SI20191A - Drug delivery devices and methods for treatment of viral and microbial infections and wasting syndromes - Google Patents

Abstract

Novel drug delivery devices, methods and therapeutic compositions are described for treating viral and microbial infections and wasting syndromes in an animal, including a human patient. According to the invention, a polar compound such as dimethylformamide or dimethylsulfoxide is administered to a patient in need of treatment, preferably by a transdermal route. The invention further provides a vaccine prepared from antibodies harvested from the body of a patient treated by the method of the invention for a viral infection.

Description

CRYOPRESERVATION TECHNOLOGIES CC 1/1738

607 21st Avenue

Rletfontein 0084, Pretoria

South Africa _l

PREPARATIONS FOR ADMINISTRATION OF THE MEDICINAL PRODUCTS AND METHODS

FOR TREATMENT OF VIRUS AND MICROBIAL INFECTIONS

AND FEEDING SYNDROME

FIELD OF THE INVENTION

The present invention relates to methods of treating an animal with a viral or bacterial infection, in particular by infection with a retrovirus such as HIV, or by a hiding syndrome, in particular by a hindering syndrome associated with HIV infection or malignancy, by administering a polar compound such as N , 'Dimethylformamide (DMF) or dimethylsulfoxide (DMSO). The invention also provides pharmaceutical compositions and devices for the administration of an active ingredient containing a polar compound, such as DMF or DMSO, for the treatment of animals afflicted with a viral or other microbial infection or with hovering syndrome.

BACKGROUND OF THE INVENTION

Human immunodeficiency virus

Human immunodeficiency virus (HIV) involves persistent and progressive infection that in most cases leads to the development of acquired immunodeficiency syndrome (AIDS) (Barre-Sinoussi et al., 1983; Science 220: 868-870; Gallo et al., 1984; Science 224: 500-503). There are at least two distinct types of HlV: HIV-1 (Barre-Sinoussi et al., 1983, Science 220: 868-870;

Gallo et al., 1984, Science 224: 500-503) and HIV-2 (Clavel et al., 1986, Science 223: 343-346; Guyader et al., 1987, Nature 326: 662-669). In humans, duplication of HlV occurs in CD ₄ ⁺ T lymphocyte populations and HIV infection leads to depletion of this cell type and to failure of the immune system, opportunistic infections, neurological outbreaks, neoplastic growths (tumors) and ultimately death.

HIV is one of the lentiviruses that are members of the retrovirus family (Teich et al., 1984; RNA Tumor Viruses, Weiss et al., Eds., CSH-press, pages 949-956). Retroviruses are small mantle viruses that contain the single stranded RNA genome and replicate via the DNA interface produced by the virus-encoded reverse transcriptase, RNA-dependent DNA polymerase (Varmus H., 1988, Science 240: 14271493). Other retroviruses include, for example, oncogenic viruses such as human T-cell leukemia viruses (HTLV-I, -II, -III) and feline leukemia virus.

The viral particle of HlV consists of a viral envelope composed of capsid proteins labeled with p24 and pl8, together with the viral RNA genome and those enzymes required for early replication. Myristylated seal proteins form an outer viral envelope around the viral cortex, which is alternately surrounded by a lipid membrane envelope obtained from an infected cell membrane.

HIV envelope surface glycoproteins are synthesized as single 160 kilodalton precursors of proteins cleaved by cellular protease during viral vaccination to two glycoproteins, gp41 and gpl20. Gp41 is a transmembrane glycoprotein, gpl20 is an extracellular glycoprotein that remains non-covalently bound to gp41, in trimeric or multimeric form (Hammerskjold, M. and Rekosh, D., 1989, Biochem. Biophys. Acta 989: 269-280).

HIV, like other enveloped viruses, inserts the viral genetic material into the host cell by combining the viral and target membranes mediated by the viral envelope. HIV targets CD4 ⁺ cells because the CD4 cell surface protein (CD4) acts as a cellular receptor for the 'HIV-1 virus' (Dalgleish et al., 1984, Nature 312: 763-767; Klatzman et al., 1984, Nature 312: 767-768; Maddon et al., 1986; Celi 47: 333-348). Virus entry into cells is dependent on gpl20, which binds cellular CD4 receptor molecules (Pal et al., 1993; Virology 194: 833-837; McDougal et al., 1986, Science 231: 382-385; Maddon et al., 1986, Whole 47 : 333-348), which explains the tropism of HlV to CD4 cells, while gp41 retains the glycoprotein complex in the virus membrane. Binding of gpl20 to CD4 causes structural changes in the virus glycoproteins, but binding alone is not sufficient to develop infection (reviewed by Sattenau and Moore, 1993; Philos.Trans.R. Soc. London (Biol.) 342: 59-66).

Studies of isolated HIV-1 have shown heterogeneity in their ability to infect different cell types in humans (reviewed by Miedema et al., 1994;

Immunol.Rev.140: 35-72). Most widely investigated HIV-1 laboratory chains easily infect T cell cultures and primary lymphocytes, but not primary monocytes or macrophages. These chains are called T-tropes. T-tropic HIV1 chains are more readily found in late-stage AIDSA in individuals infected with HIV-1 (Weiss et al., 1996, Science 272: 1885-1886). Most isolated primary HIV-1 (i.e., non-cultured viruses) replicates effectively in primary lymphocytes, monocytes, and macrophages, but grows poorly in established T cell lines. These isolates are called M-tropics. The viral determinant of T- and M-tropism contains changes in the third variable region of gpl20 (V3 loop) (Choe et al.

1996, Cel 85: 1135-1148; Cheng-Mayer et al., 1991,

J.Virol. 65: 6931-6941; Hwang et al., 1991, Science 253: 71-74; Kirn et al., 1995, J. Virol., 69-1755-1761; and O'Brien et al., 1990, Nature 348: 69-73).

Determining HIV isolates by differentiating tropism, along with the observation that binding to the CD4 cell surface of the protein is insufficient for infection, means that, in addition to CD4, specific cell type cofactors may be required for the entry of HIV-1 into the cell.

Treatment of HIV infections

HIV infection is a pandemic and is a major health problem in HIV-related diseases. Although considerable effort is being made to develop an effective drug, there is currently no active antiretroviral agent for AIDS. In an attempt to develop such agents, several stages of the HIV life cycle have been considered as targets for therapeutic intervention (Mitsuya H. et al., 1991, FASEB J. 5: 2369-2381). Many viral targets have been proposed to mediate the life cycle of HlV, but the prevailing view is that interference with the host cell protein has deleterious side effects, both physically and psychologically. For example, one aspect of drug development was viral encoded reverse transcriptase. Many active substances have been developed to target reverse transcriptase, including 2 ', 3'-dideoxynucleoside analogues, such as AZT, ddl, ddC, and d4T, which have been demonstrated to act on HIV (Mitsuya H. et al., 1991, Science 249: 1533 -1544).

New HIV-1 treatment methods show that combination of anti-HIV reverse transcriptase (RT) compounds, such as azidothymidine (AZT), lamivudine (3TC), dideoxinosine (ddl), dideoxycytidine (ddC), are used in combination with an HIV-1 protease inhibitor, a much greater effect (2 to 3 logarithmic reductions) on the amount of virus compared to AZT alone (about 1 logarithmic decrease). For example, convincing results have recently been obtained with the combination of AZT, ddl, 3TC and ritonavir (Perelson AS et al., 1996, Science 15: 1582-1586). However, long-term use of combinations of these chemicals is likely to lead to toxicity, especially for the bone marrow. Prolonged cytotoxic therapy can also lead to the inhibition of CD8 ⁺ cells required for HlV control through destructive cellular function (Blazevic V. et al., 1995, AIDS Res.Hum.Retroviruses 11: 1335-1342) and by release inhibitory factors, in particular the Rantes,,-Ια and MIP-Ιβ chemokines (Cocchi F. et al., 1995;

Science 270: 1811-1815). Another major concern in long-term chemical antiretroviral therapy is the development of HIV mutants with partial or complete resistance (Lange JM, 1995, AIDS Res.Hum. Retroviruses 10: S77-82). Such mutations are considered to be an inevitable consequence of antiviral therapy. The pattern of disappearance of the original virus type and the emergence of the mutant virus due to treatment, combined with the concomitant decline in CD4 ⁺ T cell counts, strongly suggest that the appearance of the virus mutants is the main cause of AIDS therapy failure in at least some compounds.

Attempts have also been made to develop active substances that can inhibit the entry of the virus into the cell, which is the earliest stage of HIV infection. The focus here so far has been on CD4, the cell surface receptor for CD4. For example, recombinant soluble CD4 has been shown to inhibit infection of CD4 ⁺ T cells with some HIV-1 chains (Smith DH et al., 1987, Science 238: 1704-1707). Certain primary HIV-1 isolates are relatively less sensitive to inhibition by 'recombinant CD4' (Daar E. et al., 1990, Natl. Acad. Sci. USA 87: 6574-6579). Furthermore, clinical trials of recombinant soluble CD4 give indecisive results (Schooley R. et al., 1990; Ann.Int.Med. 112: 247-253; Kahn JO et al., 1990, Ann.Int.Med. 112: 254-261; Yarchoan R. et al., 1989, Proc.Vth Int.Conf. On AIDS, page 564, MCP 137).

The late stages of HIV duplication, involving decisive viral-specific processing of certain virus-encoding proteins, have also been suggested as possible targets for the active substance in the fight against HIV. Late-stage processing depends on the activity of the viral protease, and active agents have been developed to inhibit this protease (Erickson J., 1990, Science 249: 527-533).

Recently, chemokines produced by CD8 ⁺ T cells have been implicated in the inhibition of HIV infection (Paul WE,

1994, Cel 82: 177; Bolognesi D.P., 1993, Semin.Immunol. 5: 203).

The CD8 ⁺ T-secreted R8TES, ΜΙΡ-Ια and MIP-Ιβ chemokines have been shown to inhibit the production of HIV-1 p24 antigen in cells infected with HIV-1 or HIV-2 isolates in vitro (Cocchi F. et al., 1995; Science, 270: 1811-1815).

Thus, these and other chemokines may be effective in the treatment of HIV infection. However, the clinical outcome of these and other active substance candidates remains unclear.

Attention is also focused on the development of vaccines for the treatment of HIV infections. HIV-1 envelope proteins (gpl60, gpl20, gp41) have been proven to be major antigens for anti-HIV antibodies present in AIDS patients (Barin et al., 1985, Science 228: 1094-1096). Therefore, so far, these proteins have been considered as the most promising antigen candidates in the development of anti-HIV vaccines. Several groups have begun using different doses of gpl60, gpl20, and / or gp41 as immunogenic targets for the host immune system. See, for example, Ivanoff L. et al. U.S. Pat. no. 5,141,867; Saith G. et al., WO92 / 22,654; Shafferman A. et al., WO91 / 09,872; Formoso C. et al. W090 / 07,119. Vaccines targeting HIV proteins are problematic in that the virus mutates very quickly, making many of these vaccines ineffective. Clinical results, blood concerns these vaccine candidates, but they still remain a long way to come.

Thus, although much effort has been invested in the design and testing of anti-retroviral agents, effective, non-toxic treatments are still needed.

Feeding syndrome

Feeding syndrome is a serious clinical problem, characterized by weight loss of more than 10% of body weight and uneven weight loss relative to body fat (Weinroth et al., 1995, Infectious Agents and Disease 4: 76-94; Kotler and Grunfeld, 1995, AIDS Ciin.Rev. 96: 229-275). Thus, digestion is separated from starvation, in which higher levels of body fat are depleted than body cell masses (Kotler et al., 1985;

Am.J.Ciin.Nutr. 42: 1255-1265; Cahill, 1970, N.Engl.J.Med. 282: 668-675). Feeding is associated with various conditions, including HIV infection, other infectious diseases, sepsis, cancer, chronic cardiovascular disease and diarrhea (Kotler et al., 1989; Am.J.Ciin.Nutr. 50: 444-447; Heymsfield et al., 1982 , Am.J.Ciin.Nutr. 36: 680-690). Feeding is an important factor in the mortality of patients with infection or cancer. Body cell mass depletion is even linearly proportional to the survival time of AIDS patients (Kotler et al. 1989;

Am.J.Ciin.Nutr. 50: 444-447).

The cause of the hiding syndrome in AIDS and other conditions is unclear and is likely to be due to several factors. Hating syndrome includes abnormalities in metabolism, abnormal levels of hormones and cytokines, and poor absorption. But not everyone with AIDS suffers from the syndrome of hives, which indicates that it is not caused by HIV. Most cases of HIV-related eating syndrome are apparently due to complications of AIDS, such as secondary infections and gastrointestinal disease (Kotler and Grunfeld, 1995; AIDS Ciin.Rev. 96: 229275).

Ongoing and possible therapies for the nutrition syndrome include nutritional support, appetite boosters such as dronabinol and megestrol acetate, anabolic therapies such as racial hormone and cytokine inhibitors. Anyway, we get mixed results with nutritional support and appetite boosters in those patients who are aiming to gain fat rather than total body weight. The administration of growth hormone and cytokine inhibitors is still under investigation and may cause risky side effects (Kotler and Grunfeld, 1995; AIDS Ciin.Rev. 96: 229-275; Weinroth et al., 1995, Infectious Agents and Disease 4: 76-94) .

Thus, the treatment of feeding syndrome is critical for the survival and well-being of patients with serious illnesses such as cancer and AIDS. Therefore, there is a need for safe and effective therapies against cancer syndrome associated with cancer, AIDS and other infectious diseases.

Properties of dimethylformamide and other polar substances

N, N'-Dimethylf ormamide (DMF) (Molecular Formula: C3H7ON) is a colorless, polar, hygroscopic liquid with low volatility and boiling point of 152.5 to 153.5 ° C. It mixes freely with water, alcohols and some hydrocarbons. DMF is commonly used as a polar solvent and can be absorbed through the skin, by inhalation or by oral administration. DMF is rapidly metabolized, mainly in the liver, excreted mainly in the urine. In the rat, mouse, hamster and human, the major metabolites of DMF are Nhydroxymethyl-N-methylformamide (HMMF), N-methylformamide (NMF) and N-acetyl-S- (N-methylcarbamoyl) cysteine (AMCC), as well as dihydroxymethylformamide ( DHMF) and N-hydroxymethylformamide (HMF). A small portion of the administered dose of DMF is excreted in the urine as unchanged DMF.

DMF has low acute dermal, oral and inhalation toxicity. It is a mild to moderate irritant to the skin and eyes and passes quickly through the skin. There are no indications of an increase in skin sensitivity. The major toxic effect of DMF and its metabolites is on the liver; DMF is known to cause reversible liver damage associated with typical clinical problems, common biochemical changes in blood, and the occurrence of hepatocyte necrosis in liver biopsies. DMF is teratogenic but not mutagenic or carcinogenic.

Visa et al. Report that DMF and DMSO inhibit in vitro duplication of HlV and HHV 6 (Human Herpes Virus) in certain cultured cell lines (see Visa et al., 1990, AIDS Res. Hum. Retroviruses 6: 131-132; Visa et al., 1989, AIDS-FORSCHUNG 4: 349-352; Visa et al., 1992, Antiviral Res. 18: 27-38 and corrected 19: 179).

DMF has been described as an in vitro distinguishing agent for certain altered cells in culture (see Koeffler, 1983; Blood 62: 709-721; Calabresi et al., 1979, Biochem. Pharmacol. 28: 1933-1941). When added to certain malignancies in vitro, DMFs reduce their ability to form tumors upon subsequent vaccination in a nude mouse (see Dexter, 1977; Cancer Res. 37: 3136-3140; Dexter et al., 1979, Cancer Res. 39: 1020-1025). Intraperitoneal injection into the nude mouse, DMF, and NMF slows the growth of certain alien implants of human cancer (see Van Dongen et al. 1989; Int. J. Cancer 43: 285-292; Braakhuis et al. 1989; Head & Neck 11: 511- 515; Van Dongen et al., 1988, Acta Otolaryngol 105: 488-493, Dexter et al.

1982, Cancer Res. 42: 5018-5022). However, the toxic side effects of formamide and its N-methyl derivatives in the mouse sarcoma model have led scientists to conclude that these agents are unlikely to prove to be therapeutically effective (see Clarke et al., 1953, Off. Sec. .Exp.Biol.Med., 84: 203-207).

Attempts to treat human cancer patients with DMSO have led to the conclusion that no objective effect is shown (see Spremulli & Dexter, 1984, J.Clin.Oncol. 2: 227-241). Oral administration of NMF to patients with head and neck cancer showed hepatotoxicity without any useful response (see Vogel et al., 1987; Invest. New Drugs 5: 203-206) or with only minimal activity (see Planting et al., 1987; Cancer Treat Rep. 71: 1293-1294).

U.S. Pat. No. 3,551,154 shows the use of DMF as a penetration enhancer in the transdermal absorption of topically applied drug. U.S. Pat. No. 4,855,294 discloses the use of glycerin to alleviate skin irritation resulting from the use of DMSO and DMF as penetration enhancers for transdermal absorption of topically applied drug. 0 using DMSO as a penetration enhancer for transdermal absorption of antiviral agents is reported in Woodford & Barry, 1986, J. Toxicol.Cut. &

Ocular Toxicol. 5: 167-177.

Citing or identifying with any of the references in Part 2 (or any other part) of this subject application is not intended to acknowledge that the invention was based on this reference.

SUMMARY OF THE INVENTION

The present invention relates to methods, mixtures and preparations for the administration of the active substance for the treatment of animals affected by a viral or other microbial infection, in particular infection with a retrovirus such as HIV. The invention also provides methods, mixtures and preparations for the administration of the active ingredient for the treatment of animals with hover syndrome, such as hazing associated with HIV infection or malignancy.

In accordance with the present invention, a composition comprising N, N'-dimethylformamide (dimethylformamide, DMF) is administered to the animal in need of treatment; N-hydroxymethyl-N-methylformamide (HMMF); N-hydroxymethylformamide (HMF); dihydroxymethylformamide (DHMF); N-acetyl-S- (N-methylcarbamoyl) cysteine (AMCC); N-methylformamide (NMF); dimethyl sulfoxide (DMSO); formamide; acetamide; methylacetamide; dimethylacetamide; diethylacetamide; isopropylacetamide; diisopropylacetamide; Nacetylpiperidine; N- (β-hydroxyethyl) acetamide; N, N'-di (P ~ hydroxyethyl) acetamide; N-acetylmorpholine; acrylamide; propionamide; N-fluoromethyl-N-methyl-formamide; pyridine-Noksid; or any active ingredient selected from the group consisting of amides of the general formula R ₃ -CO-NR _X R ₂ , wherein R 1 and R _{2 are} independently selected from the group consisting of H, methyl, halomethyl, saturated and unsaturated C ₂ -C ₃ alkyl groups and hydroxylated alkyl groups; or

R 1 and R ₂ are together selected from the group consisting of (CH ₂ ) ₄ , (CH ₂ ) ₅ and (CH ₂ ) ₂ O (CH ₂ ) ₂ ; and

R ₃ is selected from the group consisting of H, methyl, and saturated and unsaturated C ₂ -C ₃ alkyl groups. The therapeutic composition may comprise a mixture of any two or more of the abovementioned compounds.

In a patient infected with HIV, for the therapeutic effect, a mixture of the present invention may be combined with one or more additional agents that are effective in treating HIV infections and include, but are not limited to, a substance selected from the group consisting of nucleoside reverse transcriptase inhibitors , non-nucleoside reverse transcriptase inhibitors and protease inhibitors, in any desired combination.

The invention encompasses vaccines prepared from antibodies obtained from the bodies of animals after treatment of a viral infection with a mixture of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be better understood by the following detailed descriptions of the invention, examples of specific embodiments of the invention, and the accompanying drawings where:

Figure 1 shows the plasma concentrations of DMF as a function of time in 4 patients who were given two DMF skin patches for 8 hours.

Figure 2 shows the plasma concentrations of DMF as a function of time in three patients who received two DMF skin patches for 6 hours.

Figure 3 shows the amount of HIV-1 measured by quantitative PCR in patients treated with DMF by transdermal administration. Two DMF patches were applied to the skin in the forearm area for 12 hours on days 0, 8, and 13 (indicated by arrows).

Figure 4 shows the general condition of HIV-infected patients before and after treatment with transdermally administered DMF, as assessed by Karnofsky's rating scale, which is described in more detail below.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to methods, mixtures and preparations for the administration of the active substance for the treatment of viral and microbial infections. In one embodiment, the treated infection is a retrovirus infection such as HIV, which includes asymptomatic infections, latent infections, infections accompanied by one or more symptoms of AIDS-related complexes, and infections accompanying clinical AIDS. Alternatively, infections of any viral or microbial infection, including rubella infection, herpes virus such as HHV 6 (Human Herpes Virus), Epstein-Barr virus or cytomegalovirus, infection with any virus having a capsid protective coat and any opportunistic infection may be treated an infection associated with immune system disease such as opportunistic infection in patients infected with HlV.

The present invention also provides methods, mixtures and preparations for the administration of the active substance for the treatment and prevention of any disease or abnormality caused by weight loss. Specific conditions that can be treated with the methods and mixtures of the present invention include, but are not limited to, feeding associated with a virus (e.g., HIV), bacterium or any other type of infection or sepsis, malignancy, chemotherapy or irradiation, chirping associated with chronic cardiovascular disease, chirping caused by exposure to toxic and radioactive substances, and chirping associated with diarrhea and other gastrointestinal problems.

The subject being treated may be an animal, which includes but is not limited to, a monkey, a cow, a sheep, an ox, a pig, a horse, a cat, a dog, a chicken and the like. Preferably, if it is a mammal, it is better if it is a human and preferably an adult human or a child, for example a child weighing at least 3 kg. As used herein, the term patient or. the patient refers to any animal for the treatment required by the methods and mixtures of the present invention.

In accordance with the present invention, a DMF-containing therapeutic composition was administered; HMMF; HMF; DHMF; AMCC; NMF; DMSO; formamide; acetamide; methylacetamide; dimethylacetamide; diethylacetamide; isopropylacetamide; diisopropylacetamide; Nacetyl-piperidine; N- (β-hydroxyethyl) acetamide; Ν, Ν'-άί (βhydroxyethyl) acetamide; N-acetylmorpholine; acrylamide; propionamide; N-fluoromethyl-N-methyl-formamide; pyridine-Noksid; or any active ingredient selected from the group consisting of amides of the general formula R ₃ -CO-NR ₁ R ₂ , wherein R 1 and R _{2 are} independently selected from the group consisting of H, methyl, halomethyl, saturated and unsaturated C ₂ C ₃ alkyl groups and hydroxylated alkyl groups; and

R 3 is selected from the group consisting of H, methyl, halomethyl and saturated and unsaturated C ₂ -C ₃ alkyl groups; or any active ingredient selected from the group consisting of amides of the general formula R ₃ -CO-NR ₁ R ₂ , wherein R 1 and R _{2 are} independently selected from the group consisting of H, methyl, halomethyl, saturated and unsaturated C ₂ C ₃ alkyl groups and hydroxylated alkyl groups; or

R 1 and R ₂ are together selected from the group consisting of (CH ₂ ) ₄ , (CH ₂ ) ₅ and (CH ₂ ) ₂ O (CH ₂ ) ₂ ; and

R ₃ is selected from the group consisting of H, methyl, halomethyl and saturated and unsaturated C ₂ -C ₃ alkyl groups. In one specific embodiment, at least one of R ₃ and R _{2 is a} methyl group. In another specific embodiment, at least one of R _x and R _{2 is a} fluorinated C 1 -C 3 alkyl group.

Therapeutic compositions may contain a mixture of any two or more of the aforementioned compounds. Particularly preferred is a mixture containing DMF.

For the treatment of HIV-infected animals, for the therapeutic effect, a mixture of the present invention may be combined with one or more additional agents that are effective in treating HIV infections, such as one or more nucleoside analogues of reverse transcriptase inhibitors, such as zidovudine (AZT, ZDV), zalcitabine (ddC), didanosine (ddl), lamivudine (3TC), stavudine (d4T); one or more non-nucleoside reverse transcriptase inhibitors, such as nevirapine, delirirdine, loviride, athevirdine, pyridinone; one or more protease inhibitors such as saquinavir, indinavir, ritonavir, nelfinavir; or any combination of the above or other anti-HIV therapeutic agents. The mixture of the present invention and the additional anti-HIV therapeutic agent or agents can be administered simultaneously, sequentially or in treatment cycles according to the desired course of treatment.

The compositions of the present invention can be administered by any enteral or parenteral route, including, but not limited to, transdermal, intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, intranasal, epidural, intralymphatic and oral routes. The compounds may be administered by any suitable method, for example by infusion or injection, by absorption via epithelial or mucocutaneous substrates (eg oral, gatric, intestinal mucus, etc.) and may be administered together with other biologically active substances.

Administration can be system or local. Further, one administration of the pharmaceutical composition of the invention to the central nervous system may be by any suitable route, including intraventricular and intrathecal injection. Intraventricular injection can be performed with an intraventricular catheter attached to a reservoir such as an Ommaya reservoir. Pulmonary administration may also be involved, for example, using an inhaler or sprayer, and the mixture may contain an aerosolization substance.

If necessary, we can include any two or more routes of administration simultaneously, sequentially or in cycles of treatment according to the desired course of treatment.

In individual embodiments, the desired administration of the mixture of the present invention may be local to the site where treatment is required. This can be achieved, but not limited to, for example, by topical administration, injection, catheter, suppository, or implant, where said implant is a porous, non-porous or gelatinous substance, including membranes such as sialastic membranes or fibers.

In another embodiment, the mixture of the present invention may be administered in vesicles, especially in liposomes (see Langer, Science 249: 1527-1533 (1990); treatment and the rest, in Liposomes in Therapy of Infectious Disease and Cancer, LopezBerestein and Fidler (ed.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, same book, pp. 317-327; see generally in the same book).

In another embodiment, the mixture of the present invention may be administered by a controlled release system.

In one embodiment, a pump can be used (see Langer, supra; Sefton, CRC Crit.Ref.Biomed. Eng. 14: 201 (1987); Buchwald et al., Surgery 88: 507 (1980); Saudek et al., N.Engl J.J. 321: 547 (1989). In another embodiment, polymeric substances can be used (see Medical Applications of Controlled Release, Langer and Wise (ed.), CRC Prev.,

Boca Raton, Florida (1974); Controlled Drug

Bioavailability, Drug Product Design and Performance,

Smolen and Bali (eds.) Wiley, New York (1984); Ranger and Peppas, J.Macromol.Sci.Rev.Macromol.

Chem. 23:61 (1983): see also Levy et al., Science 228: 190 (1985); During and others, Ann. Neurol. 25: 351 (1989); Howard et al., J. Neurosurg., 71: 105 (1989). In the following embodiment, the controlled release system can be placed in close proximity to the therapeutic target and thus only part of the systemic dose is required (see, for example, Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 '(1984) ).

Other systems for controlled messaging are reported by Langer (Science 249: 1527-1533 (1990)).

The present invention also provides pharmaceutical preparations. Such preparations comprise a therapeutically effective amount of the composition of the invention and a pharmaceutically acceptable carrier. In a particular case, the term pharmaceutically acceptable means the approval of a federal, state, or other governmental entity or that it is listed in U.S. Pharmacopoeia or other commonly known pharmacopoeias, for use in animals or more specifically in humans. The term carrier refers to the solvent, adjuvant, excipient or carrier with which the mixture of the present invention is administered. Such pharmaceutical carriers may be sterile liquids such as water or oil, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water is the preferred carrier if the pharmaceutical preparation is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions may also be included as liquid carriers, particularly for injection solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and water. If desired, the pharmaceutical compositions may also contain small amounts of wetting agents or emulsifiers or pH buffering agents. These preparations may take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, extended-acting preparations and the like. They may also be in the form of suppositories, with conventional binders and carriers such as triglycerides. Oral formulations may include conventional carriers such as pharmaceutically pure mannitol, lactose, starch, magnesium stearate, saccharin sodium, cellulose, magnesium carbonate and the like. Examples of suitable pharmaceutical carriers are described in Reminton's Pharmaceutical Sciences by E.W. Martina. Such preparations will contain therapeutically effective amounts of the active substance, preferably in purified form, together with an appropriate amount of carrier to provide a form for appropriate administration to the patient. The formulation is intended to be appropriate to the mode of administration.

The composition of the present invention may be administered transdermally. In one embodiment, the mixture of the present invention is applied directly to the skin. In another embodiment, the mixture of the present invention is applied to a reservoir (for example, a cotton wool pad, a synthetic polymer such as Teflon ™ or any suitable adsorbent) that is applied to the skin, preferably under an impermeable dressing. In a specific embodiment, the mixture of the present invention is applied to the skin by means of a skin patch. The active ingredient concentration of the composition applied to the skin and contained or absorbed in the reservoir or contained in the skin patch may be between 10 and 100%, preferably at least 50%, preferably at least 90%.

In a preferred embodiment, a polar compound such as DMF is administered transdermally using any device for transferring the active substance, for example by applying one or more skin patches. The skin patches may also contain a support, a reservoir, such as an adsorbent impregnated with the polar compound of the present invention, and a permeable membrane that is contacted with the skin. The support may be any substance, such as a natural or synthetic polymer, which resists the chemical attack of the polar compound. High density polyethylene is particularly suitable. Adsorbent can be a colloidal substance such as diatomaceous earth or colloidal silica.

The permeable membrane may be of any substance that chemically resists the polar compound and may also have pores. In a preferred embodiment, the permeable Teflon membrane is a membrane having pores about 0.1 pm in diameter, about 0.5 pm in diameter, or between 0.1 pm and about 0.5 pm in diameter. The patch may be self-adhesive or held in contact with the skin by a bandage or wrapper that includes, without limitation, an elastic bandage or a sticky bandage; Elastoplast ™ bandage is suitable for this purpose. Preferably, the bandage contains greater amounts of polar compound than is intended to be administered through the skin of the treated patient. For example, a bandage may contain about 50% more polar compound than the intended amount for administration. The patch may be of any suitable size and shape and may, for example, take the form of a disc approximately 9 cm in diameter.

In one embodiment, the dressing contains a polar compound such as DMF and at least one other pharmacologically effective substance, such as a topical irritant such as glycerin. In another embodiment, the dressing contains a polar compound such as DMF and does not contain any other pharmacologically effective substance. In a further embodiment, the patch contains a polar compound such as DMF and does not contain any other pharmacologically effective substance that is capable of being systemically absorbed through the skin or does not contain any other pharmacologically effective substance in an amount that is systemically effective after transdermal absorption.

In another embodiment, the patch contains a polar compound such as DMF and does not contain any other systemically effective pharmacological agent. In yet another embodiment, the patch contains a polar compound such as DMF and does not contain any other antiviral agent, such as acyclovir or aryldone.

The present invention thus provides a skin patch containing a polar compound such as DMF in an amount that is effective in treating viral or microbial infections (such as HIV infection) in an adult or a child. The present invention further provides a skin patch containing a polar compound, such as DMF, in an amount that is effective in treating the feeding syndrome in an adult or a child. In one embodiment, the patch contains at least 0.25 g of a polar compound such as DMF, preferably at least 0.5 g, more preferably at least 1 g and most preferably at least 5 g, per. an example of 5-15 g of a polar compound such as DMF.

To minimize the loss of the polar compound by evaporation, the patch can be stored in a sealed container such as a sealed polymer bag. Each patch can be sealed for convenience. The patches may also be refrigerated prior to use, for example at 4 ° C, to reduce the loss of the polar compound by evaporation. It is best if the patches are prepared within 24 hours before use and stored in sealed containers at 4 ° C. However, patches are stable for one or more weeks if kept in sealed packaging at 4 ° C. Before applying the patch, it is best to wash the area with mild soap and water, rinse to remove soap residue, dry it and then hydrate with a suitable skin ointment and moisturizer such as KY ™ jelly. The patch is then removed from the packaging and positioned so that the permeable membrane is in contact with the prepared skin surface. The patch can be held in place with a bandage. After the desired dosing time, the patch is removed. After removing the patch, rinse the area well with mild soap and water to remove any residual polar solvent.

The compounds of the present invention can be administered at any desired interval, for example every two to three weeks; once, twice or thrice a week; every other day or day. Preferably, the composition of the present invention is administered at a dose giving the highest plasma levels of about 2-200 mg / L, more preferably between 100-200 mg / L and most preferably about 150 mg / L of the active ingredient in a mixture such as DMF. The highest levels of 100-200 mg / L or 150-200 mg / L of DMF in plasma are particularly preferred. As used herein, ppm means parts per million and is in practice equivalent to mg / L.

For transdermal administration of a polar compound, the absorption ratio is determined by the skin of the subject. After being applied to human skin, liquid DMF is absorbed at a constant rate of approximately 9.4 mg / cm ² / hour (see Frost and Nohova,

1992, Occup.Env.Health 64: 85-92). Accordingly, the desired absorption ratio can be achieved by controlling the skin surface exposed to the active substance, such as determining the area of each patch and the number of patches applied to the skin. For example, two 9 cm diameter patches expose the polar compound to a total of 127 cm ² of skin surface; for DMF this is reflected in an absorption ratio of about 1.2 g DMF per hour. Particularly preferred is a starting dose of about 15 mg / kg DMT.

In one boil, a dose of about 1.2 g DMF is equivalent to 16.7 mg / kg in a patient weighing approximately 72 kg and treated with the placement of two 9 cm skin patches. Depending on the weight of the patient being treated, the number of patches can be reduced or increased, and the initial exposure time may be shortened or extended. This starting dose can be repeated at any desired interval as described above and preferably given at weekly intervals. Preferably, at least 72 hours after DMF administration, the patient is monitored for signs of toxicity such as liver toxicity, for example by monitoring serum or plasma levels of enzymes such as aspartate aminotransferase (AST), alanine aminotransferase • r (ALT), γ- glutamyl transferase (yGT) and alkaline phosphatase, proteins such as albumin or substances such as conjugated or unconjugated bilirubin. Preferably, the serum or plasma AST and ALT levels do not exceed five times the normal upper level as determined by the reference area of the laboratory and the treated population; it is even better if the serum and plasma AST and ALT levels do not exceed the triple normal limit, but it is best not to raise the ALT and AST levels above the normal or pre-treatment level. DMF doses can be raised by applying patches for consecutive periods. In one embodiment, the patches are applied for two hours, then for four hours, then for six hours, and so on; in another embodiment, the exposure time is sequentially doubled. Preferably, the patient is monitored prior to any dose escalation in order to detect any signs of toxicity. Doses can be increased at weekly intervals if desired. Doses can be increased in this way until a dose of about 150 mg / kg / dose is calculated; or until the desired maximum plasma level is reached, for example, between 100-150 or 150-200 mg / L; or until the exposure time is 6 hours or about 8 hours. Caution should be exercised before increasing the dose to 240 mg / kg / dose.

EXAMPLE 1: TREATMENT OF HIV INFECTIONS WITH TRANSDERMAL

ADMINISTRATION OF N, N'-DIMETHYLFORMAMIDE (DMF)

Patients infected with HIV-1 are treated with dimethylformamide (DMF) by placing dimethylformamide gel-impregnated skin patches on the patient's body. Patients are administered orally or intravenously with N-acetyl-cysteine-glutathione and / or essential phospholipids, 250 mg or 300 mg daily, as renal stimulators. Alternatively, glutamine may be administered to the patient as an adjunct or as an adjuvant.

Two skin patches are applied to different parts of the patient's body, such as the forearm. Each skin patch contains about 7.06 g of DMF-containing gel (92.5% w / w) and colloidal silica (7.5% w / w). The gel serves to prevent the leakage of liquid DMF from the patches. The patch is made up to 12 hours before use because DMF evaporates quickly. The desired level of DMF in the patient's body is 100 ppm. For a patient weighing about 60 kg, the formation of 100 ppm level requires an amount of about 14 g over a 12 hour period. According to Marge and Noch studies, the surface area required to absorb this amount is about 127.2 cm ² . To obtain a blood level of about 100 ppm, about 1.272 g of DMF must be absorbed per hour, so each patch, with a surface area of 6.36 cm ² , should give 7.064 g of DMF to achieve the desired amount. The absorption ratio of DMF is 9.4 mg / cm ² / hour. Theoretically, 125-135 ppm is applied in this way, but due to the evaporation of DMF this amount is 100 ppm. The absorption capacity varies from patient to patient depending on the o'd skin type and skin thickness. To obtain the desired DMF levels in patients, plasma concentrations of DMF are monitored in each patient and the treatment is adjusted according to the DMF levels in each patient. Figure 1 represents the plasma concentrations of DMF in 4 patients who are given 2 dermal patches of DMF for 8 hours. Figure 2 represents the plasma concentrations of DMF in 3 patients who are treated with 2 skin patches of DMF for 6 hours.

Each patch is then filled with about 7,064 g of DMF gel and silica. Each patch is applied for 12 hours or once a week for 12 weeks or twice a week for 6 weeks.

Blood tests in certain patients indicate an increase in CD4 T cells from 350 to 1000 and a rapid decrease in PCR (Chain Reaction Polymerase Chain Reaction) from 120,000 to 500 / ml over three weeks with only three treatments. Figure 3 shows serial quantitative PCR measurements of HIV-1 viral load in a patient before treatment and after three treatments with two DMF skin patches for 12 hours. The PCR test is performed with a Roche amplifier HIV monitor. Virus levels <500 / mL plasma are considered incapable of detection.

Some of the patients we treat had severe acne or rubella symptoms before treatment. When treated with DMF such that the level of DMF in the patient's body is 50-100 ppm, the symptoms of rubella and severe acne improve or disappear within seven days.

Extensive clinical and physiological evaluation of the patient is performed prior to dimethylformamide treatment. The evaluation provides us with basic initial biochemical and haematological patient data. Detailed virological serological (HIV-1) tests are also performed to determine the total amount of virus in the patient. These tests are performed weekly or after each treatment.

The concentration of DMF in the patient's blood is determined every hour during the treatment period. Blood samples are taken intravenously every morning and the usual saline solution is infused at 20 mL / hour. Daily monitoring of active AMCC metabolites (for example, urine samples every 4 hours) derived from DMF is also performed. The following DMF administrations are adjusted according to the measured changes in the level of DMF concentrations in the blood, which are due to the absorption variables. Complete daily haematological and biochemical profiles are also performed to detect any changes in liver function and complete daily clinical and physiological evaluations.

Daily virologic serological reports are also maintained to determine the total amount of viruses and to monitor improvements in the patient's immune status (CD4 T-helper cells) and prediction factors. Serology is based on p24 antigen and quantitative PCR or may be by other methods. Weekly CD4 and beta-2-macroglobulin determination is also performed specifically to monitor improvements in the patient's immune status and prognosis. All clinical and laboratory data are collected into a centralized data system to 'respond quickly to any adverse change by reducing treatment, increasing clinical effects and reducing potential side effects.

Tests comprise

a) serum: Na, K, Cl, CO2, urea, urate, creatinine, Ca, Mg, phosphate, total and conjugated bilirubin;

b) hematology: hemoglobin, red cell count, hematocrit, MCV, MCH, MCHC, RDW;

c) serum protein electrophoresis: total proteins, albumin, total globulin, alpha globulin, alpha2 globulin, beta globulin, gamma globulin;

d) white blood cell analysis: differential count of white blood cells, absolute neutrophil, count of lymphocytes, monocytes, eosinophils and basophils;

e) liver enzymes: alk. fos., gamma GT, ALT (SGPT), AST (SGOT), LDH;

f) other: cell markers, PCR, beta2-macroglobulin, p24 antigen, C-reactive protein, CK-MB concentration;

g) blood analysis of DMF levels;

h) Urinary analysis of AMCC levels.

DMF appears to behave as a reverse transcriptase inhibitor or protease inhibitor. In vitro tests are performed and DMF, as a solvent, appears to dissolve viral particles, such as capsid.

EXAMPLE 2: TREATMENT OF HIV INFECTIONS WITH TRANSDERMAL

ADMINISTRATION Ν, Ν'-DIMETHYLFORMAMIDE (DMF)

A guided study was conducted to evaluate the efficacy of transdermal DMF in the treatment of HIV-infected patients. Consent was obtained from each patient. Seropositive status was confirmed by Western blotting using commercial p24 antibody detection equipment (Abbott Diagnostics) and the presence of HIV-1 was documented by quantitative PCR using commercial equipment (Roche Amplicor).

DMF is commercially available (Sigma-Aldrich) and analyzed in plasma samples by mass spectroscopy / gas chromatography (GC / MS) using a Varian 9600 gas chromatograph, OV 351 column, carbowax-PEG capillary column and Finnegan Mat ITS40 ion trap detector .

The operating parameters are as follows: temperature gradient change (GC) program: 60 ° C for one minute, followed by a temperature change of 9.4 ° C / min for 20 minutes; ionization mass spectroscopy (MS) method: electron collision; mass range: 40-80 mass units; 1 scan per second; top threshold: 3 counts / second; background weight: 69 mass units. Dimethylacetamide solution is used as internal standard. All samples were extracted with an organic solvent containing the internal standard, allowed to precipitate for 30 minutes in a refrigerator, and centrifuged at 3000 rpm for 5 minutes before transferring to GC injection bottles. The retention time of the DMF peak (peak) relative to the internal standard is 3.26 minutes; the calibration curve shows a ratio of 0.98. The quantitation of DMF is shown in a straight line up to 100 mg / L and the lower limit of detection is 0.5 mg / L based on a signal to background ratio of 3: 1.

Skin patches 9 cm in diameter are applied within 12 hours of preparation. The background of each patch is high density polyethylene (0.245 g), the skin contact area is a Teflon ™ semi-permeable membrane (pore size 0.2 pm; 0.268 g) and contains 0.573 g of colloidal silica impregnated with 7.067 g of DMF between background and semi-permeable membrane. The patches are visually inspected for leaks and weighed on an analytical balance to check less than 10% of the deviation from the total weight of 8,153 g. Apply patches to the skin of the forearms and secure with Elastoplast ™ bandages. One or both patches should be used for the starting dose, which was determined according to the intended skin transfer ratio of 9.4 mg / cm ² / hour and according to the patient's body weight.

Stage doses of DMF are used by taking blood and urine samples every two hours to determine the maximum plasma levels of DMF. Patients have been monitored clinically for the appearance of any toxic side effects and are also under extensive biochemical control, while increasing the dose as needed to achieve a peak plasma DMF level of 100 to 120 ppm. Once the right dose has been determined, DMF is administered transdermally once a week.

The initial evaluation shall include a daily determination of:

a) vital signs and body weight;

b) clinical checklist and Karnofsky scoring;

c) complete cell counting and determination of erythrocyte sedimentation;

d) serum urea, creatinine, glucose, sodium, potassium,

ALT, AST, alkaline phosphatase and total bilirubin;

e) Coulter analysis of CD4 ⁺ and CD8 ⁺ counts and ratios

CD4 / CD8;

f) quantitative determination of HIV-1 by PCR (Roche

Amplicor) and antibody analysis for p24 (Abbott);

g) Urinalysis (Dipstix).

At each weekly visit, the patients evaluate the side effects, actually repeat all these tests and collect blood and urine samples for measurements of DMF and its metabolites.

Patient 1 (ADF) started treatment relatively well, only complaining of pain in the arms and legs and insomnia. Two DMF patches were applied once a week for an average time of 8 hours. The average weekly dose of DMF was 6.11 g and the average mean peak plasma DMF levels obtained were 75 mg / L. After 9 weeks, the patient's CD4 + T cell count increased from 140 to 640 cells / pL and the PCR measured virus volume decreased from 250,000 to 50,000 copies / mL. At 10 weeks, the patient's body weight increased from 81.9 to 96.0 kg, the patient was in clinically good condition and no longer complained of limb pain.

Patient 2 (AM) complained of loss of power, pain in the arms and legs, insomnia, and had cold sores before treatment. One DMF patch was applied once a week for an average time of 8 hours. The average weekly dose of DMF was 7.12 g and the average mean peak plasma DMF levels obtained were 125 mg / L. After 9 weeks, the patient's CD4 + T cell count increased from 460 to 720 cells / pL, PCR measured viral load decreased from 29,000 to 13,000 specimens / mL, and body weight increased from 58.4 to 63.0 kg. Herpes has disappeared, as well as limb pain and the patient appears to be in clinically good condition.

Patient 3 (SM) has apparently clinically developed AIDS and complains of respiratory problems. Two DMF patches were applied once a week for an average time of 8 hours. The average weekly dose of DMF was 8.97 g and the average mean peak plasma DMF level was 121 mg / L. After 7 weeks, the patient's CD4 + T cell count increased from 39 to 138 cells / pL, PCR measured viral load decreased from 222,000 to 160,000 specimens / mL, and body weight increased from 74.2 to 100 kg. The patient's appetite improved, his breathing problems disappeared, the patient's clinical condition looked good and he started exercising again.

Patient 4 (EM) had secondary infections (including herpes), anemia, diarrhea, and acne. Two DMF patches were applied once a week for an average time of 8 hours. The average weekly dose of DMF was 7.33 g and the average mean peak plasma DMF level was 90 mg / L. After 18 weeks, the patient's CD4 + T cell count increased from 249 to 450 cells / gL, the PCR measured virus volume decreased from 13,000 to 4,000 cells / mL, and the body weight increased from

81.5 by 90.4 kg. The patient's clinical condition looks good and he has not had any active medical problems.

Patient 5 (SV) complained of poor appetite, forgetfulness, abdominal pain, and severe fatigue, forcing him to think about selling his stake in the business. Two DMF patches were applied once a week for an average time of 6 hours. The average weekly dose of DMF was 3.75 g and the mean peak plasma DMF levels 67 mg / L were obtained. After 5 weeks, the patient's CD4 + T cell count increased from 354 to 396 cells / gL, the PCR measured viral load decreased from 156,000 to 13,000 specimens / mL, and the body weight increased from 56.0 to 58.0 kg. The patient's clinical condition is good, he has acquired a partner's part of the business, and he runs the business himself.

Patient 6 (VV) has secondary infections (including herpes), ataxia and numbness of the left arm and left side of the face. Two DMF patches were applied once a week for an average time of 8 hours. The average weekly dose of DMF was

8.25 g and a mean peak plasma DMF level of 110 mg / L was obtained. After 19 weeks, the patient's CD4 + T cell count increased from 260 to 450 cells / gL, the PCR measured viral load decreased from 120,000 to 24,000 specimens / mL, and the body weight increased from 75.4 to 84.6 kg. Secondary infections have disappeared. The patient's clinical condition looks good.

Patient 7 (AJF) is severely ill. The initial CD4 + T cell count in a patient is 29 cells / gL, the initial PCR measured virus volume is 1,156,000 specimens / mL. It is treated with one DMF patch for an average time of 4 hours. The average weekly dose of DMF is 4.60 g and the mean plasma maximum DMF levels obtained are 100 mg / L. After the first treatment, the patient's CD4 + T cell count dropped to 14 cells / l. Treatment was continued daily for five days and then continued at weekly intervals. After 9 treatments, the patient's CD4 + T cell count increased to 35 cells / gL,

The PCR measured amount of the virus is reduced to 9,000 specimens / mL and the body weight is increased from 46.5 kg (at the start of DMF treatment) to 49.0 kg. The patient is feeling well and has returned to work full time.

Patient 8 (MS) has severe herpes lesions in the lower genital area. Two DMF patches are applied once a week for an average time of 8 hours. The average weekly dose of DMF is 6.24 g and the mean plasma maximum DMF levels obtained are 130 mg / L. After 8 weeks, the patient's CD4 + T cell count increased from 200 to 240 cells / pL, the PCR measured virus volume decreased from 1,200,000 to 250,000 specimens / mL, and the body weight increased from 48.1 to 52.2 kg. The changes associated with herpes have completely disappeared.

Two patients were excluded from the study, one for alcohol abuse and the other for viral hepatitis B.

Most patients experienced mild skin irritation at the site of patch placement after patch removal; the skin had a maculopapular appearance at this point, probably due to the strong hydration under the patch. In one case there was a minor blister that disappeared within 24 hours and did not cause significant discomfort to the patient. Most patients experienced mild transient nausea (usually nausea), usually on the third day after treatment, which gradually decreased during the process; one patient experienced moderate, transient nausea. Four patients showed a transient increase in liver enzyme levels that never exceeded the triple normal limit and, in most cases, returned to pre-treatment levels at the next dose of DMF. Most cases of elevated liver enzymes are associated with at least one factor that is not related to the treatment process (alcohol consumption, hepatitis, and previous anti-HIV therapy with other agents).

In fact, all patients show clinical improvement after 2 to 3 weeks of treatment. As shown in Diagram 4, for each patient, the overall condition, after DMF treatment, improves as estimated by the Karnofsky implementation scale, in which the patient's overall condition is determined by numerical values as follows; 100 = normal, no problem; 90 = possible to resume normal activities, milder signs or symptoms of the disease; 80 = normal activity with effort; 70 = take care of himself, unable to continue normal activity or active work; 60 = needs regular help but is able to handle most needs; 50 - needs significant help and frequent medical care; 40 = disabled, in need of special care; 30 - severely disabled, hospitalization required, although death is not imminent; 2.0 = very sick, hospitalization and supportive care required; 10 = dying, the process of dying is rapidly escalating; 0 = death (see Kanofsky et al., 1984, Cancer 1: 634-656). Improvements in the neurological symptoms and viral infections of herpes are remarkable. Additional antimicrobial therapy for secondary infections is rarely required. Improvements in general fatigue and appetite occur during the first 14 days of DMF treatment. All patients gained weight. Clinical improvement is well correlated with disease status, as assessed by virus volume and CD4 + T cell walk. For five of the eight patients, the relative PCR of the virus measured can be compared with the Gompertz curves; this analysis shows an 88.8% deviation in PCR of the measured amount of virus after 42 days of DMF treatment. For seven of eight patients, the relative amount of CD4 + T cells can fit into Gompertz curves; this analysis shows a 73.4% deviation in the amount of CD4 + T cells after 42 days of DMF treatment.

The scope of the present invention is by no means limited to certain embodiments which are intended only to illustrate particular aspects of the present invention. Admittedly, various modifications to the present invention, in addition to those already shown and described herein, will be soon to be understood by those skilled in the art with the aid of the foregoing descriptions and accompanying drawings. Such changes are encompassed by the appended claims.

All the publications and publications cited herein are incorporated by reference in their entirety.

for

CRiOPRESERVATION TECHNOLOGIES CC

607 21st Avenue Rietfontein, Pretoria

South Africa with soluble k j, iT ^ iSik

Claims (25)

PATENT APPLICATIONS CLAIMS 1. A transdermal drug administration device comprising a container containing or absorbing a medicament composition, which is N-hydroxymethyl-N-methylformamide (HMMF), N-hydroxymethyl formamide (HMF), dihydroxymethylformamide (DHMF) ), N-acetyl-S- (N-methylcarbamoyl) cysteine (AMCC) or pyridine-N-oxide. 2. Transdermal drug administration device, characterized in that it comprises a container containing or absorbed a drug composition comprising an active ingredient of at least 0.25 g of dimethylformamide (DMF) or dimethyl sulfoxide (DMSO). 3. Preparation for transdermal administration of a medicament, characterized in that it comprises: support; a permeable membrane suitable for attachment to the skin of an erect animal; and an adsorption agent placed between the support and the permeable membrane, wherein the adsorption agent has adsorbed a drug composition comprising a therapeutic agent, which is N-hydroxymethyl-N-methylformamide (HMMF), N-hydroxymethyl formamide (HMF), dihydroxymethylformamide (DHMF) ), N-acetyl-S- (Nmethylcarbamoyl) cysteine (AMCC), N-methylformamide (NMF), formamide, acetamide, methylacetamide, dimethylacetamide, diethylacetamide, isopropylacetamide, diisopropylacetamide, N-acetylpiperidine, N- (acetylamino), N- (acetylamino), N, N'-di-hydroxyethyl) acetamide, N-acetylmorpholine, acrylamide, propionamide, N-fluoromethyl-N-methyl-formamide, pyridine -oxide, or any amide of the general formula R3-CO-NR1R2, wherein: R 1 and R _{2 are} independently selected from the group consisting of H, methyl, halomethyl, saturated and unsaturated C ₂ -C ₃ alkyl groups and hydroxylated alkyl groups; or R 1 and R ₂ are together selected from the group consisting of (CH ₂ ) ₄ , (CH ₂ ) ₅ and (CH ₂ ) ₂ O (CH ₂ ) ₂ ; and R ₃ is selected from the group consisting of H, methyl and saturated and unsaturated C ₂ -C ₃ alkyl groups, provided that when R _x and R _{2 are} methyl R ₃ is not H; said preparation for the administration of the medicament is adapted in such a way that it can be contacted with the skin of the treated animal. 4. Preparation for transdermal administration of a medicament, characterized in that it comprises: support; a permeable membrane suitable for attachment to the skin of an erect animal; and an adsorption agent placed between the support and the permeable membrane, wherein the adsorption agent has adsorbed a drug composition containing the active ingredient at least 0.25 g of N, N-dimethylformamide (DMF) or dimethylsulfoxide (DMSO). Medication administration device according to claim 2 or 4, characterized in that the medicament composition comprises at least 5 g of DMF. Medication administration device according to any one of claims 2, 4 or 5, characterized in that it has no pharmacologically active agent other than DMF. Medication administration device according to any one of claims 2, 4, 5 or 6, characterized in that it has no pharmacologically active agent other than DMF which is capable of being systematically adsorbed through the skin. Drug administration device according to any one of claims 3 to 7 inclusive, characterized in that the adsorbing agent is colloidal silica, while the permeable membrane is a Teflon membrane having pores with a diameter of from about 0.1 pm to about 0.4 pm. A medicament composition for use in a method of treating a syndrome of urination comprising the step of administering to the animal in need of treatment a medicament composition comprising N, N'-dimethylformamide (DMF), N-hydroxymethyl-Nmethylformamide (HMMF), N-hydroxymethyl formamide (HMF), dihydroxymethylformamide (DHMF), N-acetyl-S- (Nmethylcarbamoyl) cysteine (AMCC), N-methylformamide (NMF), dimethylsulfoxide (DMSO), formamide, acetamide, methylacetamide, dimethylacetamide, diethylacetamide, diethylacetamide Nacetylpiperidine, N- (β-hydroxyethyl) acetamide, N, N'-di (phidroxyethyl) acetamide, N-acetylmorpholine, acrylamide, propionamide, N-fluoromethyl-N-methyl-formamide, pyridine-Noxide, or any amide of the general formula R3-CO-NR1R2, where: R 1 and R _{2 are} independently selected from the group consisting of H, methyl, halomethyl, saturated and unsaturated C ₂ -C ₃ alkyl groups and hydroxylated alkyl groups; or R 1 and R ₂ are together selected from the group consisting of (CH ₂ ) 4 / (CH ₂ ) ₅ and (CH ₂ ) ₂ O (CH ₂ ) ₂ ; and R ₃ is selected from the group consisting of H, methyl, and saturated and unsaturated C ₂ -C ₃ alkyl groups. The pharmaceutical composition of claim 9, characterized in that it contains an amide of the general formula R ₃ -CO-NR ₁ R ₂ , wherein: R 1 and R _{2 are} independently selected from the group consisting of H, methyl, halomethyl, saturated and unsaturated C ₂ -C ₃ alkyl groups and hydroxylated alkyl groups; or R 1 and R ₂ are together selected from the group consisting of (CH ₂ ) ₄ , (CH ₂ ) ₅ and (CH ₂ ) ₂ O (CH ₂ ) ₂ ; and R ₃ is selected from the group consisting of H, methyl, and saturated and unsaturated C ₂ -C ₃ alkyl groups. A pharmaceutical composition according to claim 9 or 10, characterized in that it contains an amide of the general formula R ₃ -CO-NR ₁ R ₂ , wherein: R 1 and R _{2 are} independently selected from the group consisting of H, methyl, halomethyl, saturated and unsaturated C ₂ -C ₃ alkyl groups and hydroxylated alkyl groups; and R ₃ is selected from the group consisting of H, methyl and saturated and unsaturated C ₂ -C ₃ alkyl groups and hydroxylated alkyl groups. Medicinal composition according to any one of claims 9 to 11 inclusive, characterized in that it contains DMF, HMMF, HMF, DHMF, AMCC, NMF, DMSO, formamide, acetamide, methylacetamide, dimethylacetamide, diethylacetamide, isopropylacetamide, diisopropylacetamide, Nacetyl, Nacetyl N- (β-hydroxyethyl) acetamide, N, N'-di-di-hydroxyethyl) acetamide, N-acetylmorpholine, acrylamide, propionamide, N-fluoromethyl-N-methyl-formamide or pyridine N-oxide. Medicinal composition according to claim 12, characterized in that it contains DMF, HMMF, HMF, DHMF, AMCC or NMF. A medicament composition according to any one of claims 9 to 13 inclusive for use in a method of treating chorionic syndrome, wherein the administration of said medicinal composition is followed by the administration of at least one agent effective in the treatment of HIV infection that is complementary to at least one other agent, which is effective in treating HIV infection. A medicament composition according to claim 14 for use in a method of treatment of chirping syndrome, wherein the administration of said medicinal composition is followed by the administration of at least one nucleoside reverse transcriptase inhibitor analogue, at least one non-nucleoside reverse transcriptase inhibitor analogue, or at least one protease inhibitor thereof inhibitor analogs and complementary inhibitors. Medicinal composition according to any one of claims 13 to 15 inclusive, comprising DMF. Medicinal composition according to claim 12, 14 or 15, characterized in that it contains DMSO. A medicament composition according to any one of claims 9 to 17 inclusive, characterized in that it is suitable for transdermal administration. A medicament composition for use in a method of treating a viral or microbial infection, wherein the method of treatment comprises the administration of a medicament composition of an animal in need of treatment comprising N-hydroxymethyl-Nmethylformamide (HMMF), N-hydroxymethyl formamide (HMF), dihydroxymethylformamide (DHMF) , N-acetyl-S- (N-methylcarbamoyl) cysteine (AMCC), dimethylsulfoxide (DMSO) or pyridine-N-oxide. A medicament composition according to claim 19, characterized in that it is effective in treating a retroviral infection. 21. The medicament composition of claim 20, wherein said retroviral infection is HIV infection. A medicament composition according to any one of claims 19 to 21 inclusive for use in a method of treatment of a chirping syndrome, wherein the administration of said medicinal composition is followed by the administration of at least one agent effective in the treatment of HIV infection that is complementary to at least one other agent, which is effective in treating HIV infection. A medicament composition according to any one of claims 19 to 22 inclusive for use in a method of treatment of chorionic syndrome, wherein the administration of said medicinal composition is followed by the administration of at least one nucleoside analogue of a reverse transcriptase inhibitor, at least one non-nucleoside analogue of a reverse transcriptase inhibitor, or at least one inhibitor proteases, characterized in that it is complementary to said inhibitor analogs and inhibitors. A medicament composition according to any one of claims 19 to 23 inclusive, characterized in that it is suitable for transdermal administration. A vaccine, characterized in that it is prepared from antibodies derived from the body of an animal treated for viral infection with a medicament composition according to claim 19.