (and consequently terminate reverse transcription by preventing elongation of nascent DNA) is substantially increased.
• nucleoside derivative combinations for the purpose of clarity of disclosure, and not by way of limitation, the description of the present invention will be divided into three sections: (1) nucleoside derivative combinations; (2) _in vitro assay for demonstrating the HIV-inhibitory effect of nucleoside derivative combinations, and (3) therapeutic uses of HIV- inhibitory nucleoside derivative combinations.
• nucleoside derivative combinations for the purpose of clarity of disclosure, and not by way of limitation, the description of the present invention will be divided into three sections: (1) nucleoside derivative combinations; (2) _in vitro assay for demonstrating the HIV-inhibitory effect of nucleoside derivative combinations, and (3) therapeutic uses of HIV- inhibitory nucleoside derivative combinations.
• nucleoside derivatives which may be used in combination include, but are not limited to, 2 ',3 , -dideoxyadenosine (ddA) ; 2',3'- dideoxyguanosine (ddG) ; 2 ' ,3'-dideoxyinosine (ddl) ;
• halogenated nucleoside derivatives may be used, preferably 2',3 / -dideoxy-2 , -fluoronucleosides including, but not limited to 2 ' , 3 '-dideoxy-2'-fluoroadenosine; 2' ,3 ' - dideoxy-2'-fluoroinosine; 2',3'-dideoxy-2'-fluorocytosine; and 2',3'-dideoxy-2 ' , 3 '-didehydro-2'-fluoronucleosides including, but not limited to 2 ',3 / -dideoxy-2 / ,3'- didehydro-2 -fluorothymidine (Fd4T) .
• the halogenated nucleoside derivatives may be used, preferably 2',3 / -dideoxy-2 , -fluoronucleosides including, but not limited to 2 ' , 3 '-dideoxy-2'
• 2' , 3'-dideoxy-2'-fluoronucleosides of the invention are those in which the fluorine linkage is in the beta configuration, including, but not limited to, 2'3'- dideoxy-2'-beta-fluoroadenosine (F-ddA) , 2',3'-dideoxy- 2'-beta-fluoroinosine (F-ddl) , and 2',3'-dideoxy-2'-beta- fluorocytosine (F-ddC) .
• F-ddA dideoxy-2'-beta-fluoroadenosine
• F-ddl 2',3'-dideoxy- 2'-beta-fluoroinosine
• F-ddC 2',3'-dideoxy-2'-beta- fluorocytosine
• the combination of 2',3'-dideox inosine (ddl) and 2',3'dideoxy-2',3'-didehydrothy idine (d4T) represents a preferred embodiment of the invention.
• the combination of 2',3'-dideoxy-2'-beta-fluoroinosine (F-ddl) and 2',3 - dideoxy-2',3'-didehydrothymidine (d4T) also represents a preferred embodiment.
• nucleoside derivatives may be tested for anti-viral activity according to methods known in the art.
• the ability of a nucleoside combination to inhibit HIV cytotoxicity, syn ⁇ ytia formation, reverse transcriptase activity, or generation of viral RNA or proteins may be tested in vitro.
• Combinations of nucleoside derivatives over wide concentration ranges for each may be tested for antiviral and/or cytotoxic activity, and combination indeces may be derived, according to methods outlined in Section 6.1. infra.
• a preferred method for demonstrating the HIV inhibitory effect of nucleoside derivative combinations is set forth in section 5.2 and example section 6, infra.
• nucleoside derivatives may be tested for anti-viral activity in vivo using an animal model system for AIDS, such as the simian immunodeficiency virus (SIV) system (Kanki et al., 1985, Science 230:951- 954) ; however, because different species of animals (or even different cell types within one species) differ in the efficiency with which they phosphorylate these drugs, extreme caution should be used in extrapolating the experimental results obtained in one species (or in one cell type within a species) to another (Yarchoan and Broden, 1987, N. Engl. J. Med. 316:557-564; Waqar, 1984, J. Cell. Physiol.
• SIV simian immunodeficiency virus
• the inhibitory activity of the nucleoside derivative combinations may be tested using an in vitro g assay system such as any of those described in Section 6 et seq. herein.
• the efficacy of any nucleoside derivative combination selected may be assessed by its relative ability to inhibit (a) the formation of syncytia, and (b) the production of HIV 0 particles in HIV-infected cells in vitro using a target cell line that can be infected with HIV.
• a target cell line that can be infected with HIV.
• such cell lines would be of a T-cell or myelocytic/monocytic lineage or another cell type transfected with the gene for
• the target cell line should express the appropriate cell surface antigen or receptor for the molecule conjugated to the nucleoside derivative.
• the target cell should be grown _in vitro, infected with HIV and treated with an array of doses of the nucleoside derivatives before, during or after infection (e.g. , limited dilution 5 techniques can be used) .
• the inhibitory effect on virion production may be assessed as described, e.g.
• HIV proteins such as the 25 gag viral core protein or reverse transcriptase
• the culture media by measuring (a) production of HIV by assaying for HIV proteins, such as the 25 gag viral core protein or reverse transcriptase, in the culture media; (b) the induction of 0 HIV antigens in cells by immunofluorescence; or (c) the reduction in syncytia formation assessed visually.
• the ability of a nucleoside derivative combination to inhibit HIV is indicative of the inhibitory activity and
• the synergistic nucleoside derivative combination may be used in accordance with the invention jLn vivo to prevent the formation of syncytia and the production of
• nucleoside derivatives formulated in suitable pharmacological carriers may be administered by any appropriate route including but not limited to injection (e.g. , intravenous, intraperitoneal, intramuscular, subcutaneous, etc.), by absorption through epithelial or mucocutaneous linings (e.g. , oral mucosa, rectal and vaginal epithelial linings, nasopharyngeal mucosa, intestinal mucosa, etc.); etc.
• injection e.g. , intravenous, intraperitoneal, intramuscular, subcutaneous, etc.
• epithelial or mucocutaneous linings e.g. , oral mucosa, rectal and vaginal epithelial linings, nasopharyngeal mucosa, intestinal mucosa, etc.
• epithelial or mucocutaneous linings e.g. , oral mucosa, rectal and vaginal epithelial linings, na
• nucleoside derivatives may be mixed in any suitable pharmacological carrier, linked to a carrier or targeting molecule (e.g. , antibody, hormone, growth factor, etc.) and/or incorporated into liposomes, microcapsules, and controlled release preparations prior to administration in vivo.
• a carrier or targeting molecule e.g. , antibody, hormone, growth factor, etc.
• synergistic nucleoside derivative combinations may be used in conjunction with other treatments for HIV infection.
• synergistic nucleoside derivatives may be used in conjunction with other antiviral compounds that inhibit reverse transcriptase activity (e.g. , AZT) ; with soluble CD4 or monoclonal antibodies that inhibit HIV absorption to cells; or with other cytokines and growth factors (e.g.
• interferon a ⁇ or 7
• tumor necrosis factor interleukin-2, granulocytic/monocytic colony stimulating factor; colony stimulating factor-1, etc.
• agents that are used to treat other microorganisms or viruses that opportunistically infect AIDS patients are used.
• synergistic nucleoside derivatives can be used in vitro to test the efficacy of different drugs.
• bone marrow derived from AIDS patients exhibits very poor marrow colony formation in vitro. This is probably due to infection of the precursor CD 34 cells with HIV.
• the use of synergistic nucleoside derivatives to inhibit HIV in such an assay system should increase marrow colony formation _in vitro and therefore, permit the screening of various other protocols and drugs on the marrow activity in vitro.
• CELLS AND VIRUS CEM-F cells were originally derived from the acute human lympyhoblastic leukemia and represent an established T lymphoblastoid line. They are available at the American Type Culture Collection as CCRF-CEM cells (ATCC No. CCL 119) .
• the LAV _ . strain of human immune deficiency virus (HIV) was obtained from Dr. Luc Montagnier, Institut
• the virus was adapted to CEM-F cells, and stored i.n small ali.quots i.n li.qui.d ni.trogen.
• TCID- tissue culture inhibitory doses
• the medium consists of RPMI 1640, supplemented with 1% glutamine, 100 U/ml of Penicillin,
• results can be expressed as a tissue culture toxic dose 50 (TCTD 5 _) , which represents the amount in ⁇ g of the drug or drugs necessary to reduce the number of cells by 50% as compared to the control. 6.1.4. INHIBITION OF HIV REPLICATION
• the CEM-F cells were plated in 96 well plates at
• the assay uses two monoclonal antibodies against the viral core protein p24gag (Hu, S.H. et al. , 1987, Nature 328:721-723; and Kinney Thomas, E. et al. , 1988, AIDS 2:25-29) .
• ANTIGEN-CAPTURE ASSAY For this assay Microtiter plates (96 well plates) were coated with two monoclonal antibodies: 25-2 (ATCC #9407) and 25-3 (ATCC #9408), each diluted at 1:2500. These antibodies (capture reagents) are specific for p24, p40, and p55 HIV gag proteins. Horseradish peroxidase (HRP)-conjugated human IgG purified from a serum of a seropositive individual was used as a signal. The absorbance (450/630 nm) is determined after the addition of substrate - tetramethyl benzidine (TMB) .
• HRP horseradish peroxidase
• TMB substrate - tetramethyl benzidine
• the antiviral effect of the nucleoside derivative(s) is expressed as the percent p24gag binding of the control. For example, if that value is 20%, it means that the viral replication, measured indirectly through p25gag binding, is inhibited by 80%. 6.1.6.
• SYNCYTIA FORMATION Prior to collecting supernatants for the antigen-capture assay-, all the wells were visually examined. This was done to assure that the infection took place and also to check the state of the cells. The syncytia were easy to observe, and although they were not counted, the differences in their numbers between wells were very apparent.
• CEM-F is a T-cell line that constitutively expresses the CD4 receptor, and therefore, is an appropriate host cell target for HIV infection.
• the effect of D4T and DDI on proliferation of uninfected cells was assessed by measuring thymidine incorporation in uninfected CEM-F cells treated with D4T and DDI.
• Table I presents the results of a series of experiments used to discern the optimal concentrations and ratios of concentrations of d4T and DDI for achieving maximal anti-viral activity. A wide range of concentrations were tested by evaluating logarithmic increments in the concentration of each derivative in multiple combinations, using a "checkerboard" pattern of testing.
• Cytotoxi .ci.ty assays measuri.ng 3H-thymi.dm. e incorporation show that d4T and ddl used in combination are not more cytotoxic to CEM-F cells than the same total concentration of either compound used individually, despite increased toxicity to virus.
• the results of these assays over a wide range of concentrations of d4T, ddl, or d4T in combination with ddl in 1:1 ratio are shown in Table II.
• Figure 1 contains a graph which shows the antiviral activities of d4T, ddl, and (d4T + ddl at the same total concentration of nucleoside, and clearly shows the synergistic effects of d4T used in conjunction with ddl.
• the combination index (CI) is a numerical representation of the synergistic or antagonistic effects of drug combinations.
• the CI value is obtained using an isobologram equation and computer simulation according to
• a CI value of less than one represents synergy (i.e., the whole is greater than the sum of its parts)
• CI greater than one represents antagonism (i.e. the whole is less than the sum of its parts) and CI equal to one represents additivism, (i.e., the whole is equal to the sum of its parts) .
• Table III shows the CI values of (d4T + ddl) , (d4T + AZT) , and (ddl + AZT) for antiviral effect, when AZT, d4T, and ddl concentrations were in the ratio of 1:10:50.
• the therapeutic window for treating HIV infection is therefore broadened by using these nucleoside derivatives in combination; therapeutic anti-HIV effects may be achieved in patients without risking dangerous or painful complications.

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