HUT73178A - Pharmaceutical composition containing thymoctonan and azt - Google Patents

Description

The present invention relates to the use of thymoctonan in combination with other compounds which inhibit the retrovirus to control the immune system in the treatment of AIDS (Acquired Immunodeficiency Syndrome) or ARC (AIDS related complex). replication equally well. The invention also relates to a pharmaceutical composition for use in such treatments and to processes for the preparation of the pharmaceutical compositions.

AIDS is caused by HIV, a human retrovirus of the lentivirus group. The four human retroviruses so far identified belong to two distinct groups; one is human T lymphotropic (or leukemia) retroviruses such as HTLV-I and HTLV-II, while the other is human immunodeficiency viruses HIV-1 and HIV-2. The former are transforming viruses and the latter are cytopathic viruses. The most common cause of AIDS worldwide is HIV-1. HIV-2 has about 40% sequence homology to HIV-1 and is much more closely related to some members of the simian immunodeficiency viruses (SIV) family. HIV has the usual retroviral genes (env, gag, and pol), and the replication of the virus and other biological activities include six additional extra genes.

In the case of various types occurring AIDS are each characterized by a pronounced immunosuppression, predominantly of cell mediated immunity is suppressed, which in various ···· · * "· 4", _Μ, * ,, _ · · · · · · · · ·· · 9 9 «4 • · · · · 4 *.

· * ··· ·· »t» causes diseases, especially certain infections and neoplasms. In AIDS, the major cause of immune deficiency is a lack of quantity and quality in a subset of thymic (T) lymphocytes, called the T4 population. This subset of cells is characterized by the presence of the CD4 surface cell molecule in terms of phenotype, which serves as a cellular receptor for HIV in the CD4 surface cell molecule. Although the T4 cell is the major cell type infected with HIV, virtually any human cell expressing a CD4 molecule on its surface is capable of binding to HIV or of being infected with HIV. Of particular importance are the monocyte-macrophage affinity of cells.

It is not yet clear to what extent certain parts of the immune system contribute to the host's ability to control HIV. However, significant efforts have been and are being made to enhance the host organism's immune defense against HIV infection, in the hope that this will advantageously alter the course of the disease. Immune regulatory intervention refers to the use of a process or agent that acts primarily on the host's immune system but has no direct antiviral effect. In particular, an immunomodulatory agent, such as thymoctonan, which is known to play an important role in the differentiation and maturation of T-lymphocytes and reverses cell-mediated immunity depression in a number of viral infections, has a regulatory effect by enhancing the immune response · ♦ ··· «« _E ··· «·. * Ί. * * Fej · fej fej fej fej fej 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4

Thymoctonan is a synthetic octapeptide originally isolated and analyzed from fetal calf thymus (U.S. Patent No. 4,621,135).

The present invention relates to products comprising thymoctonant and an antiretroviral agent for use as a combined preparation for simultaneous, separate or sequential use in the treatment of a retroviral disease. The products of the invention are particularly useful in the treatment of patients infected with HIV, in particular HIV-1.

For example, the antiretroviral agent useful in the present invention may be selected from, for example, reverse transcriptase inhibitors (RT inhibitors), such as the HIV or reverse transcriptase nucleoside analogue or non-nucleoside inhibitor (NNRTI); protease inhibitors; substances that block the entry of HIV into the cell; nucleic acid-based drugs; and Tat inhibitors [Tat is a regulatory protein required for HIV replication in cultured cells and is a positive transactivator that stimulates transcription; see, for example, BM Peterlin et al., Proc. Natl. Acad. Sci. USA, 83, 9734 (1986)]. The above classes of antiretroviral agents, with particular reference to HIV, have been summarized in greater detail by Johnston and Hoth, Science, Vol. • · · · · t. · ♦ · ♦ · · «* ♦ • · · · · a _# · ♦ ♦ ··« · · _W

1993).

Examples of RT inhibitors include, but are not limited to: AZT (3'-azidothymidine, zidovudine, Retrovir);

ddl (2 ', 3'-dideoxy-inosine, Didanosine, Videx); ddC (2 ', 3'-dideoxycytidine, Zalcitabine, HIVID); 3TC ((-) - enantiomer of 2'-deoxy-3'-thia-cytidine, Lamivadine); d4T (didehydro-thymidine, Stavidine); 3'-halo-dideoxy-pyridine analogs such as FLT (3'-fluorothymidine); and PMAE {9- [2- (phosphonomethoxy) ethyl] adenine, an acyclic nucleotide}.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) include, but are not limited to, the following: tetrahydroimidazo [4,5,1-gk] [1,4] benzodiazepine-2

- (1H) -one; 11-cyclopropyl-7-methyl-dipyrido [2,3-b: 3 ', 3'-f] -1,4-diazepin-6H-5-one (BI-RG-587, nevirapine); and bis (heteroaryl) piperazines [BHAP, U-87201E, Alevidine Mesylate, ATV; see, for example, D. L. Romero, et al., Proc. Natl. Acad. Sci. USA, 88, 8806 (1991)].

The following three antiretroviral agents are currently being proposed for use in HIV disease: 3'-azidothymidine (AZT, Zidovudine); 2 ', 3'-dideoxy-inosine (ddl, Didanosine); and 2 ', 3'-dideoxycytidine (ddC, Zalcitabine). There are several other substances undergoing clinical trials, of which rIFNA, rIFNβSer17 and rIFNγ are the cytokines; phosphonoformate as an inhibitor of reverse transcription; and ribavirin, amphotericin B, and castanospermine, which attack the retrovirus in different ways. Any of the above can be used as an antiviral agent according to the present invention. · ··· · · · e · ·· - ··· ·· «» »solution.

The mixture of thymoctonan and antiretroviral agent is administered to the patient in an amount sufficient to inhibit retroviral replication; it is noted that thymoctonan is also capable of controlling or reducing side effects associated with antiretroviral agents such as 3'-azidothymidine (AZT).

The invention also relates to pharmaceutical compositions comprising thymoctonant as an immunostimulant and an antiretroviral agent. Such compositions typically include a pharmaceutically acceptable carrier or diluent.

As shown below, the combination treatment has positive and beneficial effects.

The combination therapy of the invention enhances the antiviral activity of the antiretroviral agent and thus provides the most effective and least toxic treatment of ARC or AIDS.

Clinical study of an antiretroviral agent used in combination with thymoctonan has shown that thymoctonan alone specifically provides a synergistic supplement for the treatment of HIV infections, including ARC and AIDS. We have found that thymoctonan used in combination with antiretroviral agents prolongs the survival of HIV-infected individuals.

Preferred anti-retroviral agents for use in the present invention include AZT, ddl and ···· ···· .. ,,

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ddCs, which may be used as antiretroviral agents alone or in admixture with each other.

The amount of antiretroviral agent to be administered is from 10 mg to 1500 mg per day, preferably from 50 mg to 1000 mg per day. For example, the daily dose of AZT for oral administration is 600-1200 mg, while the daily dose of ddl is also 500-750 mg for oral administration.

Thymoctonant is administered in an amount of 0.25-1000 µg / week, preferably 0.5-100 µg / week; the route of administration for thymoctonan is parenteral (intramuscular or subcutaneous).

More preferably, the anti-retroviral agent is administered at the usual dose whereas thymoctonant is administered by intramuscular injection once daily for 15 days (induction period) and then for at least 12 months twice daily at 0.5, 4 or 40 µg.

Thymoctonan, in particular in combination with AZT, was administered to symptomatic HIV infected individuals with a lower CD4 count of 500 / μ1-ηέ1; the results provide convincing evidence that the use of the present invention provides a surprisingly beneficial effect in terms of viral load compared to treatment with AZT alone.

The combined administration of thymoctonan and an anti-retroviral agent according to the present invention includes both when the two agents are administered in a therapeutic mixture, and when the two agents are administered separately, e.g., thymoctonant, intramuscularly or subcutaneously. injection, while the antiretroviral agent is administered orally. The combined administration also includes the case that the two active ingredients are administered separately by administering the other active ingredient a few seconds after administration of the other active ingredient.

Clinical results

As part of a multiple site controlled, double blind clinical trial, 12 patients (4 AIDS, 6 CDC III and 2 CDC II patients) were treated with 4 or 40 mg thymoctonan or placebo twice weekly for the first 6 months. After this period, all patients voluntarily received the highest dose of the unlabeled drug. Patients were also receiving 5000 mg AZT orally daily from the start of treatment.

A case-control plan was chosen to evaluate treatment not specifically labeled. In the control group (1: 2 ratio), there were 24 people enrolled in our health service who started AZT treatment over the same time period; the control group was compared with the thymoctonan-treated group based on gender, age, disease CDC classification, baseline CD4 + T cell count (117.5 and 165 cells / μΐ, respectively), and previous opportunistic infections. All cases and controls received PCP prophylaxis if CD4 + T cell count fell below 200 / μ1. The groups were homogeneous with respect to all of the initial variables considered.

Cases were followed for 19 ± 5 months and controls for ± 5 months. There were no deaths in the thymoctonan-treated group, whereas in the control group (P = 0.01 Fisher), there were 9 deaths (37.5%). No cases of disease progression were observed in the thymoctonan-treated group (based on changes in the CDC group of patients in Phase II or III), whereas in the control group 4 cases occurred, of which 3 died. Four subjects in the thymoctonan group and 11 patients in the control group required hospitalization during the observation period, and 3 and 12 patients, respectively, showed intolerance to AZT. In addition, patients in the thymoctonan-treated group did not require hospitalization without AZT or only spent shorter periods in hospital (P <0.0001 Kruskal-Wallis).

Claims (8)

PATENT CLAIMS CLAIMS 1. Products comprising Thymoctonant and an antiretroviral agent, for use as a combined preparation for simultaneous, separate or sequential use in the treatment of a retroviral disease. Products according to claim 1 for use in the treatment of HIV-infected patients. Products according to claim 1 or 2, for use in the treatment of patients infected with HIV-1. 4. Products according to any one of claims 1 to 6, wherein the antiretroviral agent is 3'-azidothymidine - AZT -, 2 ', 3'-dideoxy-inosine - ddl - or 2', 3'-dideoxy-cytidine - ddC -. A pharmaceutical composition comprising thymoctonant and an antiretroviral agent as an active ingredient in addition to a pharmaceutically acceptable carrier or diluent. The pharmaceutical composition according to claim 5, wherein the antiretroviral agent is 3'-azidothymidine - AZT -, 2 ', 3'-dideoxy-inosine - ddl - or 2', 3'-dideoxy-cytidine - ddC -. . Use of Thymoctonan and an antiretroviral agent in the manufacture of a medicament for the treatment of HIV infected patients. The use according to claim 7, wherein the antiretroviral agent is 3'-azidothymidine - AZT -, 2 ', 3'-dideoxyinosine ddl - or 2', 3'-dideoxy cytidine - ddC -.