JPH05504774A - Use of metalloporphyrins to enhance AIDS treatment - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Applications related to the use of metalloporphyrins to enhance AIDS treatment This application is a part of patent application number (171560, 191) pending with the same applicant. T! This is a continuation application.

Background of the invention The present invention treats viral infections, such as retroviral infections, in mammals, particularly humans. METHODS AND COMPOSITIONS.

Retroviruses are a broad group of RNA viruses that, during their replication, contain RNA molecules. Reverse transcriptase (RT) is used to convert the page to DNA. virus leto The Roviridae family includes the Lentivirinae family (Visna, Medi, late-onset pneumonia virus [ Slow virus J), subumavirinae (foaming viruses) and oncoviruses Includes virus subfamilies (Am, type B, type C, type D, and RNA tumor viruses) . Retroviridae are members of the family that infect primates such as rodents, birds, cats, and humans. It is shown that

Human immunodeficiency virus (HIV-1) or human T-cell lymphotropic virus (HTLV-I[[) is the cause of acquired immune deficiency syndrome (AIDS AI[S)]. , AIDS is related to the complex (ARC), and AIDS related to the disease is retro. It's a virus. Feline leukemia virus (FeLV) is also a retrovirus. Ru.

Retroviruses of the HIV species, such as HIV-1 and HIV-2, are grown in vitro. Destroy auxiliary/inductor cells. The HIV virus is the cause of AIDS and the disease Involved. To date, many cases of AIDS have been reported in the United States; The incidence and prevalence of diseases continues to increase. Reported to the Centers for Disease Control There were 35,238 cases of AIDS in 1989 alone, the highest since 1981. There are over 100,000 cases in the department.

Most people with AIDS always die within one to two years of the first clinical signs of the disease. ing. The disease was initially diagnosed in four high-risk groups: homosexuals, hemophiliacs, and haemophiliacs. was described and characterized among individuals with intravenous drug addiction and intravenous drug users). however , people who are not in this obvious high-risk group also suffer from the disease. workman infection is commonly caused by intimate sexual contact or by administering infected blood products. In some cases, it is also spread by the maternal-fetal route. AIDS symptoms The majority of patients who are now showing up have a period of 6 months to 5 years (or more) between infection and onset of symptoms. ), there is an incubation period, so there are no symptoms when you come into contact with someone and transmit your disease.

Historically, nucleosides have been used to treat NA virus infections, such as retrovirus infections. and the best anti-retroviral agents for treating RNA virus infections. It is one of the. 3-azido-3'-deoxythymidine for the treatment of AIDS Among these therapeutic agents, AZT has shown the most favorable results. But why , AZT has known deficiencies, and many others, most of which are not nucleosides. Several drugs are currently being studied in vitro and in vivo. Among these Some have reached the stage of clinical trials. these are: Dextran sulfate AS I 01 Castanospermine Ambiliken Interferons GM-C3P Ribavirin interleukin-2 Doxorubicin Fusu Skull Net AL721 Suramin Ansumycin Nekobutin HPA-29 Details of the use of AZT and related nucleosides can be found in U.S. Pat. No. 4,724.23. No. 2, and is also disclosed in the references thereto.

Are antiviral treatments for the treatment of AIDS linked to continued retroviral replication? It is based on the assumption that there is a relationship between the onset and progression of the disease. Therefore, RT is This has been a major target for antiviral treatment of AIDS, and indeed Research has been carried out on agents containing AZT that act on enzymes. The properties of these compounds Sulforylated compounds inhibit H[V replication by acting as chain terminators. Ru. HIV reverse transcriptase is more sensitive to these proteins than mammalian DNA polymerases. It is much more sensitive to the inhibitory effects of sphorylated dideoxynucleotides. AZ Administration of T, with its consequent immunological improvements, offers survival benefits to AIDS patients. It shows that it gives benefits.

Successful treatment of AIDS with AZT, however, has been shown to reduce red blood cell anemia and neutropenia. and limiting serious adverse consequences including thrombocytopenia. AZT is administered Depending on the amount and time, erythrocytes, granulocytes, macrophages and primitive hematopoietic system Suppresses the proliferation of strains. Dietary regimens of AZT are associated with significant bone marrow toxicity. Furthermore, A Long-term treatment with ZT allows the virus to reproduce rapidly with a drug-resistant phenotype. may produce selective blood pressure. Such variants are advanced HIV - Isolated from patients with 1 complication, sometimes as early as 6 months after starting treatment. It has been isolated from patients in the early stages of cancer.

Heme or iron protoporphyrin■ is a red color containing four units called pyrroles. is a pigment: these units are chemically combined to form one large tetravirole ( Porphyrin) forms a ring structure. A metal atom is attached to the center of this porphyrin. rated: in higher organicity, this metal is iron, and this porph This ring structure is called protoporphyrin ■. in physiological tissues , heme is bound to the proteins that make it up. These heme proteins contain metal atoms. Components of membranes that combine with oxygen or are connected to electron transport systems It works. Cellular respiration, energy production and chemical oxidation are Depends on heme protein. Hemin is the chloride of heme. Heme synthesis and Mucle degradation is essential for maintaining cellular heme homeostasis and for hematopoietic differentiation. is important.

Tsutsui and Muel 1er (1) are Rauscher+-Rauscher net. Zumi's leukemia virus-binding RT activity was determined by hemin at a concentration of 100 μm. reported to be suppressed. Hemin is the chloride of iron protoporphyrin (heme) It is. This inhibition of RT by high concentrations of hemin is reversible and It appears to be directed toward the enzyme rather than toward the enzyme (late). On the other hand, Hemi did not inhibit the activity of RT purified from avian myeloid leukemia virus.

Synthetic hemes are either chelated atoms or contain tin, chromium, cobalt, zinc or minerals. organometallic porphyrins or porphyrins that are metals other than iron, such as iron Ring structure changed as in protoporphyrin neck or metuporphyrins It includes a wide range of analogues. Representative examples can be shown Synthetic hemes include tin protoprophyrin (SnPP) and tin mesoporphyrin ( SnMP), tin short deuteroporphyrin (Sn[zDP) and this Zinc, chromium, manganese and cobalt compounds corresponding to All are known or can be produced by known methods. Everything is a book It is useful in carrying out the invention. Tin protoporphyrin and tin mesoporphyrin These compounds are preferred because they are readily available and have particularly high activity.

Other derivatives of heme useful in the practice of this invention include acid addition salts of heme, particularly Includes amino acid salts of heme such as L-amino acids such as luginine. Heme's Arginine salts are preferred for the practice of this invention. Other non-toxic inorganic and organic acids It is also possible to use acid addition salts of natural amino acids, especially acid addition salts of natural monoamino acids.

AZT and AZT pear nucleosides in the treatment of retroviral infections Due to these shortcomings, an alternative drug, or at least a reduced dose can be used to reduce side effects of addiction, or to reduce long-term use of therapeutic drugs. To discover agents that enhance the antiviral effects of known therapeutic agents to enable A lot of time, effort and money is spent on it.

Brief summary of the invention Heme, synthetic hemes and heme acid addition salts alone or in combination with anti-HIV drugs. The combination was found to be useful in the treatment of AIDS. For convenience, heme, heme acid addition salts and synthetic hemes are sometimes referred to below as "heme substances". The heme substance is to enhance the activity of antiviral compounds, especially antiretroviral compounds such as AZT. Ru. The present invention utilizes nucleotides such as AZT or dideoxyinosine (DDI). It is particularly useful in combination with CID therapeutics. The present invention also provides erythroboetin (EPO) along with one or more heme substances, including anti-HIV drugs such as AZT. Also included within its scope are pharmaceutical compositions that include. Combination of heme substances and EPO has been observed to be effective in counteracting the adverse effects of anti-HIV drugs.

Therefore, the present invention is directed to mammals, particularly humans, in need of such treatment. Includes methods and compositions for the treatment of torovirus infections. The present invention is characterized by It can be applied to control human AIDS infection.

Brief description of the drawing Figures 1, 2.3.4 and 5 show hemin, AZT, and the combination of hemin and AZT. The results of the studies described here using EPO and these drugs in combination are shown in the graph. It is shown in f.

Detailed description of the invention As used herein, "coadministration" The term refers to the simultaneous administration of multiple therapeutic agents, or the administration of one therapeutic agent to the effect of other therapeutic agents. Continuous administration should be done at sufficiently close time intervals to have a positive effect on seedling growth. It means. Usually, therapeutic agents are administered parenterally in one dose unit. However, the invention is not limited thereto. In fact, one component of the therapeutic combination is For example, nucleosides can be administered orally and heme substances parenterally. Ru.

For convenience, the present invention will be mainly related to heme, AZT (azidothymidine) and EPO. As is clear from the above, the present invention applies to these substances. It is not limited.

To determine the antiviral efficacy of heme alone or with various concentrations of AZT, both AZT-susceptible strains of HIV and AZT-resistant strains of HIV isolated from patients (humans) , and AZ obtained from E RC Bioservices Corporation A number of tests were performed using the T-sensitive strain HTLV-IIIB.

Combination of heme substances and EPO to reverse the negative effects of antiretroviral drugs such as AZT Other tests were conducted to verify its ability to be used.

cells and viruses In this study of heme substances co-administered with AZT, a total of three types of H A type IV-1 strain was used. The two strains were isolated from blood obtained from AIDS patients. (Reference 2).

One isolate was obtained from a patient who had been on AZT treatment for 4 months (1 solat e): This isolate is AZT-resistant (lμMAZT) in Table 1. It is clearly stated as. Other isolates were from patients who had never received AZT. and is cited as AZT-sensitive (at lμM AZT) in Table 1. Ru. Third HIV strain (HTLV-IIIB)+! , NIATD (National National Institute of Infectious Diseases) AIDS Investigation and Standard Testing (NIAID AIDSRes) ERCBios by the search and Reference) program From services Corporation (Rockville, MD) That's what I got.

HTLV-[11B (Reference 3.4) was transferred to H99 cells (Reference 5.6) (E RCB Replicated in ioservices Carp. From AZT-resistant patients AZT-sensitive HIV (Table 1) was also adapted to H99 cells. It was not possible to adapt to these cells.

2 types (7) HTV strain 10% fetal serum (FBS) (Gib IMDM (Iscorp modified Durbecco medium) supplemented with co) (Gibc o) H9 cells were inoculated (passage) L/, and subcultured for 3 to 4 days.

H9 infection by HTV H9 cells (0.5X 10'/d) eHIV (HTLV-III B O and an isolate from an AZT-resistant patient). graded concentration of hemin (Sigma, St, Louis) (0-15.0 ttM) The following two cultures were added. This culture was incubated at 37°C for 10 Maintained in RPMI 1640 medium supplemented with % FBS and 5% of medium containing hemin. 0% was replaced twice within 7 days. At the 78th point, a partial sample of 0, 5 rIdl is divided into equal volumes. The cells were collected with FBS and frozen at -70°C until assayed.

p24 test The Abbott HI V antigen detection system was used according to the Abbott protocol (Reference 7). Samples were assayed in duplicate for the HIV antigen, p24, by the stem. contrast (200μI) or diluted sample (20ul of Triton X for 180μI) 100 to each well and then coated with human antibody against I(T[,V-IIIB). Inverted polystyrene beads were added. Keep the assay plate at room temperature for 16-20 hours. I held it. After washing the beads with water, rabbit antibody against HTLV-rII (20 0 μl was added to each well and the assay plate was incubated at 40”C for 4 hours. . After washing the beads, they were conjugated with horseradish peroxidase (c Add 200 μl of goat anti-rabbit IgG (onjugated) to each well and assay Plates were incubated for 2 hours at 40”C. After the final wash, the beads were placed in the assay plate. Transferred from the rate to the tube and newly made with wj4 containing 0.02% hydrogen peroxide. Add 300 μl of the substrate solution of OPD (o-)22-diamine dihydrochloric acid) Added to each assay tube containing one bead. Place the test tube in the dark for 30 minutes. and incubated at room temperature. Stop the reaction by adding 1 i of sulfuric acid IN to each tube. I made it stop. Control and treated cultures were blotted spectrophotometrically at 492n+n. It was measured with

Culture of HIV in Peripheral Blood Lymphocytes (PBL) Human PBL from Healthy Blood Donors (o, 5xlO'/mj) with 1nVi tro- to two AIDS patients ( The cells were infected with HIV isolated from Table 1). A Z T (Burroughs Wellcome) was added to the culture at a final concentration of 18M, while hemin was added to the culture at a final concentration of 18M. Added at a final concentration of 18M or 10MM in a total volume of 2rnl. These cultures culture medium containing AZT, hemin or a combination of AZT and hemin. 50% of the ground was replaced twice within 7 days. On day 7, aliquots were added with an equal volume of FBS. The samples were collected and frozen at -70°C until assayed.

Cell Viability Tribumble the vitality of cells -Evaluated using the elimination method. In all experiments reported herein, cell life The ability was over 72%.

In the experiments shown in Table 1, AZT (14M) was added to the PBL in VitrO H? in the drug-susceptible strain (Table 1, patient 1) on day 7 of culture. Complete V replication inhibited. Hemin enhances the antiviral effects of AZT when administered at the same time as that drug. Didn't change it. Furthermore, hemin alone (10MM) has no effect on viral replication. It had a suppressive effect. against the AZT drug-resistant IV isolate (Table 1, patient 2). Therefore, hemin alone or AZT had no antiviral activity at the concentrations studied. won. However, the combination of AZT (1 μM) and hemin (1 μM or 10 MM) HIV replication was completely inhibited when using the vaccine.

To extend these observations, additional experiments on hemin and AZT were performed. HrV replication in H99 cells was investigated. In these experiments, AZT from patient 2 Resistant HIV was adapted to H9 cells. HTLV-[type 11B also replicates in H99 cells. was produced and served as an AZT-sensitive strain. AZT sensitivity from patient I in H9 cells It could not be demonstrated that it is possible to adapt sexually transmitted HIV isolates. H9 thin cells were infected with two strains of HIV, and graded doses of AZT (0~1 μM) were added to the culture. Added to two groups of cultivated stocks. Cultured strains were grown in RPMI supplemented with 10% FBS. Hemin (l or 10 MM) was maintained in 1640 medium at 37°C and inoculated twice within 7 days. 50% of the containing medium was replaced. 0.5- aliquots were collected and an equal volume of F was collected on day 7. BS was added and frozen at -70°C until assayed. HTLV-Irl Type B AZ For T-sensitive HIV, the 5096 degree of inhibition (ICf.) of AZT is o, o o sμM (Figure 1). Hemin alone at a concentration of IOμM almost completely replication was blocked (Figure 1). Adding hemin to AZT significantly increases the IC5o of the drug. (Figure 1).

Due to the potency of hemin alone at a dose of 10 MM, the virus-killing efficacy of AZT Fruit increase could not be measured.

In the AZT-resistant HIV strain from patient 2, the IC6 of AZT alone in H9 cells was It exceeded 1 μM. 1 μM hemin alone had no effect on virus replication; 10 M Substantial inhibition (40%) on virus growth was observed at the concentration of M (second figure).

in H9 cells of both AZT-resistant and AZT-sensitive strains of HIV. The dose-response effect of hemin alone on HIV replication was also determined. drug sensitive strains Viral replication was reduced by 50% at hemin concentrations <O, OS μM (Figure 3): For drug-resistant strains, the comparable inhibitory concentration of hemin was approximately 15 μM.

These data demonstrate that hemin (10 MM) alone inhibits AZ in cultured PBLs. In combination with AZT, 18M or is IO μM concentration of hemin or AZ against drug-resistant HIV strains (in HIV strains). This shows that the efficacy of T was greatly enhanced. AZT sensitive grown in H9 cells and AZT-resistant viral strains, either hemin alone or virus disruption and the antiviral properties of AZT against AZT-susceptible virus isolates. Increased action. The dose of hemin required for these effects was determined by Rauscher Required to inhibit virus-associated RT (resistance transfer) activity of murine leukemia virus The dose of hemin was clearly lower than that of standard hemin (Reference 1), and there is no evidence that it is non-cytotoxic. than the doses used in other mammalian cell lines that have been described (ref. 8.9). It was significantly less.

To determine the effect of the combination of heme and EPO on the adverse effects of AZT, normal Human bone marrow hematopoietic colonies were grown in methylcellulose medium and [5cove et al. According to the method (Reference 10), CFU-E (colony forming unit, red blood cells) and 1. To obtain BFU-E (burst forming unit, red blood cells). OU/+J~ 6U/rnl of EPO (Epo Toyo Toyo Jinsaka, Japan) was added to create a colony of red blood cells. The effect on proliferation was demonstrated. Proliferation of CFU-H was recorded for 7 days and BFU-E was recorded for 14 days. Cultures contained 0.1 μm/L AZT, and growth was It was observed with and without the addition of hemin. The results are shown in FIG.

As seen in Figure 5, EPO alone caused AZT cytotoxicity at all concentrations tested. It was not possible to overcome the harmful effects. In all cultures without hemin, total Similar inhibition of CFU-E proliferation was obtained at all concentrations of Epo, with less than IU/d Greater inhibition on BFU-E proliferation was obtained at all Epoa degrees above.

On the other hand, hemin counteracts the cytotoxic effects of AZT and inhibits CFU-E and BFU-E components. We were able to protect Ronnie's proliferation. By AZT (0,1 μmol/L) Addition of hemin (10 μmol/L) to inhibited cultures inhibited CFU-E colonies. - counts up to 279%, BFU-E counts up to 282%, respectively. It increased. The stimulatory effect of hemin was greatest on CFU-E colony formation. IU/- of Epo for BFU-E colony formation or 2U/- of Epo for BFU-E colony formation. This was the case when po existed.

Preferred compositions of the invention are designed for parenteral administration. one or it The above antiviral agents are usually isotonic, aqueous buffered solutions, typically those made isotonic by the addition of sodium chloride, glucose or other standard solutes. It is. The composition may further contain propylene glycol, sesame oil or other inert excipients. It may also contain excipients. As suggested above, AZT and similar agents ( agents) may be administered separately by the oral route.

The therapeutic compositions of the present invention usually contain heme substances and are useful for treating retroviral infections, especially H. One or more compounds useful in the treatment of HIV infection caused by IVI or HIV2 It may additionally contain a compound. Heme substances and antiretrovirals are common , to treat mammals such as humans afflicted by such infections. Exists in useful and effective amounts. Anti-HIV nucleic acids such as AZT and DDI Oside is preferred. As indicated above, the composition further includes EPO. You can stay there.

Useful dosage ranges for the active agents of the present invention vary depending on the selected agent, the age of the patient, and the age of the patient. , weight, general physical condition, and other factors readily assessed by your physician or veterinarian. varies depending on the factors.

For heme materials of the present invention, typically useful dosage ranges include Usually about 0.5 to 50 μg/kg body weight, with or without other anti-HIV drugs. be. Dosage ranges for anti-I (IV agents) are based on those commonly used for these drugs. of the same order of magnitude as the heme content, or the significant contribution of the heme material to this composition. Therefore, the concentration of anti-HIV agent in a particular composition depends on whether the agent is used alone or not. May be lower than recommended if available.

Various dosage units are provided to accommodate treatment at such dosage levels. It will be done. A typical dosage unit is 0.2 heme, whether used alone or not. It may contain 5 to 50 μ/kg of heme material. The concentration of anti-HIV drugs is probably , in an amount of the same order of magnitude as if it were used alone.

For AZT, the dosage levels when administered with the hemin products of the invention are: , usually about 5 to 250 cm/kg body weight. Such a level is about 1~80■/ This can be conveniently achieved by administering a parenteral dosage unit containing kg of AZT. Ru.

If the compositions of the present invention contain EPO, the dosage range will generally be Normally, the weight is 50 to 300 cm/kg body weight. Typically, the dosage unit will be about 10 to 10 Contains 0 units/kg of EPO.

Acid addition salts are more hydrated than heme or heme, which is the commonly used form of hemin. Because it is soluble, heme alginate is preferable to heme for use in the present invention. preferable. Moreover, it can be used intravenously without the complications associated with intravenous use of heme. It can be administered to Also, it is more stable than heme. Both substances are common Since it is obtained from animal sources, it is free of undesirable impurities and In addition, to ensure that the material is free of viruses or other infectious organisms, In order to be fruitful, they must be manufactured by tedious and expensive methods.

Synthetic hemes are present at concentrations where they are useful in the buffered, isotonic, aqueous compositions of the present invention. soluble and can be administered by any parenteral route, including intravenously is particularly preferred for the practice of the present invention, not only because it can be used, but also for several other reasons. Yes. They can be chemically synthesized and should be handled with ordinary care. does not suffer from viruses or other contamination and, in contrast to natural products, lasts for several years. It can be manufactured into a lyophilized form that is stable for a long time.

The compositions of the present invention can achieve the above-mentioned purposes using standard, readily available ingredients. Manufactured using conventional methods.

Typically, the pH of the buffered composition is usually about 7-8, preferably about 7. ．． It is 4 to 7.5.

Table 1 HTV Antigen, P24, pg/ml (% inhibition) Treatment AZT Sensitivity AZT Resistance AZT-susceptible H[V isolate AZT O11800 (0,0) 101000 (0,0) AZT l am 42 (100,0) 90000 (11,0) Hemin 1 μm 104000 (12,0) 99500 (1,5) Hemin 10μm 35000 (70,0 )” 101500 (0,0) AZTI μm + Hemin 1 μm 42 (100,0 )"+400(99,0)"AZTIμm+heminIOμm 29(100, 0) @+45(100,0)”*p value 0,01~O,OO1 Literature 1, Tsutsui, K, and G, C, 1jueller, 1987 Hemin inhibits the virion-associated reversal enzyme of the murine leukemia virus.

Biochem, and Biophys, Res, Comm, 14 9: 6282, Ho, D, D,, T, R, Rota, R, T, 5chooley, J., C. Kaplan.

J, D, A11an, J, ε, Groupman, L, Re5ni k, D, Fe1senstein.

C, A, Andrews and M, S, Hirsch 1985, acquired. H from cerebrospinal fluid and nervous tissue of patients with neurological syndromes associated with immunodeficiency syndromes. Isolation of TLV-III. N, Engl, Jr,! Jed, 313: 1493.3, Popovic, M,, M, G, Sanrgadha ran, E, Read and R,C.

Ga1lo, 1984, x-AIDS and pre-AIDS (pre-AIDS) Detection, isolation and isolation of cytopathic retrovirus (HTLV-11) from patients with and continuous manufacturing. 5science, 224: 497°4, Ga1lo , R, C, , S, 5alahuddin, M, Popovic, G. M, 5hearer.

M., Kaplan, B., F. Haynes, T. J., Pa1ken, R. Red. field, J.

01eske, B, 5ofai, G, White, P, Foste r and P, D, Markham.

1984 Cells of patients with AIDS or at risk of AIDS Routine detection and isolation of modified retroviruses (HTLV-[[I] 5cie nce, 224: 5005, Popovic, M,, E, Read -Connole and R, C, Ga1lo, 1989 Sensing HTLV-III A facile and permissive T4 positive human neoplastic cell line. Tantodan, 100: 1472. 6, Mann, D, L,, S, J, 0' Br1en, D, A, G11bert, Y, Re1d.

M, Popov, E, Read-Connole, R, C, Ga1lo and A, F, Gazder.

1989. Origin of the HIV-susceptible human CDJ+ cell line H9.

AIDS Res, and Human Retroviruses, 5 : 2537, 5pivak, J, L,, D, C, Barnes, E, Fuchs and T, C, Quinn 1989, in patients with HIV infection. Serum immunoreactivity of erythroboetin.

JAMA, 261: 3104゜ 8, Yarchoan, R,, R, W, Klecker, K, J, W einhild, K, H.

Lyerry, E., Gelman, R.M., Blum, G.M., 5hearer. , H., Mitsuya.

J, M, Colins, C, E, Myers, P, D, Mar kham, D, T, Durak.

S.N., Lehrman, D.W., Barry, M.A., Fischl, R.C. , Ga1lo.

P., P. Bolognesi and S. Broder, 1986, Administration of 3'-azido' 3'-deoxythymidine and AIDS or AIDS-related HTLV-1 [[/LAV] for patients with linophore complex virus) inhibition of replication. Lancet, 1: 575°9, 8rown, A, , J., D., Lutton, J., C., Nelson, N., G., Abr. aham and R,D, Levere, +987, Small Habitat Cytokinesis and and expression of erythroid heme-metabolizing enzymes. Blood Ce1ls, 13: 12 3.

10.1scove NN, 5ieber F, stomach 1nterhalter KH, Gel filtration and affinity analysis using agarose concanavalin. Mouse and human erythropoietin requirements by chromatography Colony formation of red blood cells in cultures for bone marrow analysis.

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Claims (19)

[Claims] 1. Treatment of retroviral infections in mammals in need of treatment A method comprising heme, acid addition salts of heme, organometallic porphyrins, and mixtures thereof. A buffered isotonic aqueous solution containing a drug selected from the group consisting of A method consisting of administering a sufficient amount parenterally. 2. Methods for treating retroviral infections in humans in need of treatment and heme, acid addition salts of heme, organometallic porphyrins, and mixtures thereof. A buffered isotonic aqueous solution containing a drug selected from the group consisting of: A method consisting of parenteral administration in a sufficient amount. 3. Methods for treating retroviral infections in humans in need of treatment and heme, acid addition salts of heme, organometallic porphyrins, and mixtures thereof. A buffered isotonic aqueous solution containing an anti-HIV agent together with a drug selected from the group consisting of A method consisting of parenteral administration in a therapeutically sufficient amount. 4. A method for treating HIV infection in a human in need of treatment, the method comprising: heme; selected from the group consisting of acid addition salts of heme, organometallic porphyrins and mixtures thereof; A buffered isotonic aqueous solution containing the drug along with AZT is sufficient to carry out the above treatment. A method consisting of parenteral administration of a certain amount. 5. A method for treating HIV infection in a human in need of treatment, the method comprising: heme; selected from the group consisting of acid addition salts of heme, organometallic porphyrins and mixtures thereof; A buffered isotonic aqueous solution containing the drug along with AZT is sufficient to carry out the above treatment. parenteral administration of erythropoietin in an amount sufficient to reverse the adverse effects of AZT. A method consisting of doing. 6. Claim 2, 3, 4 or 5, wherein the acid addition salt of heme is heme alginate. Law. 7. Claims 2, 3, 4, wherein the organometallic porphyrin is tin protoporphyrin. Or method 5. 8. Claims 2, 3 and 4, wherein the organometallic porphyrin is tin mesoporphyrin. Or method 5. 9. 6. The method of claim 2, 3, 4 or 5, wherein said agent is heme. 10. consisting of heme, acid addition salts of heme, organometallic porphyrins and mixtures thereof. Drugs selected from the group are available in combination with antiretrovirals to A drug set for treating retroviral infections in mammals consisting of a buffered isotonic aqueous solution containing A product. 11. consisting of heme, acid addition salts of heme, organometallic porphyrins and mixtures thereof. Drugs selected from the group are available in combination with antiretrovirals to A pharmaceutical composition for treating human retrovirus infection comprising a buffered isotonic aqueous solution containing . 12. consisting of heme, acid addition salts of heme, organometallic porphyrins and mixtures thereof. Contains a drug selected from the group consisting of anti-HIV drugs in an amount sufficient to carry out the above treatment. A pharmaceutical composition for treating human HIV infection comprising a buffered isotonic aqueous solution. 13. consisting of heme, acid addition salts of heme, organometallic porphyrins and mixtures thereof. A mild drug containing a drug selected from the group consisting of AZT and a sufficient amount to carry out the above treatment. A pharmaceutical composition for treating human HIV infection comprising an isotonic aqueous solution. 14. consisting of heme, acid addition salts of heme, organometallic porphyrins and mixtures thereof. The above treatment is carried out with a drug selected from the group consisting of anti-HIV drugs and erythropoietin. A drug set for the treatment of human HIV infection consisting of a buffered isotonic aqueous solution containing a sufficient amount of A product. 15. Heme, amino acid addition salts of heme, organometallic porphyrins and mixtures thereof The above treatment is carried out with a drug selected from the group consisting of AZT and erythropoietin. A drug for the treatment of human HIV infection consisting of a buffered isotonic aqueous solution containing a sufficient amount to Composition. 16. Claims 10, 11, 1 wherein the heme amino acid addition salt is heme alginate. Compositions 2, 13, 14 or 15. 17. Claim 10, 1, wherein the organometallic porphyrin is tin protoporphyrin. Compositions 1, 12, 13, 14 or 15. 18. Claims 10 and 11 wherein the organometallic porphyrin is tin mesoporphyrin. , 12, 13, 14 or 15. 19. Claim 10, 11, 12, 13, 14 or 15, wherein the drug is heme. Composition.