Composition for reducing the content of ceramides

 

Proposed: pharmaceutical compositions for reducing the content of ceramides on the basis of L-carnitine or acyl-S-carnitine or L-carnitine or acyl-L-carnitine and nucleotidebinding reverse transcriptase inhibitors, not nucleotidebinding reverse transcriptase inhibitors or inhibitor of HIV protease. The compositions cure HIV infection or AIDS by reducing the level of ceramide, viral load and enhance the immune activity of patients. The invention expands the Arsenal of tools specified destination. 3 s and 5 C.p. f-crystals, 4 PL.

The present invention relates to a new use of L-carnitine, its derivatives and pharmacologically suitable salts in combination with antiretroviral drugs to treat HIV infection and AIDS. In more detail, the present invention relates to the use of L-carnitine, acyl-L-carnitine, where acyl group, a linear or branched, has 2-6 carbon atoms, and their pharmaceutically acceptable salts in combination with nucleocytoplasmic reverse transcriptase inhibitors, not nucleoside analog reverse transcriptase inhibitors and HIV protease inhibitors for reducing the content of ceramides and increasing the activity of the decree is s mechanisms, that contribute to the progression of the infection caused by the human immunodeficiency virus 1 and 2 (HIV-1, HIV-2), directly or indirectly related to the state General activation of the immune system.

Chronic activation of the immune system activates viral replication through the secretion of several cytokines, favoring the expression of HIV, and by the conservation reserve activated immune cells that act as targets for HIV and promote its replication.

In addition, the steady state activation of the immune system induces pathology of this nature (for example, increased apoptosis), leading to weakening of the immune reactions.

Thus, we have a vicious circle: the progressive loss of the normal functioning of the immune system --> viral disseminirovanne reduced remove virus --> chronic activation of the immune system. This process can last for years until until is specified depletion of the immune system that leads to uncontrolled viral replication and attack opportunistic infections or the development of acquired immunodeficiency syndrome (AIDS).

On the basis of the above pathogenic mechanisms becomes clear that one must have in mind Lubna antiretroviral therapy, unfortunately, HIV is characterized by a high degree of genetic variability, occurring mainly at a very significant disadvantage of reverse transcriptase. Retroviral enzyme deprives enzymatic system control possible errors of transcription. The result is the emergence of virus variants is beyond the range that is a function of viral replication is responsible for the progressive deviation of the immune system and resistance to antiretroviral drugs. In the case of zidovudine (zidovudine - AZT,ZDV) loss of clinical efficacy in situations monotherapy is widely recognized. Even open recently antiretroviral agents, for example, zalcitabine [ddc], didanosine [ddI] and lamivudine [ZTS] suffer from such a disadvantage.

Recently it was demonstrated that ceramide stimulates HIV-expression. Moreover, ceramide is one of the factors able to induce cell apoptosis, a phenomenon that is enhanced in people with HIV infection and which contributes to the reduction in the number of TCD4 and TCD8 cells. Thus, it is clear that changes in the concentration or metabolism of ceramide may affect viral load and cell apoptosis in HIV-infected, namely acyl-L-carnitine, in which acyl group, a linear or branched, has 2-6 carbon atoms, and their pharmaceutically suitable salts inhibit the synthesis of ceramide, at least 25%, and when used in combination with antiretroviral drugs, such as AZT, stavudine [4dT], fertility [FLT], isidorean [Azdu], Vospominanie acyclic nucleosides [RMAA], HIV-1 specific oligonucleotides ([TSAO], zalcitabine [ddC] , didanosine [ddI] and lamivudine [3TC], dipyridodiazepinone, tetrahydroxybenzophenone, pyridone or L drugs, bis-heteroarylboronic, derivatives of alpha-anilinoquinazoline, derivatives finokalia, Ro-31-8959, U-81749, INSTITUTE of 227, SC-52151, HOE/BAY 793 and the like, increase potency and protection of the immune system, which is affected by these drugs.

Pharmaceutically acceptable salts of L-carnitine or acyl-L-carnitine include, in addition to internal salts of any salt of these substances with acids, which do not cause unwanted toxic or side effects. Such acids are well known professionals pharmacologists and experts in pharmaceutical technology.

Non-limiting examples of suitable is t; tartrate; phosphate, in particular, acid phosphate; fumarate, in particular, acid fumarate; glycerol; phosphate glucose; lactate; maleate, in particular, acid maleate; orotate; oxalate, in particular the acid oxalate; sulphate, in particular acidic sulfate; trichloroacetate; triptorelin and methanesulfonate.

Particularly preferred L-carnitine, acetyl, propionyl, butyryl, valeryl and isovaleryl-L-carnitine.

Co-administration of L-carnitine and its derivatives, as defined above, together with the antiretroviral agent is usually carried out oral or parenteral way at a daily dose of from 1 to 500 mg/kg, particularly preferred doses from 20 to 100 mg/kg, with a ratio of L-carnitine and its derivatives defined above and antiretroviral agent in the range from 1:40 to 40:1, particularly preferably a ratio of from 1:10 to 10:1.

Usually the drug is administered in the form of standard dosage forms, including both active ingredient, which may also include fillers and additional active ingredients, well known in the art, such as, for example, dextran, TNF-alpha inhibitors (e.g, pentoxifylline), glutathione and other antioxidant drugs (e.g., acetylcysteine, immunomodulatory drugs is C, it should be noted that, apparently, other basic amino acids, particularly lysine, acyl derivatives of basic amino acids and their pharmaceutically acceptable salts can reduce the content of ceramides and to increase the activity of antiretroviral drugs for the treatment of HIV infection and AIDS.

The purpose of the following examples is to illustrate the present invention, they should not be construed as limiting in any way the range of possibilities.

Example 1 was Evaluated the effect of combining L-carnitine (8 g daily by mouth for 4 weeks) plus zidovudine (600 mg daily by mouth) 13 patients suffering from AIDS, with normal serum and intracellular levels of carnitine and azetilcarnitin, which were treated with AZT (600 mg daily by mouth) for at least 6 months.

Determination was performed before treatment combination, when patients took only AZT (THAT), after 4 weeks of therapy with combination of L-carnitine-Z (T1) and one month after stopping treatment with L-carnitine (T2), leaving patients only AZT therapy. Measured TCD4 lymphocytes by flow cytometry using specific monoclonal antibodies (number of lymphocytes / mm3and outrage cells with hypodiploidy cores (the number of lymphocytes at 50,000 cells). Viral load (the number of viral particles per ml of serum) were determined by quantitative determination of HVI-1 RNA using polymerase chain reaction (detection system Roche: Amplicor HIV detection system by Roche). The statistical analysis used the Wilcoxon test.

The results are shown in table. 1.

The same patients the levels of lymphocyte-ceramide measured through studies of DAG(diacylglycerol)kinase (Cifone, M. G., and others, J. Exp. Med. , 180(4), 1547-52), reduced from 488 picomoles/106lymphocytes [measured before treatment combination (THAT)] 275 picomoles/106lymphocytes (T1) (P<0.01), and again increases to 389 picomoles/106lymphocytes month after termination of the introduction of L-carnitine (T2).

These results clearly show that treatment only AZT, even lasting more than 6 months (THAT) may not give such immunological and virological improvements that can be achieved with the combination of L-carnitine-AET within only 4 weeks (T1). These improvements tend to decline after the end of treatment (T2).

Example 2 Four patients with AIDS treated, giving 600 mg of AZT daily by mouth. Two of them also took L-is these muscles. The content of ceramide in the cells of the muscles was determined before and after treatment after cell disruption by ultrasound and homogenization of biopsy material. Viral load was determined in the same homogenates as described in example 1.

The results are presented in table. 2.

It is clear that treatment with the combination of L-carnitine-AZT significantly more effective in reducing viral load and content of ceramide, also content in muscle, compared with treatment with AZT alone.

Example 3 the peripheral blood Lymphocytes of a subject affected by AIDS, isolated in accordance with the classical methods. Cells for 30 min incubated with L-carnitine or isovaleryl-L-carnitine at 37oWith and then for 30 min with monoclonal anti-Fas antibody. The cells are then centrifuged, removed the supernatant and the cell sediment delipetrou. Conduct quantitative analysis of the organic phase (containing ceramide) in the test kit DAG-kinase to determine the content fosforiliruyusciye ceramide, which subsequently confirmed by means of autoradiography.

The results are presented in table. 3.

It is known that appropriately stimulated cells (i.e., Fas-L, interleukine-1 and so on) generate tzera/sup> cells were used anti-Fas antibody.

Example 4 With respect to the Protocol of example 3, but using U937 cells (line tumor cells monocytic leukemia, human) were obtained the results presented in table. 4.

To increase production of ceramide from the basal value 56,51 pcmall 106cells to 70,67 pcmall 106cells were used anti-Fas antibody.

Claims

1. Oral or parenteral pharmaceutical composition for reducing the content of ceramides, comprising as an active ingredient such amount of L-carnitine, acyl-L-carnitine, in which acyl group, a linear or branched, has 2-6 carbon atoms, and their pharmacologically acceptable salts, which is effective to reduce the content of ceramides, and at least one pharmacologically acceptable excipient.

2. Oral or parenteral pharmaceutical composition for therapeutic treatment of HIV infection and AIDS in patients with normal serum and intracellular levels of carnitine, characterized in that it includes at least one of nucleocytoplasmic reverse transcriptase inhibitors, dinucleoside is a, acyl-L-carnitine, in which acyl group, a linear or branched, has 2-6 carbon atoms, and their pharmacologically acceptable salts, which is effective to reduce the level of ceramide and viral load and to enhance the immune activity of HIV-infected patients, and at least one pharmacologically acceptable excipient.

3. Oral or parenteral pharmaceutical composition for reducing the content of ceramides and increase the effectiveness of antiretroviral drugs to treat HIV infection and AIDS in patients with normal serum and intracellular levels of carnitine, characterized in that it includes at least one antiretroviral drug is selected from nucleocytoplasmic reverse transcriptase inhibitors, non-nucleoside reverse transcriptase or HIV protease inhibitors, and the amount of L-carnitine, acyl-L-carnitine, in which acyl group, a linear or branched, has 2-6 carbon atoms, and their pharmaceutically acceptable salts, effective to reduce the levels of ceramides and viral load and to enhance the immune competence of HIV-infected patients, and at least one shall icesto L-carnitine, acyl-L-carnitine, in which acyl group, a linear or branched, has 2-6 carbon atoms, and their pharmacologically acceptable salts, such that the daily dose of L-carnitine, acyl-L-carnitine, in which acyl group, a linear or branched, has 2-6 carbon atoms, and their pharmacologically acceptable salts and antiretroviral drug is from 1 to 500 mg/kg, and the ratio of L-carnitine, acyl-L-carnitine, in which acyl group, a linear or branched, has 2-6 carbon atoms, their pharmacologically acceptable salts and antiretroviral drug is from 1:40 to 40:1.

5. The pharmaceutical composition according to p. 2, characterized in that the amount of L-carnitine, acyl-L-carnitine, in which acyl group, a linear or branched, has 2-6 carbon atoms, and their pharmacologically acceptable salts, such that the daily dose of L-carnitine, acyl-L-carnitine, in which acyl group, a linear or branched, has 2-6 carbon atoms, and their pharmacologically acceptable salts and antiretroviral drug ranges from 20 to 100 mg/kg, and the ratio of L-carnitine, acyl-L-carnitine, in which acyl group, a linear or razvetvlenno the ATA is from 1:10 to 10:1.

6. Oral or parenteral pharmaceutical composition according to p. 3, characterized in that the amount of L-carnitine, acyl-L-carnitine, in which acyl group, a linear or branched, has 2-6 carbon atoms, and their pharmacologically acceptable salts, such that the daily amount of L-carnitine, acyl-L-carnitine, in which acyl group, a linear or branched, has 2-6 carbon atoms, and their pharmacologically acceptable salts and antiretroviral drug is from 1 to 500 mg/kg, and the ratio of L-carnitine, acyl-L-carnitine, in which acyl group, a linear or branched, has 2-6 carbon atoms, their pharmacologically acceptable salts and antiretroviral drug is from 1:40 to 40:1.

7. Oral or parenteral pharmaceutical composition according to p. 3, characterized in that the amount of L-carnitine, acyl-L-carnitine, in which acyl group, a linear or branched, has 2-6 carbon atoms, and their pharmacologically acceptable salts, such that the daily amount of L-carnitine, acyl-L-carnitine, in which acyl group, a linear or branched, has 2-6 carbon atoms, and their pharmacologically acceptable salts and entire is, what are acyl group, a linear or branched, has 2-6 carbon atoms, their pharmacologically acceptable salts and antiretroviral drug is from 1:10 to 10:1.

8. Composition according to any one of paragraphs.1-7, characterized in that it further includes at least one component selected from dextran, alpha TNF-inhibitors, antioxidant drugs, immunomodulators, immunosuppressants, chemotherapeutic agents, vitamins and trace elements.

 

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