JP2002511862A - Drug delivery device and method for treating viral and microbial infections and wasting syndrome - Google Patents

Abstract

  (57) [Summary] Novel drug delivery devices, methods and therapeutic compositions for use in treating viral and microbial infections and wasting syndrome in animals, including human patients, are described. According to the present invention, a highly polar compound such as dimethylformamide or dimethylsulfoxide is administered to a patient for treatment, preferably by the transdermal route. The present invention further provides a vaccine prepared from antibodies harvested from the body of a patient who has been treated for a viral infection by the method of the present invention.

Description

DETAILED DESCRIPTION OF THE INVENTION     Drug supplies for the treatment of viral and microbial infections and wasting syndrome Feeding device and method1. Field of the invention   The present invention relates to N, N'-dimethylformamide (DMF) or dimethyl sulfo. By administering a highly polar compound such as oxide (DMSO), Or an animal infected with a microbial infection, especially a retrovirus such as HIV, or Movements associated with attrition syndrome, especially attrition syndrome associated with HIV infection or malignancy Related to the treatment of things. The invention also relates to viral or other microbial infections. Or a polarity such as DMF or DMSO for the treatment of animals with wasting syndrome And a drug supply device comprising a compound having a high content of a compound.2. Background of the Invention 2.1 Human immunodeficiency virus   Human immunodeficiency virus (HIV) induces persistent and progressive infections, In most cases, the disease progresses to acquired immunodeficiency syndrome (AIDS) (Barre-Sinoussi et al.) , 1983, Science 220: 868-870; Gallo et al., 1984, Science 224: 500-503). Small At least two types of HIV, HIV-1 (Barre-Sinoussi et al., 1983, Scie nce 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) exists. HIV replication in humans is primarily CD4⁺With T lymphocytes When this occurs, infection with HIV depletes this cell type, resulting in immune dysfunction, Seen infections, neurological dysfunction, and tumor growth can occur, ultimately leading to death.   HIV belongs to the lentivirus subfamily of retroviruses (Teich et al., 1984, RNA Tumor Viruses, edited by Weiss et al., CSH-press, pp. 949-956). Retrovirus This is a small virus with a velop, a single-stranded RNA genome, Produced by the encoded reverse transcriptase, an RNA-dependent DNA polymerase (Varmus H., 1988, Science 240: 14). 27-1439). Retroviruses also include, for example, human T-cell leukemia virus (HTLV-I, -II, -III) and oncogenic viruses such as feline leukemia virus Contains I will.   HIV virions are part of the capsid proteins designated p24 and p18. Core, and an enzyme that requires viral RNA genome and early replication Made of elementary. The myristinated gag protein is located outside the viral core The virus shell constitutes a virus shell, whereas the virus shell is a lipid membrane It is surrounded by envelopes. Glycoproteins on the surface of the HIV envelope Is synthesized as a single precursor protein of 160KD, followed by two types of virus In the process of germination in the glycoproteins gp41 and gp120, Is torn. gp41 is a transmembrane glycoprotein, and gp120 is not shared with gp41. Extracellular glycoprotein, possibly present as a trimer or multimer due to covalent binding (Hammerskjold, M. and Rekosh, D., 1989, Biochem. Biophys. Acta 989: 269- 280).   HIV, like other enveloped viruses, is associated with the viral membrane. Viral inheritance in host cells via viral envelope-mediated fusion of target membrane Introduce the substance. CD4 cell surface protein (CD4) is intracellular in HIV-1 virus HIV acts as a receptor for CD4⁺Targeting cells (Dalgleish et al., 1984, Nature 312: 763-767; Klatzmann et al., 1984, Nature 312: 767-768; Maddon et al. 1986, Cell 47: 333-348). Entry of the virus into the cell is based on the intracellular CD4 receptor. (Pal et al., 1993, Virology 194: 833-83). 7; McDouga1 et al., 1986, Science 231: 382-385, Maddon et al., 1986, Cell 47: 333-348. This explains the tendency of HIV toward CD4 cells. On the other hand, gp41 Established in the envelope glycoprotein complex in the irs membrane. gp120 to CD4 Binding induces a conformational change in the viral glycoprotein, but this binding alone leads to infection (Sattentau and Moore review, 1993, Philos. Trans. R. Soc . London (Biol.) 342: 59-66).   Studies on isolated HIV show non-homology in the ability to infect various human cells (Review of Miedema et al., 1994, Immunol. Rev. 140: 35-72). Widespread inheritance Most of the HIV-1 experimental strains performed were the primary culture T cell line and the primary culture T lymphocyte. Easily infected the spheres, but no infection was found in primary cultures or macrophages. won. These strains are called T-tropics. T-tropic HIV -1 strain is considered likely to be detected in HIV-1 infected individuals in the late stage of AIDS (Weiss et al., 1996, Science 272: 1885-1886). Primary isolation of HIV-1 The strain (ie, the virus that has not been extensively passaged) contains primary cultured lymphocytes, It replicates effectively in monocytes and macrophages, but does not grow in successively cultured T cell lines. Inferior. These isolates are called M-tropics. Virus T- and And M-trend determinants are changed in the third fluctuation region (V3 loop) of gp120. (Choe et al., 1996, Cell 85: 1135-1148; Cheng-Mayer et al., 199 1, J. Virol. 65: 6931-6941; Hwang et al., 1991, Science 253: 71-74; Kim et al., 1995, J. Virol., 69: 1755-1761; O'Brien et al., 1990, Nature 348: 69-73). Clear trend Characteristic of HIV isolates that have no and binds only to CD4 cell surface proteins Is not enough to lead to infection, HIV-1 invades host cells Requires cell-type specific co-factors in addition to CD4 It suggests.2.2 Treatment of HIV infection   HIV infection is a pandemic, and HIV-related illness is a major global health problem. One. Great efforts are being made to design effective treatments Nevertheless, there are currently no antiretroviral agents against AIDS. So In the development of drugs such as, some stages of the HIV life cycle Considered as a target for therapeutic intervention (Mitsuya, H. et al., 1991, FASEB J. 5: 2 369-2381). It is widely believed that blocking host cell proteins has deleterious side effects. Many viral targets have been proposed to intervene in the HIV life cycle Have been. For example, reverse transcriptase encoded by the virus is considered the focus of drug development Have been. 2 ', 3'-dideoxynucleases such as AZT, ddI and d4T Many reverse transcriptase targeting drugs, including oside analogs, have been developed and are active against HIV (Mitsuya, H. et al., 1991, Science 249: 1533-154). Four).   Azidothymidine targets reverse transcriptase (RT) in a new HIV-1 therapy (AZT), lamivudine (3TC), dideoxyinosine (ddI), dideoxy An anti-HIV compound such as cytidine (ddC) and an HIV-1 protease inhibitor When used in combination, AZT alone (reduced by approximately 1 log) It has been found to be much more effective (a 2-3 log reduction). For example, Impressive results with combination of near AZT, ddI, 3TC and ritonabie (Perelson, AS et al., 1996, Science 15: 1582-1586). But these Long-term use of compounds may cause toxicity, especially to bone marrow There is. In addition, long-term treatment with cytotoxic therapy may result in killer cell activity. Sex (Blazevic, V., et al., 1995, AIDS Res. Hum. Retroviruses 11: 1335-1342) And inhibitors, especially the chemokins Lantes, MIP-1α and MIP-1β Of HIV by supply of food (Cocchi, P., et al., 1995, Science 270: 1811-1815) Essential CD8⁺T cell suppression occurs. Other long-term chemical antiretroviral therapy A major problem of the law is the development of partially or fully resistant HIV mutations. (Lange, JM, 1995, AIDS Res. Hum. Retroviruses 10: S77-82). Anti huie Such a mutation would be unavoidable in Lus therapy. Fields associated with treatment Loss of live virus and emergence of mutant virus, with concomitant CD4⁺T cells The pattern of decline in numbers indicates that the emergence of virus variants It is a major cause of AIDS treatment failure.   In addition, a drug that inhibits virus entry into cells at the earliest stage of HIV infection has been developed. Attempts have been made to do so. In this case, the focus is on the HIV receptor on the cell surface Located on CD4. For example, genetically modified soluble CD4 in certain HIV CD4 by -1 strain⁺It has been shown to inhibit T cell infection (Smith, D . H., et al., 1987, Science 238: 1704-1707). However, some primary HIV-1 Isolates are relatively insensitive to inhibition by recombinant CD4 (Daar , E., et al., 1990, Proc. Natl. Acad. Sci. USA 87: 6574-6579). In addition, genetic In clinical trials using recombinant soluble CD4, no clear results were obtained (Sc hooley, R., et al., 1990, Ann. Int. Med. 112: 247-253; Kann, J .; O., et al., 1990, Ann. Int. Med. 112: 254-261; Yarchoan, R., et al., 1989, Proc. Vth Int. Conf. On AIDS, p. 564, MCP 137).   Also, the determination of certain virally encoded proteins as potential targets for anti-HIV drugs A late stage of HIV replication has been proposed that results in specific virus-specific synthesis . Late-stage synthesis depends on the activity of the viral protease, Inhibitory drugs are being developed (Erickson, J., 1990, Science 249: 527-53). 3).   Recently, CD8⁺Chemokins produced by T cells suppress HIV infection (Paul, WE, 1994, Cell 82: 177; Bolognesi, DP, 1 993, Semin. Inlmunol. 5: 203). CD8⁺The chemokines Rantes, MIP-1α, secreted by T cells and Cells in which MIP-1β infected HIV-1 or HIV-2 isolates in vitro Has been found to suppress HIV-1 p24 antigen production in E. coli (Cocchi , F. et al., 1995, Science 270: 1811-1815).   Thus, these and other chemokines are useful in treating HIV infection. It appears that there have been some clinical trials of all of these and other candidate drugs. The results of the experiment are still questionable.   Attempts have also been made to develop vaccines for use in the treatment of HIV infection. D The major antigen of anti-HIV antibodies present in patients with HIV is the HIV-1 envelope. Proteins (gp160, gp120, gp41) (Bati n et al., 1985, Science 228: 1094-1096). Therefore, these proteins are anti-HIV viruses. It seems to be the best candidate as an antigen for developing Kuching. Immunogen of the host immune system Various proteins such as gp160, gp120 and / or gp41 may be used as sexual targets. It has begun to be used by several research groups. For example, Ivanoff, L., et al. No. 5,141,867, Saith, G., et al., WO 92 / 22,654; Shafferman, A., WO9. 1 / 09,872; Formoso, C., et al., WO 90 / 07,119. But the virus suddenly suddenly Mutations cause many of these vaccines to become ineffective and target HIV proteins There is also a problem with the vaccinated vaccine. However, clinical results were not obtained for these candidate vaccines. Will be much more in the future.   A great deal of effort is being put into the design and testing of antiretroviral agents Nevertheless, there remains a need for effective, non-toxic treatments.2.3 Wasting syndrome   Wasting syndrome is more than 10% weight loss from body weight and proportional to body fat Is a clinically serious problem characterized by inefficient weight loss (Weinroth et al., 1995, In fectious Agents and Disease 4: 76-94; Kotler and Grunfeld, 1995, AIDS Cli n. Rev. 96: 229-275). Therefore, wasting is the loss of body fat rather than somatic cell mass. Can be distinguished from starvation, which is prominent (Kotler et al., 1985, Am. J. Clin. Nut r. 42: 1255-1265; Cahill, 1970, N.M. Engl. J. Med. 282: 668-675). Consumption is H IV infection, other infectious diseases, sepsis, cancer, chronic cardiovascular disease, diarrhea, etc. It is associated with many conditions (Kotler et al., 1989, Am. J. Clin. Nutr. 50: 444-447; He ymsfield et al., 1982, Am. J. Clin. Nutr. 36: 680-690). The important thing is Or wasting is a prominent cause of death in cancer patients. In fact, in AIDS patients the body There is a linear correlation between cell mass loss and survival (Kotler et al., 1989, Am. JC). lin. Nutr. 50: 444-447).   The cause of wasting syndrome in AIDS and other conditions is not clear, Seems not to be a single factor. In wasting syndrome, metabolic disorders, hormone levels Irregularities, cytokins and malabsorption are all recognized. All about AIDS patients Is not necessarily the cause of wasting, so it is thought that the cause of wasting is not HIV itself. It is. Most of the wasting syndromes associated with HIV are clearly secondary infections and disappearances. Due to AIDS complications such as gastrointestinal tract disease (Kotler and Grunfeld, 1995, AIDS Clin. Rev. 96: 229-275).   Treatment of wasting syndrome, including current ones, includes nutrition, Appetite enhancers such as nabinol and mogestol acetate, and anabolic therapies such as growth hormone , And cytokin inhibitors. But with nutrition and appetite enhancers Have mixed results and tend to increase fat only in that patient. No significant increase in somatic cell mass was observed. Growth hormone and cytokin inhibition The administration of the drug is currently being tested, but may have side effects (Kotler and Grunf eld, 1995, AIDS Clin. Rev. 96: 229-275; Weinroth et al., 1995, Infectious Agen. ts and Disease 4: 76-94 = B   Therefore, treatment of wasting is the survival of patients with serious illnesses such as cancer and AIDS. And wasting essential for well-being and associated with cancer, AIDS and other infectious diseases There is a need for safe and effective treatments for sexual syndrome.2.4 Properties of dimethylformamide and other polar compounds   N, N'-dimethylformamide (DMF) (molecular formula C_ThreeH₇ON) indicates that the polarity is High, colorless, hygroscopic liquid, low volatility, boiling point 152.5-153.5 ° C It is. It is soluble in water, alcohols and certain hydrocarbon solvents. DMF Is widely used as a polar solvent and is easily absorbed by dermal, inhalation and ingestion Is done. DMF is rapidly metabolized, especially in the liver, and is excreted primarily in urine. Luck The major metabolite of DMF in mice, mice, hamsters and humans is Roxymethyl-N-methylformamide (HMMF), N-methylformamide (NMF), N-acetyl-S- (N-methylcarbamoyl) cysteine (AM CC), and dihydroxymethylformamide (DHMF) and N-hydrido Roxymethylformamide (HMF). Part of DMF administered is unchanged Excreted in urine as DMF.   DMF has low acute dermal, oral and inhalation toxicity. Mild to moderate skin and Eye irritating and easily penetrates skin. Targets for toxicity of DMF and its metabolites The organ is the liver, typical clinical complaints, classic blood biochemical changes and the liver Can cause reversible liver damage with hepatocellular necrosis observed in human biopsies Are known. DMF is teratogenic but not mutagenic or carcinogenic It is believed that.   Viza et al. Describe a class of cultured cells in which DMF and DMSO are in vitro. Inhibiting the replication of HIV and human herpesvirus 6 (HHV-6) in the strain (Viza et al., 1990, AIDS Res. Hum. Retroviruses 6: 131-132; Viza et al. 1989, AIDS-FORSCHUNG 4: 349-352; Viza et al., 1992, Antiviral Res. 18: 27-38 And 19: 179).   DMF is an in vitro fractionator for certain transformed cells in cultured cells. (Koeffler, 1983, Blood 62: 709-721; Calabresi et al., 1979, Bioc hem. Pharmacol. 28: 1933-1941). In vitro for certain malignant cells Addition of DMF reduces its tumorigenicity even after inoculation in nude mice (Dexter, 1977, Cancer Res. 37: 3136-3140; Dexter et al., 197 9, Cancer Res. 39: 1020-1025). DMF and NMF intraperitoneally in nude mice Injection has been reported to reduce the growth of certain human carcinoma xenografts (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; Dext er et al., 1982, Cancer Res. 42: 5018-5022). However, mouse sarcoma allogeneic Toxic side effects of formaldehyde and its N-methyl derivative found in plant model Researchers could not demonstrate the therapeutic utility of these drugs. (Clarke et al., 1953, Proc. Sec. Exp. Biol. Med. 84: 203-20). 7).   Attempt to treat human cancer patients with DMSO, no objective response (See Spremulli & Dexter, 1984, J. Clin. Oncol. 2: 227-241.) See). Oral administration of NMF to human patients with head and neck cancer has hepatotoxicity No beneficial response (Vogel et al., 1987, Invest. New Drugs 5: 2 03-206) or only a small amount of activity was reported (Plan ting et al., 1987, Cancer Treat Rep. 71: 1293-1294).   U.S. Pat. No. 3,551,154 promotes transdermal absorption of topically treated drugs The use of DMF as a permeation enhancer is disclosed. US Patent 4,8 No. 55,294 discloses a penetration enhancer for promoting percutaneous absorption of a topically treated drug. For reducing skin irritation due to DMSO and DMF used as glycerin Is disclosed. Woodford & Barry (1986) describes transdermal absorption of antivirals. Report the use of DMSO as a permeation enhancer to promote lipase (J. Toxic ol. Cut. & Ocular Toxicol. 5: 167-177).   Reference citations made in Section 2 (or other sections) of this specification The use or description states that these references exist as prior art to the present invention. I do not admit.3. Summary of the Invention   The present invention relates to the infection of viruses or other microorganisms, especially retroviruses such as HIV. Methods, compositions, and drug delivery for use in treating animals affected by Lus infection It relates to a feeding device. In addition, the present invention provides a method for treating exhaustion related to HIV infection or malignant disease. Provided are a method, a composition, and a drug supply device used for treating an animal exhibiting wasting syndrome. Offer.   According to the present invention, N, N'-dimethylformamide (dimethylformamide, DMF), N-hydroxymethyl-N-methylformamide (HMMF), N- Hydroxymethylformamide (HMF), dihydroxymethylformamide ( DHMF), N-acetyl-S- (N-methylcarbamoyl) cysteine (AM CC), N-methylformamide (NMF), dimethyl sulfoxide (DMSO ), Formamide, acetamide, methylacetamide, dimethylacetamide , Diethylacetamide, isopropylacetamide, diisopropylacetoa Amide, N-acetylpiperidine, N- (β-hydroxyethyl) acetamide, N, N'-di-([beta] -hydroxyethyl) acetamide, N-acetylmorpholine Acrylamide, propionamide, N-fluoromethyl-N-methyl-pho Lumamide, pyridine-N-oxide, or a compound of the general formula R_Three-CO-NR₁R_TwoSmile And R₁And R_TwoIs independently H, methyl, halomethyl, saturated or unsaturated Sum C_Two-C_ThreeSelected from the group consisting of alkyl groups, and hydroxylated alkyl groups Or R₁And R_TwoAre together (CH_Two)_Four, (CH_Two)_Five,and( CH_Two)_TwoO (CH_Two)_TwoSelected from the group consisting of_ThreeIs H, methyl, halo Methyl, and saturated or unsaturated C_Two-C_ThreeSelected from the group consisting of alkyl groups. A composition comprising a compound selected from the group consisting of amides represented by Administer to the animals of interest. The therapeutic composition comprises two or more of the above compounds. It may be a mixture.   Therapeutic compositions used for HIV patients may optionally include a composition of the present invention and the following: Nucleoside-related reverse transcriptase inhibitors, non-nucleoside H selected from the group consisting of a related reverse transcriptase inhibitor and a protease inhibitor It may be combined with one or more other drugs effective for IV treatment.   The present invention also relates to a method for treating a virus-infected composition of the present invention, comprising the steps of: Vaccines prepared from the obtained antibodies are also included.4. Brief description of figures   The present invention is fully understood with reference to the following detailed description, examples and accompanying drawings. Can be here,   FIG. 1 shows blood in four patients patched at two sites with DMF for 8 hours. The time course of plasma DMF concentration is shown.   FIG. 2 shows blood in three patients patched at two sites with DMF for 6 hours. The time course of plasma DMF concentration is shown.   FIG. 3 shows the results measured by quantitative PCR in three patients transdermally treated with DMF. 1 shows HIV-1 viral load. The DMF patch was tested on days 0, 8 and 13 (arrow (Indicated by a mark) on the forearm for 12 hours at two locations.   FIG. 4 shows the performance evaluation score of Karnofsky before and after percutaneous treatment with DMF. 1 shows the general condition of HIV-infected patients. See section 7 for details.5. Detailed description of the invention   The present invention relates to methods, compositions and drugs for the treatment of viral and microbial infections. An agent supply device is provided. According to the examples, the infection to be treated is asymptomatic, latent Sexually transmitted infections, infections with one or more symptoms of AIDS-related complications, and Infections with retroviruses such as HIV, including infections with clinical AIDS . Otherwise, the infection to be treated is herpes such as rubella, human herpesvirus 6, etc. Infection by virus, EB virus or cytomegalovirus, capsid protection Infection by any virus with membrane, acquired infection in HIV infected patients, etc. Other viruses or microorganisms, including any acquired infection with an immune system disorder Sexually transmitted.   The present invention also treats or treats any disease or disorder characterized by reduced body mass. Provide methods, compositions and drug delivery devices for prevention. The method of the present invention And conditions that can be treated with the compositions are viruses (eg, HIV), Bacteria or other types of infection or sepsis, cachexia associated with malignancy, Depletion associated with chemotherapy or radiation therapy, depletion associated with chronic cardiovascular disease, Consumption due to exposure to toxic or radioactive materials, and diarrhea and other Including but not limited to digestive disorders.   All animals are treated, including monkeys, cows, sheep, steers, pigs, horses and cats. , Dogs, chickens, etc., and is preferably a mammal, more preferably a human adult or infant. Infants, for example infants weighing at least 3 kg, but not limited to Absent. As used herein, a "patient" requires treatment with a method or composition of the present invention. Means any animal that does   According to the present invention, DMF, HMMF, HMF, DHMF, AMCC, NMF, DMSO, formamide, acetamide, methylacetamide, dimethylacetamide Amide, diethylacetamide, isopropylacetamide, diisopropylacetamide Cetamide, N-acetylpiperidine, N- (β-hydroxyethyl) acetoa Amide, N, N'-di-([beta] -hydroxyethyl) acetamide, N-acetyl Ruphorin, acrylamide, propionamide, N-fluoromethyl-N-methyl Ru-formamide, pyridine-N-oxide, general formula R_Three-CO-NR₁R_Two(This Where R₁And R_TwoIs independently H, methyl, halomethyl, saturated or Saturated C_Two-C_ThreeSelected from the group consisting of alkyl groups and hydroxylated alkyl groups R_ThreeIs H, methyl, and saturated or unsaturated C_Two-C_ThreeGroup consisting of alkyl groups Selected from A) a compound selected from the group consisting of amides represented by General formula R_Three-CO-NR₁R_Two(Where R₁And R_TwoIs independently H, methyl , Halomethyl, saturated or unsaturated C_Two-C_ThreeAlkyl groups, and hydroxylated Selected from the group consisting of₁And R_TwoTogether CH_Two)_Four, (CH_Two)_Five, And (CH_Two)_TwoO (CH_Two)_TwoSelected from the group consisting of R_ThreeIs H, methyl, halomethyl, and saturated or unsaturated C_Two-C_ThreeAlkyl group Selected from the group consisting of: A) a compound selected from the group consisting of amides represented by Is administered.   According to one embodiment of the present invention, R₁And R_TwoAt least one is a methyl group . According to another embodiment, R₁And R_TwoAt least one of the fluorinated C₁-C_ThreeAl It is a kill group. Therapeutic compositions are mixtures of two or more of the above compounds. There may be. Particularly preferred compositions are those comprising DMF.   A composition used for treating an HIV-infected animal may optionally contain the composition of the present invention and H One or more agents effective in treating IV infections, such as azidobudine (A ZT, ZDV), zalcitabine (ddC), didanosine (ddI), lamivudine (3TC), stavudine (d4T), etc., one or more nucleosides Kind Rim reverse transcriptase inhibitors, nevirapine, delavirdine, loviride, atevirdin, One or more non-nucleoside-related reverse transcriptase inhibitors such as lydinone; One kind such as Quina Building, Internal Building, Ritonal Building, Nelfinal Building or After additional protease inhibitors or the above or other anti-HIV therapeutics It may be used in combination with an agent selected from any mixture. Compositions of the invention and other anti- HIV therapeutics or mixtures thereof may be administered simultaneously according to the desired treatment protocol. Can be administered sequentially or in cycles.   The composition of the present invention may be administered in any desired route, such as enteral or parenteral, e.g. Intra, subcutaneous, intramuscular, intraperitoneal, intravenous, intranasal, epidural, intralymphatic and oral Administration can be by way of, but not limited to. The composition comprises: For example, infusion or bolus injection, epithelial or mucosal skin lining (eg, oral mucosa, stomach Mucosa, intestinal mucosa, rectal mucosa, etc.). Alternatively, they may be administered together with other physiologically active substances.   Administration can be systemic or local. Furthermore, the present invention The pharmaceutical composition can be supplied to the central nervous system by an appropriate route such as intraventricular and intratracheal injection. May be desirable. Intraventricular injection is performed, for example, using a reservoir such as an Ommaya reservoir. This can be done by a ventricular catheter connected to the bar. Also, for example, inhalers Alternatively, the preparation may be mixed with an aerosol and administered to the pulmonary artery using a nebulizer. If necessary, use two or more routes of administration and follow the treatment protocol simultaneously. Administration, sequential administration or cyclic administration may be performed.   In another embodiment, it may be desirable to administer the compositions of the invention to the area in need of treatment. It may be good. This includes, for example, topical treatments, injections, catheters, suppositories, in-plans However, the present invention is not limited to these. The above in-plan The membrane is porous, including membranes or fibers, such as shearastic membranes. Made of a porous, non-porous or gelatinous material.   According to another embodiment, the composition of the present invention is delivered to vesicles, especially liposomes. (Langer, 1990, Science 249: 1527-1533; Treat et al., Therapy of Infect ious Disease and Cancer, edited by Lopez-Berestein & Fidler, Liss, 1989, New York , Pp. 353-365 liposomes; Lopez-Berestein, ibid. See 317-327. one See above for general information).   According to yet another embodiment, the composition of the present invention is delivered using a sustained release system be able to.   In some embodiments, a pump can be used (Langer, supra; Sefton, 1987). , CRC Crit. Ref. Biomed. Eng. 14: 201; Buchwald et al., 1980, Surgery 88: 507; Sa udek et al., 1989, N.M. Engl. J. Med. 321: 547). According to another embodiment, the polymer (Medical Applications of Controlled Release, Langer & Wise, CRC Pres., Boca Raton, Florida (1974); Controlled Drug Bi oavailability, Drug Product Design and Performance, Smolen & Ball, Wil ey, New York (1984); Ranger & Peppas, 1983, J. Amer. Macromol. Sci. Rev. Macromo l. Chem. 23:61; Levy et al., 1985, Science 228: 190; During et al., 1989, Ann. Neurol . 25: 351; Howard et al., 1989, J. Am. Neurosurg. 71: 105). According to another embodiment If possible, implant a sustained release system near the treatment site and use part of the systemic dose (Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138, 1984).   Langer's review (Science 249: 1527-1533, 1990) describes another controlled release system. Are being considered.   Further, the invention provides a pharmaceutical preparation. The preparation is a therapeutically effective amount of the book. It comprises the inventive composition and a pharmacologically acceptable carrier. According to an embodiment of the present invention Thus, the term “pharmacologically acceptable” should be used for animals, especially humans. Has been approved by a federal or state regulatory agency, or Means listed in the generally recognized pharmacopeia. "Carrier" refers to Refers to a diluent, adjuvant, adjuvant or solvent with which to administer the composition. This The carrier of the pharmaceutical is sterilized liquid such as water and oil, peanut oil, soybean oil, mineral Includes those derived from petroleum such as oil and sesame oil, animals, plants or synthetics. Pharmaceutical preparation Is administered intravenously, water is preferred as the carrier. Saline, dextrose Aqueous solutions and glycerol solutions are also used as liquid carriers, particularly for injectable solutions. Can be. Pharmaceutically suitable excipients include starch, glucose, lactose, Sugar, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate Lium, glycerol monostearate, talc, sodium chloride, dried Milk, glycerol, polyethylene glycol, water, ethanol and the like. The pharmaceutical preparations optionally contain minor amounts of wetting or emulsifying agents or pH buffering agents. It may be. These preparations include solutions, suspensions, emulsions, tablets, pills, capsules , Powders, sustained-release preparations and the like. The preparation should be triglycerol or similar. Suppositories may be formulated using fixatives and carriers which have been used in the past. Oral Formulations include pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, Standard carriers such as kalin, cellulose, magnesium carbonate and the like may be included. Suitable Severe carriers are described in "Reminton << Pharmaceutical Scienccs, EW Martin. ing. The preparations may contain a therapeutically effective amount of a therapeutic agent, together with a suitable amount of carrier. Or purified form, and may be in a form suitable for administration to a patient. Formulation Should be appropriate for the mode of administration.   The compositions of the present invention may be administered transdermally. According to the embodiment of the present invention, The light composition is applied directly to the skin. According to another embodiment, the composition of the present invention is Bar (eg cotton pad, Teflon^TMOr other suitable synthetic polymers To the skin, preferably under the occlusive dressing. In another embodiment According to the invention, the composition is applied to the skin using a skin patch. Apply to skin If absorbed in or into reservoir, or added to skin patch In some cases, the concentration of the active ingredient in the composition is about 10 to 100%, desirably at least It is 50%, more preferably at least 90%.   In a preferred embodiment, polar compounds such as DMF are used with a suitable drug delivery device. For example, a skin patch is applied at one or several places, and is administered transdermally. Necessary If present, the skin patch is backed up, and a reservoir such as an absorbent material impregnated with the polar compound of the present invention is used. It may be composed of a bar and a permeable membrane that adheres to the skin. As back Is a natural or synthetic polypeptide that is not chemically altered by polar compounds. Any material, such as rimmers, can be used. Particularly preferred is high density poly. It is behind ethylene. The absorbent is a colloidal substance, such as diatomaceous earth or It may be colloidal silicon dioxide. The permeable membrane is suitable for polar compounds Any material can be used as long as it is chemically stable, and if necessary, porous It may be. According to a preferred embodiment, the permeable membrane has a pore size of about 0.1 μm. m or about 0.5 μm, or Teflon in the range of about 0.1 to about 0.5 μm^TM It is a membrane. Patch may be sticky, or elastic bandage or sticky Applicators such as wrapping materials and bandages including, but not limited to, bandages May be brought into close contact with the skin. Preferably, the patch is supplied from the skin of the test subject. Contains polar compounds in excess of desired amounts. For example, a patch may be about 5 Contains 0% more polar compounds. The size and shape of the patch can be anything you want For example, a disk having a diameter of about 9 cm may be used.   According to one embodiment of the present invention, the patch comprises a polar compound, such as DMF, and at least one Contains another type of pharmacologically active ingredient, for example an anti-local stimulant such as glycerin . According to another embodiment, the patch comprises a polar compound such as DMF and other pharmacology Contains no active ingredients. According to yet another embodiment, the patch is a pole such as DMF. Pharmacologically active ingredients or active ingredients that contain Contains no pharmacologically active ingredients in an amount that affects the whole body after skin absorption. Another According to an embodiment of the invention, the patch comprises a polar compound such as DMF, but other anti-viral Excipients, such as acyclovir or allyldon.   Thus, the present invention relates to viral or microbial Skin containing a polar compound such as DMF in an amount effective to treat an infection (eg, an HIV infection) Provides skin patches. Furthermore, the present invention relates to wasting disorders in human adults or infants. A skin patch is provided which comprises an effective amount of a polar compound such as DMF for treating a symptomatic group. Book According to an embodiment of the invention, the patch weighs at least 0.25 g, desirably at least 0.5 g, more preferably at least 1 g, more preferably at least 5 g For example, 5 to 15 g of a polar compound such as DMF.   A sealed container such as a sealed polymer bag to prevent loss due to volatile compounds You may put a patch in and save it. If necessary, use each patch for convenient use. May be sealed separately. If necessary, refrigerate patches before use, eg at about 4 ° C It may be stored to prevent loss due to evaporation of the polar compound. Desirably 24 hours Immediately before the patch may be prepared and stored at 4 ° C. in a sealed container. However, Chives are stable for more than one week when stored in a sealed container at 4 ° C. Patch application Before washing, wash the skin on the application site with weak soap and water, rinse and wash off the rest of the soap, Dry and dry KY^TMMoisturize with a suitable skin lubricant and wetting agent such as Jerry desirable. The patch is then removed from the packaging and a permeable membrane is applied to the prepared skin surface. Paste so that the blanc adheres. The patch may be fixed with the applicator . After a predetermined treatment time, the patch is removed. After removing the patch, treat with weak soap and water. Thoroughly wash the site and wash away any remaining polar compounds.   The compositions of the present invention may be administered at intervals as needed, for example, once every 2-3 weeks, once a week, It may be administered once or three times, once every two days or daily. Preferably, the set of the present invention The composition has a maximum plasma concentration of the active ingredient such as DMF in the composition of about 2 to 200 mg / L. More preferably about 100-200 mg / L, more preferably 150 mg / L Administer as needed. Maximum plasma concentration of DMF 100-150 mg / L or 15 0 to 200 mg / L is particularly desirable. The “ppm” used here is parts per million by weight 1 means substantially equal to mg / L.   For transdermal administration of polar compounds, measure the rate of absorption from the skin of the subject . About 9.4 mg / cm of liquid DMF applied to human skin^Two/ Constant speed of time (See Mraz & Nohova, 1992, Occup. Env. Health 64: 85-92) . Therefore, depending on the area of each patch and the number of patches to be applied to the skin, etc. By controlling the surface area of the skin to be treated, the desired absorption rate can be obtained. Can be. For example, two patches with a diameter of 9 cm impregnated with a polar compound are used in total area. 127cm^TwoWhen applied to the skin of DMF, DMF has an absorption rate of about 1.2 g / hour. can get. It is particularly desirable that the initial dose of DMF be about 15 mg / kg.   In one embodiment of the present invention, a 9 cm diameter patch 2 is applied to a patient weighing about 72 kg. When DMF is treated by sticking one sheet for 1 hour, the initial absorption of DMF is about 1.2 g, corresponding to about 16.7 mg / kg. Depending on the weight of the patient , Increase or decrease the number of patches, or increase or decrease the sticking time. This initial treatment dose is As described above, administration is repeated at predetermined intervals, preferably once a week. Preferably, DM Aspartic acid in serum or plasma for at least 72 hours after F administration Transferase (AST), alanine aminotransferase (ALT) , Γ-glutamyltransferase (γGT) and alkyl phosphatase Or conjugated or unconjugated bilirubin, etc. The toxic symptoms such as hepatotoxicity of the patient are monitored by measuring the concentration of the substance. Serum or blood AST and ALT concentrations in plasma are above the upper normal range of the laboratory or the population. It is preferably within 5 times, more preferably within 3 times the upper limit of the normal value. In particular, it is desirable not to exceed normality or to not exceed the concentration before treatment. DMF The dose may be escalated by sequentially increasing the patch application time. No. According to the embodiment of the present invention, the patch application time is set to 2 hours, 4 hours, 6 hours, or the like. Lengthen. According to another embodiment, the patch application time is doubled sequentially. Pasting time If escalating, consult the patient in advance to detect toxic symptoms. Is desirable. If necessary, escalate the application time at weekly intervals. This Until the calculated dose reaches about 150 mg / kg / dose, or To obtain the highest plasma concentration, for example 100-150 or 150-200 mg / L. Escalate the dosage until it is applied or until the application time is about 6 or 8 hours. Let it rate. Be careful when increasing the dose to 240 mg / kg / time or more .6. Example: H by transdermal administration of N, N'-dimethylformamide (DMF) Treatment of IV infection   Apply a skin patch impregnated with dimethylformamide (DMF) gel to the patient's body HIV-1 infected patients were treated with dimethylformamide. As liver boosters, N-acetyl-cysteine-glutathione and / or Essential phospholipids were administered to patients at a dose of 250-300 mg / day (oral or Is intravenous injection). Glutamine instead of or in addition to these liver booths It may be administered to patients as a target.   Two skin patches were applied to different parts of the patient's body, for example, the forearm. Each skin The patches consisted of DMF (92.5% m / m) and colloidal silicon dioxide (7.5% m / m) of the gel. The gel shows the leakage of liquid DMF from the patch. It works to prevent going out. Because DMF evaporates rapidly, patches are about to be used. Prepared 12 hours ago. The target value of the DMF concentration in the patient's blood was set to 100 ppm. To obtain a blood concentration of 100 ppm for a patient weighing about 60 kg, about 14 g It needs to be applied for 2 hours. This amount calculated based on the Marz & Nohova test Surface area required for absorption is about 127.2 cm^TwoIt is. 100 ppm blood concentration Approximately 1.272 g of DMF needs to be absorbed per hour or so . Thus, to supply a predetermined amount, each sticker has about 7.064 g of 6. Add DMF and add 6.36 cm^TwoSurface area was required (each sticker). The absorption rate of DMF is 9.4 mg / cm^Two/ Hour. With this process, Theoretically, 125 to 135 ppm should be supplied, but due to the volatilization of DMF, , 100 ppm were obtained. Absorbency depends on factors such as skin type and skin thickness. Depends and varies from patient to patient. To obtain a given DMF concentration, Plasma DMF concentration was measured and treatment was adjusted according to the DMF concentration of each patient. DMF FIG. 1 shows the plasma DMF concentration of four patients to which two patches were applied for 8 hours. DMF par FIG. 2 shows the plasma DMF concentration of three patients to which two patches were applied for 6 hours.   Each sticker thus has about 7.0 gels containing DMF and silicon dioxide. 64 g had been filled. Each patch is once a week for 12 weeks or twice a week for 6 weeks For 12 hours each time.   In some patients' blood tests, CD4 T-cells within 3 weeks after only 3 treatments From 350 to 1000 and PCR (polymerase chain reaction) A sharp decrease from 120,000 to 500 / ml was observed. H in patients before treatment and after three treatments with two DMF skin patches applied for 12 hours A series of quantitative values of the IV-1 viral load by PCR are shown in FIG. PCR test , Roche Amplicor HIV monitor. Virus load Was 500 / ml.   Some treated patients had severe acne or rubella symptoms prior to treatment . When DMF is treated so that the blood DMF concentration of the patient becomes 50 to 100 ppm, Within 7 days, rubella symptoms and severe acne disappeared.   Prior to treatment with dimethylformamide, a comprehensive clinical and psychological A radiological baseline assessment was performed. Perform a biochemical and hematological assessment of the patient and Baseline data was obtained. A detailed viral serological (HIV-1) test was also performed, The total number of viruses in the patient was counted. These tests are performed weekly or at each treatment. Was.   The patient's blood DMF concentration was measured every hour during the treatment period. Collect a blood sample Vein catheter is inserted every morning to inject physiological saline at a rate of 20 ml / hour. Inserted and left inserted, preventing clogging. Active metabolism derived from DMF The product AMCC was measured daily (eg, a 4-hour urine sample was taken). Subsequent DMF Adjust throughput based on changes in absorption variables, complete daily hematological and biochemical Profiles were measured to detect changes in liver function. Also complete clinical and mental Physical evaluation was also performed.   The total number of viruses in the body was determined and the immune status (CD4 T-helper cells) of the patient was revised. Virological serological tests were performed daily to track good and prognostic factors. Serologic tests include p24 antigen and quantitative PCR, or possibly another Performed according to law. In particular, to track the patient's immune status and improve prognosis, Measurements of D4 count and β-2-macroglobulin were also performed weekly. Rapid to harmful changes Application times to maximize clinical efficacy and minimize side effects. All clinical and laboratory data were entered into a centralized data system so that .   This test includes the following items:   a) Serum: Na, K, Cl, CO_Two, Urea, creatinine, Ca, Mg, inorganic Phosphorus, total and conjugated bilirubin   b) Hematological tests: hemoglobin, red blood cell count, hematocrit, MCV, MC H, MCHC, RDW   c) Serum protein electrophoresis: total protein, albumin, total globulin, α-globulin , Α2-globulin, β-globulin, γ-globulin   d) Leukocyte analysis: leukocyte percentage, absolute neutrophils, lymphocytes, monocytes, eosinophils, and And basophil count   e) Liver enzymes: alkaline phosphatase, γ-GT, ALT (SGPT), AS T (SGOT), LDH   f) Others: cell marker, PCR, β2-macroglobulin, p24 antigen, C-reactive protein, CK-MR concentration   g) Analysis of blood DMF concentration   h) Analysis of AMCC concentration in urine   DMF inhibits at least one of reverse transcriptase and protease as described above. Acts as an agent. In an in vitro test, DMF was identified as a solvent. Virus particles, such as capsids.7. Example: H by transdermal administration of N, N'-dimethylformamide (DMF) Treatment of IV infection   Pilot study to evaluate the effects of dermally administered DMF in HIV-infected patients Was done. Informed consent was obtained from each patient. City for p24 antibody detection Western using a kit (Abbott Diagnostics) for sale A seropositive state was confirmed by lot analysis, and a commercial kit (RocheAmplicon) was confirmed. ) Was used to record the presence or absence of HIV-1.   The purchased DMF (Sigma-Aldrich) and DMF in plasma samples were , Varian 9600 gas chromatograph, OV 351 column, carbo Wax-PEG capillary column, Finnegan Mat ITS40 ion Mass spectrometer / gas chromatography using a trap detector GC / MS). The operating parameters were set as follows. GC heating Program: temperature gradient at 60 ° C. for 1 minute, then at 9.4 ° C./min for 20 minutes .   MS ionization method: EI method. Mass range: 40-80 mass units, 1 scan / Seconds. Peak threshold: 3 counts / sec. Background mass: 69 mass units. Inner mark Was used as a stock solution of dimethylacetamide. Perform all tests using organic solvents including internal standards. The material was extracted and left in a refrigerator for 30 minutes to precipitate. Then, 3000g 5 Centrifuged for minutes and transferred to GC vials for injection. Of the DMF peak relative to the internal standard The retention time was 3.26 minutes, and the correlation coefficient of the calibration curve was 0.98. DMF Quantitation is linear up to a concentration of 100 mg / L and the limit of detection is signal vs. background. 0.5 mg / L at a round ratio of 3: 1.   A 9 cm diameter skin patch was used within 12 hours after preparation. Each patch is dense Polyethylene backing (0.245g) and Teflon for skin contact^TM It has a permeable membrane (pore size 0.2 μm, 0.268 g), 0.573 g of silicon dioxide impregnated with 7.067 g of DMF between the blanks Was included. Patches are visually inspected for leaks and weighed on an analytical balance. It was confirmed that the difference from the amount of 8.153 g was within 10%. Patch on forearm skin Affixed to Elastoplast^TMSecured with a bandage. For the first process, Skin transfer rate 9.4 mg / cm^Two1 or 2 pieces / time and patient weight Patches were used.   Blood and urine are collected every two hours using graduated doses of DMF to obtain plasma DMF. The concentration peak was determined. Plasma DMF concentration peaks at 100-120 ppm In the course of escalating doses, patients should follow up clinically for adverse Placed under biochemical examination. Once the correct dose is established, transdermal DMF once a week Was administered. The following items were measured daily as an initial evaluation.   a) Signs of survival and body weight   b) Clinical checklist and Karnofsky score   c) Complete blood count and blood sedimentation   d) Serum urea, creatinine, glucose, Na, K, ALT, AST, Lucari phosphatase and total bilirubin   e) CD4⁺And CD8⁺Coulter counter for number and CD4 / CD8 ratio ー Analysis   f) Evaluation of the amount of HIV-1 by PCR (Roche Amplicor) Of p24 and p24 antibodies (Abbott)   g) Urine test (Dipsix)   At weekly outpatient visits, assess patients for adverse effects and perform almost all of these tests. Again, blood and urine were collected for analysis of DMF and its metabolites.   Patient 1 (ADF) was in relatively good health at the start of the study and was primarily He complained of pain in the limbs and insomnia. Two DMF patches once a week, average application time 8 Administered at time. The average weekly DMF dose was 6.11 g, and the resulting plasma DMF concentration Was 75 mg / L on average. Nine weeks later, the patient's CD4⁺T cell count Increased from 140 to 640 cells / μL and the viral load measured by PCR was 2 It was reduced from 50,000 to 50,000 copies / mL. 10 weeks later, Increased from 81.9 to 96.0 kg and the patient was in good clinical condition He no longer complains of limb pain.   Patient 2 (AM) complained of loss of power, insomnia, limb pain at the start of the study, Herpes was observed in the oral cavity. One DMF patch once a week with an average application time of 8 hours Was administered. The average weekly DMF dose was 7.12 g, and the peak plasma DMF concentration obtained was The average was 125 mg / L. Nine weeks later, the patient's CD4⁺4 T cells From 60 to 720 cells / μL, the viral load measured by PCR was 29, From 000 to 13,000 copies / mL. Patient weight from 58.4 to 6 Increased to 3.0 kg. The patient's herpes disappeared, pain in the extremities disappeared, and clinically good. It seemed good.   Patient 3 (SM) clinically manifested AIDS at the start of the study and Complained of difficulties. Two DMF patches were administered once a week for an average application time of 8 hours. week The average DMF dose was 8.97 g, and the resulting peak plasma DMF concentration was 1 on average. It was 21 mg / L. Seven weeks later, the patient's CD4⁺T cell count from 39 to 138 Cells / μL and the viral load as measured by PCR was from 222,000 to 1 Reduced to 60,000 copies / mL and increased patient weight from 74.2 to 100 kg Added. The patient regained his appetite, his dyspnea disappeared, and he was clinically And exercise started.   Patient 4 (EM) had a secondary infection (rubella), anemia, diarrhea and Acne was noted. Two DMF patches were administered once a week for an average application time of 8 hours . The average weekly DMF dose was 7.33 g, and the peak plasma DMF concentration obtained was The average was 90 mg / L. Eighteen weeks later, the patient's CD4⁺T cell count is 249 From 450 cells / μL, and the viral load measured by PCR was 13,000 0 to 4,000 copies / mL reduced and patient weight 81.5 to 90.4 k g. The patient was clinically good and had no medical complaints.   Patient 5 (SV) had anorexia, amnesia, abdominal pain, severe Was thinking about selling business assets because of fatigue. 2 DMF patches once a week , With an average application time of 6 hours. The weekly average weekly DMF dose is 3.75 g. The peak plasma DMF concentration obtained averaged 67 mg / L. 5 weeks later, CD4⁺T cell count increased from 354 to 396 cells / μL and measured by PCR Virus load decreased from 156,000 to 13,000 copies / mL, The person's weight increased from 56.0 to 58.0 kg. Patients are clinically good and joint He bought a stake in a business owner and started doing business on his own.   Patient 6 (VV) had a secondary infection (rubella), ataxia, left arm and She complained of numbness on her left face. Two DMF patches once a week, average application time 8 Administered at time. The average weekly DMF dose was 8.25 g, and the resulting plasma DM concentration was The peak of the degree was 110 mg / L on average. 19 weeks later, the patient's CD4⁺T The cell number increased from 260 to 450 cells / μL and the viral load measured by PCR The amount is reduced from 120,000 to 24,000 copies / mL and the patient weighs 75 4 to 84.6 kg. The secondary infection has disappeared and the patient is clinically Was.   Patient 7 (AJF) had a significantly worse state of health at the start of the study. Patient CD4⁺The number of T cells was 29 cells / μL, and the viral load measured by PCR Was 1,156,000 copies / mL. Average application time for one DMF patch Dosing was performed at 4 hours. The average weekly DMF dose was 4.60 g and the resulting plasma DM The concentration peak averaged 100 mg / L. After the first treatment, the patient's CD4⁺ T cell count was reduced to 14 cells / μL. Treatment is continued for 5 days every day. After that, treatment was continued once a week. Nine weeks later, the patient's CD4⁺T cell count is 3 5 cells / μL and the viral load as measured by PCR was 9,000 copies / mL and the patient weighs from 46.5 kg (at the start of DMF treatment) to 49.0 k g. The patient was in good mood and returned to regular work.   Patient 8 (MS) showed severe lumbar and perineal herpes at the start of the study Was done. Two DMF patches were administered once a week for an average application time of 8 hours. Average week The DMF dose was 6.24 g, and the peak plasma DM concentration obtained was 130 m on average. g / L. Eight weeks later, the patient's CD4⁺200 to 240 T cells / ΜL and the viral load as measured by PCR is from 1,200,000 to 2 Reduced to 50,000 copies / mL. Patient weight 48.1 to 52.2 kg And the rubella lesions completely disappeared.   Two patients were excluded from the study. One is alcohol abuse and one is B-type liver This is because he was infected with a flame virus.   Most patients experienced mild local skin irritation at the application site after patch removal . Macular papules on the skin at the application site and excessive moisturization under the patch I think that the. In one case, mild blistering was observed, but disappeared within 24 hours. There was no noticeable discomfort to the patient. Most patients are usually mild on the third day after treatment Experienced transient nausea and gradually decreased as the trial progressed. The patient complained of moderate transient nausea. Four patients had a transient increase in liver enzymes However, it did not exceed three times the upper limit of the normal value. It returned to the pre-treatment value by the time F was administered. In most cases, elevated liver enzymes are At least one factor unrelated to treatment (drinking, hepatitis, anti- HIV treatment history).   Consequently, clinical improvement was noted in most patients after 2-3 weeks of treatment. Figure As shown in FIG. 4, when evaluated according to the performance score of Karnofsky, Improvement in general condition was observed in patients with deviation. In this way, the general condition of the patient The evaluation was made by the points as follows. 100 = normal (no symptom complaint), 90 = normal Can do the activity (the symptoms of the disease are very slight), 80 = normal with effort Possible activities, 70 = take care of yourself (normal activity or exercise your body) Difficult to work with), 60 = occasionally need help, but most of the time Can be taken care of, 50 = need considerable assistance, need frequent medical care, 40 = incompetent Needs special medical care, 30 = Severe incompetence, Needs to be hospitalized, Near death 20 = Severely ill, needs hospitalization and frequent nursing care 10 = Dying, rapidly Death is imminent, 0 = death (see Kanofsky et al., 1984, Cancer 1: 634-656). Nerve Improvements in clinical symptoms and herpesvirus infection were significant. Another antimicrobial cure Treatment of secondary infections with therapy was rarely necessary. Within 14 days after DMF treatment Had noticeable improvement in general fatigue and appetite. Weight gain in all patients Addition was accepted. Viral load and CD4⁺Clinical as assessed by T cell count There was a good correlation between improvement and disease status. Measured by PCR in 5 out of 8 patients The relative virus load when fitted was fitted to the Gombertz curve and the analysis showed a D An 88.8% reduction in viral load measured by PCR was observed 42 days after MF treatment. Was. Relative CD4 in 7 out of 8 patients⁺T cell counts fit the Gombertz curve In this analysis, CD4 was found 42 days after DMF treatment.⁺73.4% increase in T cell count Admitted.   The illustrated embodiments are not intended to limit the scope of the present invention, but rather to limit the scope of the present invention. It is for explaining one aspect. In fact, for experts in the field, , From the above description and the accompanying drawings, in addition to those shown and described herein, various It goes without saying that modifications are possible. Such modifications are subject to the claims of the present invention. It is considered to be included.   The publications cited herein are incorporated by reference in their entirety.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI Theme coat ゛ (Reference) A61K 39/395 A61K 39/395 D A61P 31/12 A61P 31/12 31/18 31/18 (81) Designation Country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG) , CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, K, EE, ES, FI, GB, GE, GH, GM, GW, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU , LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW

Claims (1)

[Claims] 1. A drug delivery device for transdermally administering a therapeutic drug, comprising an N-hydroxyl. Cimethyl-N-methylformamide (HMMF), N-hydroxymethylform Amide (HMF), dihydroxymethylformamide (DHMF), N-acetyl -S- (N-methylcarbamoyl) cysteine (AMCC), dimethylsulfo Including therapeutic compositions comprising oxide (DMSO) or pyridine-N-oxide Or a drug delivery device having an impregnated reservoir. 2. A drug supply device for transdermally administering a therapeutic drug,   Backing,   A permeable membrane suitable for application to the skin at the treatment site of the animal;   An absorbent provided between the backing and the permeable membrane; Is N, N'-dimethylformamide (DMF), N-hydroxymethyl-N- Methylformamide (HMMF), N-hydroxymethylformamide (HMF ), Dihydroxymethylformamide (DHMF), N-acetyl-S- (N- Methylcarbamoyl) cysteine (AMCC), N-methylformamide (NM F), dimethyl sulfoxide (DMSO), formamide, acetamide, methyl Ruacetamide, dimethylacetamide, diethylacetamide, isopropyl Acetamide, diisopropylacetamide, N-acetylpiperidine, N- ( β-hydroxyethyl) acetamide, N, N′-di- (β-hydroxyethyl ) Acetamide, N-acetylmorpholine, acrylamide, propionamide , N-fluoromethyl-N-methyl-formamide, pyridine-N-oxide, Or the general formula R_Three-CO-NR₁R_Two(Where R₁And R_TwoAre independent of each other H, methyl, halomethyl, saturated or unsaturated C_Two-C_ThreeAlkyl group, hydroxyl Selected from the group consisting of₁And R_TwoTogether (CH_Two)_Four, (CH_Two)_Five, And (CH_Two)_TwoO (CH_Two)_TwoSelected from the group consisting of And R_ThreeIs H, methyl, halomethyl, and saturated or unsaturated C_Two-C_ThreeA Selected from the group consisting of alkyl groups. ) Containing a therapeutic composition containing an amide represented by And have it,   The drug delivery device is adapted to be placed in close contact with the skin at the treatment site of the animal. Drug supply device. 3. 3. The drug delivery device according to claim 2, wherein the therapeutic composition includes DMF. 4. The therapeutic composition comprises at least 0.25 g DMF. Drug supply device. 5. 5. The method of claim 4, wherein said therapeutic composition comprises at least 5 g of DMF. Feeding device. 6. The therapeutic composition may be viral or microbial in a human adult or infant. 6. A method according to any one of claims 3 to 5, comprising an effective amount of DMF for treating infection or wasting syndrome. A drug supply device according to any one of the preceding claims. 7. 7. The method according to claim 3, which does not contain a pharmacologically active substance other than DMF. 3. The drug supply device according to item 1. 8. Pharmacologically active substances other than DMF that can be absorbed systemically through the skin The drug supply device according to any one of claims 3 to 7, which does not include: 9. The absorbent is colloidal silicon dioxide, and the permeable membrane is Is Teflon with a pore size of about 0.1μm to about 0.5μm^TMClaim 3no which is a membrane 9. The drug supply device according to any one of to -8. 10. A method of treating wasting syndrome,   N, N'-dimethylformamide (DMF), N-hydroxymethyl-N-meth Tilformamide (HMMF), N-hydroxymethylformamide (HMF) , Dihydroxymethylformamide (DHMF), N-acetyl-S- (N- Tylcarbamoyl) cysteine (AMCC), N-methylformamide (NMF ), Dimethylsulfoxide (DMSO), formamide, acetamide, methyl Acetamide, dimethylacetamide, diethylacetamide, isopropyl alcohol Cetamide, diisopropylacetamide, N-acetylpiperidine, N- (β -Hydroxyethyl) acetamide, N, N'-di-([beta] -hydroxyethyl) Acetamide, N-acetylmorpholine, acrylamide, propionamide, N-fluoromethyl-N-methyl-formamide, pyridine-N-oxide, Or the general formula R_Three-CO-NR₁R_Two(Where R₁And R_TwoAre independently H , Methyl, halomethyl, saturated or unsaturated C_Two-C_ThreeAlkyl group, hydroxylation Selected from the group consisting of alkyl groups, or R₁And R_TwoTogether CH_Two)_Four, (CH_Two)_Five, And (CH_Two)_TwoO (CH_Two)_TwoSelected from the group consisting of And R_ThreeIs H, methyl, halomethyl, and saturated or unsaturated C_Two-C_ThreeAl It is selected from the group consisting of a kill group. Treating a therapeutic composition comprising an amide represented by: Administering to an animal in need thereof. 11. The therapeutic composition has the general formula R_Three-CO-NR_TwoR_Two(Where R₁and R_TwoIs independently H, methyl, halomethyl, saturated or unsaturated C_Two-C_ThreeA Selected from the group consisting of alkyl groups, hydroxylated alkyl groups, or R₁ And R_TwoTogether (CH_Two)_Four, (CH_Two)_Five, And (CH_Two)_TwoO (CH_Two )_TwoSelected from the group consisting of_ThreeIs H, methyl, halomethyl, and saturated Or unsaturated C_Two-C_ThreeSelected from the group consisting of alkyl groups. Amide represented by The method of claim 10 comprising: 12. The therapeutic composition has the general formula R_Three-CO-NR₁R_Two(Where R₁and R_TwoIs independently H, methyl, halomethyl, saturated or unsaturated C_Two-C_ThreeA Selected from the group consisting of alkyl groups and hydroxylated alkyl groups;_ThreeIs H , Methyl, halomethyl, and saturated or unsaturated C_Two-C_ThreeAlkyl groups, and It is selected from the group consisting of droxylated alkyl groups. ) Containing amide represented by 12. The method according to claim 10 or claim 11. 13. The therapeutic composition is DMF, HMMF, HMF, DHMF, AMCC , NMF, DMSO, formamide, acetamide, methylacetamide, Tilacetamide, diethylacetamide, isopropylacetamide, diiso Propylacetamide, N-acetylpiperidine, N- (β-hydroxyethyl ) Acetamide, N, N′-di- (β-hydroxyethyl) acetamide, N- Acetylmorpholine, acrylamide, propionamide, N-fluoromethyl 11. N-methyl-formamide or pyridine-N-oxide. 13. The method according to any one of claims 1 to 12. 14． The therapeutic composition may be DMF, HMMF, HMF, DHMF, AMCC or the like. 14. The method of claim 13, comprising NMF. 15. And administering at least one other agent effective in treating HIV infection. 15. The method according to any of claims 10 to 14, comprising: 16. Furthermore, at least one kind of reverse transcriptase inhibitors of nucleoside analogs Or at least one non-nucleoside compound reverse transcriptase inhibitor Or administering at least one protease inhibitor. The method described. 17． 17. The method according to any one of claims 14 to 16, wherein the therapeutic composition comprises DMF. The method described. 18. 17. The therapeutic composition comprises DMSO. the method of. 19. 19. The method according to claim 10, wherein the therapeutic composition is transdermally administered. The described method. 20. A method of treating a viral or microbial infection,   N-hydroxymethyl-N-methylformamide (HMMF), N-hydroxy Cimethylformamide (HMF), dihydroxymethylformamide (DHMF ), N-acetyl-S- (N-methylcarbamoyl) cysteine (AMCC), Therapeutic containing dimethylsulfoxide (DMSO) or pyridine-N-oxide A method comprising administering a composition to an animal in need of treatment. 21. 21. The method according to claim 20, wherein the therapeutic composition is administered to treat a retroviral infection. Method. 22. 22. The method of claim 21, wherein said retroviral infection is an HIV infection. 23. And administering at least one other drug effective in treating HIV infection. A method according to any of claims 20 to 22. 24. Furthermore, at least one kind of reverse transcriptase inhibitors of nucleoside analogs Or at least one non-nucleoside compound reverse transcriptase inhibitor 24. The method according to claim 20, wherein at least one protease inhibitor is administered. The method described in any of them. 25. 25. The method according to claim 20, wherein the therapeutic composition is transdermally administered. The described method. 26. From the body of an animal treated for a viral infection according to claim 20 Vaccine prepared from harvested antibodies.