CN1260703A - Drug delivery device and method for treating viral and microbial infections and wasting syndromes - Google Patents

Drug delivery device and method for treating viral and microbial infections and wasting syndromes Download PDF

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CN1260703A
CN1260703A CN98806085A CN98806085A CN1260703A CN 1260703 A CN1260703 A CN 1260703A CN 98806085 A CN98806085 A CN 98806085A CN 98806085 A CN98806085 A CN 98806085A CN 1260703 A CN1260703 A CN 1260703A
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dmf
acetamide
therapeutic combination
treatment
methyl
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米歇尔·奥尔加·帕特里夏·吉斯泰瑞·维瑟
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Cryopreservation Technologies CC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

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

Treatment is by the doser and the method for virus and the infected by microbes and the syndrome of becoming thin
1. invention field
The present invention relates to treat by viral and the infected by microbes influence, especially the infection of retrovirus retrovirus such as HIV influences, the syndrome of perhaps being become thin influences, particularly pass through as N, the polar compound composition administration of N '-dimethyl formamide (DMF) or dimethyl sulfoxine (DMSO), the animal that the syndrome of becoming thin that treatment is relevant with the infection of HIV or malignant diseases influences.The present invention also provides pharmaceutical preparation and doser, wherein comprises the polar compound that is used for the treatment of by the animal of virus or other infected by microbes or the syndrome of becoming thin influence, for example DMF or DMSO.2. background of invention
2.1. human immune deficiency virus
Human immune deficiency virus (HIV) causes a kind of lasting and progressive infection, causes development (Barre-Sinoussi etc., 1983, Science (science) 220:868-870 of acquired immunity syndrome (AIDS AIDS) in most cases; Gallo etc., 1984, Science 224:500-503).Have two kinds of dissimilar HIV:HIV-1 (Barre-Sinoussi etc., 1983, Science 220:868-870 at least; Gallo etc., 1984, Science224:500-503) and HIV-2 (Clavel etc., 1986, Science 223:343-346; Guyader etc., 1987, Nature (nature) 326:662-669).In the mankind, duplicating of HIV mainly is at CD4 +Carry out in the T lymphocyte, and HIV infects and to cause the minimizing of this cell type, and fundamentally cause immune anergy, opportunistic infection, delayed ischemic neurological deficits, tumor to generate, finally cause death.
HIV be the Lenti virus family of retrovirus retrovirus a member (Teich etc., 1984, RNATumor Viruses, Weiss etc., eds., CSH-press, pp.949-956).Retrovirus retrovirus is the small-sized shell virus that has, and this virus contains the single stranded RNA genome, and through the reverse transcription by encoding viral, a kind of DNA dependency polymerase (Varmus, H., 1988, Science240:1427-1439) the DNA intermediate of Sheng Chenging duplicates.Other retrovirus retrovirus comprises, for example, the human T-leukemia virus (HTLV-I ,-II ,-III) and the oncogenic virus of Feline leukemia virus.
The virus nuclear that the HIV virion is made up of the part of the envelope protein that is named as P24 and P18 is formed, and has the viral RNA genome and be used for duplicating in early days required enzyme.Myristylated gag albumen forms the virus coat that surrounds this virus nuclear, and this shell is surrounded by the deutero-adipose membrane of the after birth of infected cell again conversely.HIV case surface glycoprotein synthesizes with single 160,000 dalton's precursor proteins, and described precursor protein is gone in two glycoprotein gp41 and the gp120 process, by the cell protein enzymatic lysis in viral bud grafting.Gp41 wears membrane glycoprotein, and g120 is the outer glycoprotein of the born of the same parents that get in touch that keeps non-key altogether with gp41, and may there be (Hammerskjold with the form of trimerization or poly in they, M. and Rekosh, D., 1989, Biochem.Biophys.Acta 989:269-280).
Being similar to other has shell virus, and HIV is introduced viral gene material by membrane-mediated fusion to host cell by the virus and the virus of target film.The target cell of HIV is CD4 +Cell is because cd4 cell surface protein (CD4) plays cell receptor (Dalgleish etc., 1984, the Nature 312:763-767 of HIV-1 virus; Klatzmann etc., 1984, Nature 312:767-768, Maddon etc., 1986, Cell 47:333-348).Virus enters cell and depends on gp120 in conjunction with cell CD4 acceptor molecule (Pal etc., 1993, Virology 194:833-837; McDougal etc., 1986, Science 231; 382-385, Maddon etc., 1986, Cell 47:333-348), this is the reason of HIV to the cd4 cell aeoplotropism, gp41 is being anchored on the viromembrane by membrane glycoprotein simultaneously.Gp120 and combining of CD4 cause the change of glycoprotein configuration in the virus, but only this in conjunction with also being not enough to cause infect (summary of Sattentau and Moore, 1993, Philos.Trand.R.Soc.London (Biol.) 342:59-66).
The research of HIV-1 separated strain indicates that they are at the disparity of the ability that infects different human cells (summary such as Miedema, 1994, immunol.Rev.140; 35-72).The T cell line and the original T lymphocyte of cultivation can be easily infected in most laboratory cultures HIV-1 strains, but is difficult for infecting primary mononuclear cell or hugely has a liking for cell.These strains are called the T-parental plant.T-parent HIV-1 strain is easier to find (Weiss etc., 1996, Science 272:1885-1886) in the late period that HIV-1 infects in the AIDS patient's body.The most of original HIV-1 separated strains virus of sophisticated cultivation (promptly without) effectively lymphoblast, mononuclear cell and huge have a liking in the cell duplicate, but in sophisticated T cell line undergrowth.These separated strains are called the M-parental plant.The viral determinant of T-and M-parental plant replaces (Choe etc., 1996, Cell 85:1135-1148 in the 3rd variable region of gp120 (V3 group); Cheng-Mayer etc., 1991, J.Virol.65:6931-6941; Hwang etc., 1991, Science 253:71-74; Kim etc., 1995, J.Virol., 69:1755-1761; And O ' Brien etc., 1990, Nature 348:69-73).Characteristic with HIV separated strain of different tropisms, and only be not enough to cause infecting this observed result prompting with combining of cd4 cell surface protein, except CD4, also need cell type-specific cofactor to enter host cell.
2.2. the treatment that HIV infects
It is epidemic that HIV infects, and the disease relevant with HIV represented world's health problem.Make great efforts to design effective treatment greatly though used, the current medicine that does not still have the anti-retroviral of effective treatment AIDS.For developing this type of medicine, several HIV life link stages considered as therapeutic intervention target (Mitsuya, H., etc., 1991, FASEBJ.5:2369-2381).Proposed the viral target of many intervention HIV life cycle, main points of view has serious adverse for intervening host cell proteins.For example, the reverse transcription of encoding viral has been a focus of drug development.Having developed a series of is the medicine of target with the reverse transcription, comprises 2`, 3`-di-deoxynucleoside class, and as AZT, ddI, ddC and d4T, these medicines have demonstrated the activity (Mitsuya, H. is etc., 1991, Sicence 249:1533-1544) of anti-HIV.
New therapeutic scheme to HIV-1 shows, the chemical compound of the anti-HIV-1 of targeting reverse transcription (RT) such as azido thymidine (AZT), come Mi Fuding (lamivudine) (3TC), dideoxy inosine (ddI) and dideoxy born of the same parents' (ddC) a kind of mixture and HIV-1 protease inhibitor are united use, compare with independent use AZT, viral load is had bigger effect (reduction of 2 to 3 logarithms).For example, the mixture of AZT, ddI, 3TC and ritonavir obtained recently tangible result (Perelson, A.S., etc., 1996, Science15:1582-1586).But the compositions of these medicines of life-time service can cause toxicity probably, particularly to the toxicity of bone marrow.Secular cytotoxicity treatment also can cause CD8 +T cell inhibiting, and CD8 +The T cell is the activity (Blazevic by cell killing, V., Deng, 1995, AIDS Res.Hum.Retroviruses 11:1335-1342) and release inhibiting factor with control HIV key element, particularly chemical agonist Rantes, MIP-1 α and MIP-1 β (Cocchi, F etc., 1995, Science 270:1811-1815).Another main consideration to the treatment of life-time service chemistry anti-retroviral be have a part or the development (Lange, J.M., 1995, AIDS Res.Hum.Retroviruses 10:S77-82) of the HIV sudden change of resistance completely.It is believed that this sudden change may be the inevitable result of antiviral therapy.The phenomenon of the disappearance of the unmanifest virus that treatment causes and the appearance of variant viral is in conjunction with the CD4 that descends simultaneously +The quantity of T cell, prompting consumingly, at least for some chemical compound, the appearance of virus variation is the key factor that the AIDS treatment was lost efficacy.
People also attempt to develop the medicine that the early stage inhibition virus that infects at HIV enters cell.These effort mainly concentrate on the CD4, i.e. the HIV cell surface receptor.For example, the soluble CD4 that recombinates has shown and can suppress some HIV-1 strain to CD4 +The infection of T cell (Smith, D.H., etc., 1987, Science 238:1704-1707).Yet, some primary HIV-1 separated strain relative to recombinant CD4 suppress insensitive (Daar, E., etc., 1990, Proc, Natl.Acad.Sci.USA 87:6574-6597).In addition, the soluble CD4 clinical trial of recombinating has produced uncertain result (Schooley, R. etc., 1990, Ann.Int.Med112:247-253; Kahn, J.O., etc., 1990, Ann.Int.Med.112:254-261; Yarchoan, R., etc., 1989, Proc.Vth Int.Conf.on AIDS, p.564, MCP 137).
The HIV in late period that relates to the viral special process of the proteic key of certain encoding viral duplicates and points out the target that can be used as inverase.Late period, process depended on the virus protein enzymatic activity, and was developing the medicine (Erickson, J., 1990 Science 249:527-533) that suppresses this kind protease.
Recently, by CD8 +The chemical agonist of T emiocytosis have the sign that suppresses HIV and infect (Paul, W.E., 1994 Cell 82:177:Bolognesi, D.P., 1993, Semin.Immunol.5:203).
By CD8 +The chemical agonist RANTES of T emiocytosis, MIP-1 α and MIP-1 β demonstrate suppressing HIV-1p24 antigen product (Cocchi, F is etc., 1995, Science 270:1811-1815) in the cell that infects at external use HIV-1 and HIV-2 separated strain.Therefore, though the chemical agonist susceptible of proof of these and other infects effective to treatment HIV.But clinical effectiveness is that all these and other candidate medicine also have problems.
People also notice the vaccine that exploitation treatment HIV infects.(gp160, gp120 gp41) have shown it is to be present in the intravital major antigen to anti-HIV antibody of AIDS patient (Barin etc., 1985, Science 228:1094-1096) to described HIV-1 envelope protein.Therefore these albumen are the antigenic most possible material standed fors as the anti-HIV vaccine.Wherein several groups have begun to be used for gp160 as the immunogenic target of host immune system, the different piece of gp120 and/or gp41.See Ivanoff, the United States Patent (USP) 5,141,867 of L etc., Saith G, the WO92/22 that waits, 654, Shaffermarn, A, WO91/09,872; The WO90/07 of Formoso C etc., 119.For this purpose, the problem that is intended to the proteic vaccine of anti-HIV is that viral mutation makes many these vaccine failures very soon.But, also draw far away about the clinical effectiveness of these candidate vaccines.
Therefore, although made the medicine that huge effort is intended to design and test anti-retroviral, still need effective avirulent treatment.
The syndrome 2.3. become thin
The syndrome of becoming thin is a kind of serious clinical problem, is characterized in, and more than 10% of the benchmark of losing weight, and also body weight reduces and fat decline disproportionate (Weinroth etc., 1995, Infectious Agents and Disease 4:76-94; Kotler and Grunfeld, 1995, AIDSClin.Rev.96:229-275).Therefore, the syndrome of becoming thin is different from hungry disease (Kotler etc., 1985, AmJ.Clin.Nutr, the 42:1255-1265 of body fat height disappearance rather than soma minimizing; Cahill, 1970, N.Engl.J.Med.282:668-675).It is relevant with multiple situation to become thin, and comprises that HIV infects, other infectious disease, septicemia, cancer, chronic cardiovascular disease and diarrhoea (Kotler etc., 1989, Am.J.Clin.Nutr, 50:444-447; Heymsfield etc., 1982, Am..J.Clin.Nutr.36:680-690).Importantly, becoming thin is infected patient or cancer patient's important lethal factor.In fact, soma exhausted with the AIDS VICTIMS have the time-to-live linear relationship (Kotler etc., 1989, Am.J.Clin.Nutr.50:444-447).
The cause of disease of the syndrome of becoming thin of AIDS and other disease it be unclear that, and multiple factor is arranged probably.Metabolism is not normal, and hormone is all pointed out relevant with the syndrome of becoming thin with the cytokinin amount is undesired with malabsorption etc.Be not that all AIDS VICTIMSs all become thin, this shows that the reason of becoming thin is not HIV itself.Most HIV obviously are caused by the complication of AIDS with the case of the syndrome of becoming thin, as infecting for the second time and gastroenteropathy etc. (Kotler and Grunfeld, 1995 AIDS Clin.Rev.96:229-275).
The current treatment with the potential syndrome of becoming thin comprises nutritional support, and appetite promoter is dronabinol and megestrol acetate for example, and anabolic treatment is growth hormone and cytokinin inhibitor for example.Yet, the blended result of nutritional support and short appetite agent is that the patient tends to only increase fat rather than TBW.The medication of growth hormone and cytokinin inhibitor also in test and possibility (Kotler and Grunfeld, 1995, the AIDS Clin.Rev.96:229-275 of danger of side effects arranged; Weinroth etc., 1995 Infectious Agents andDisease 4:76-94).
Therefore, the treatment of marasmus is the key of serious disease such as cancer and AIDS VICTIMS's existence and rehabilitation; Therefore, need safety and treatment the become thin syndrome relevant effectively with cancer, AIDS and other infectious disease.
2.4. the characteristic of dimethyl formamide and other polar compound
N, (molecular formula: be colourless polar hygroscopic liquid C3H7ON), have low volatility, boiling point is 152.5-153.5 ℃ to N '-dimethyl formamide (DMF).It easily mixes with water, pure and mild some hydro carbons.DMF generally is used as polar solvent and is easy to and absorbs, breathes, reaches oral absorption through skin.The DMF metabolism is very fast, mainly at hepatic metabolism, and mainly through homaluria.In rat, mice, hamster and human body; the main metabolites of DMF is N-hydroxymethyl-N-methylformamide (HMMF); N-methylformamide (NMF); with N acetyl group-S-(N-methylamino formoxyl) cysteine (AMCC), and dihydroxy methylformamide (DHMF) and N-hydroxymethyl Methanamide (HMF).Unaltered DMF drains in urine, only accounts for the very little ratio of DMF dosage.
The toxicity that DMF has low acute skin, mouth and breathes.Being considered to has little zest and the easy skin that infiltrates to moderate to skin and eye.No skin sensitization sign.The main toxic action of DMF and its metabolism are in liver; Known DMF causes the reversed hepatic injury that is associated with the typical clinical main suit, typical biochemical change in the blood, and in liver biopsy visible hepatic necrosis.DMF is deforming, but does not think mutagenesis or carcinogenic.
Report DMF such as Viza and DMSO suppress duplicating of HIV in some cultured cell system and human herpes virus 6 (HHV-6) in vitro tests.(see Viza etc., 1990, AIDS Res.Hum.Retroviruses 6:131-132; Viza etc., 1989, AIDS-FORSCHUNG 4; 349-352; Viza etc., 1992, Antiviral Res.18:27-38 and at the errata of 19:179).
The differentiating solvent that DMF is described to a kind of in vitro tests be used for some ameboid cell cultivation (see Koeffler, 1983, Blood 62:709-721; Calabresi etc., 1979, Biochem.Pharmacol.28:1933-1941).Report, when adding some malignant cell in vitro, DMF can reduce afterwards inoculation go into the oncogenicity of these malignant cells of nude mice (see Van Dongen etc., 1989, Int.J.Cancer 43:285-292; Braakhuis etc., 1989, Head﹠amp; Neck 11:511-515; VanDongen etc., 1988, Acta Otolaryngol.105:488-493, Dexter etc., 1982, Cancer Res.42:5018-5022).But amide and N-methyl-derivatives thereof the toxic and side effects in rat meat tumor homotransplantation model is reached a conclusion research worker: these medicaments can not confirm that therapeutic use is arranged (see Clarke etc., 1953, Proc.Sec.Exp.Biol.Med.84:203-207).
The conclusion that obtains with DMSO treatment human cancer patient's trial is: do not see objective reaction is arranged (see Spremulli and Dexter, 1984, J.Clin.Oncol.2:227-241).The human patients of suffering from the incidence cancer is carried out the oral administration of NMF, it is reported to causing hepatotoxicity, do not have optimum reaction and (see Vogel etc., 1987, Invest.New Drugs 5:203-206), or has only minimum effect (see Planting etc., 1987, Cancer Treat Rap.71:1293-1294).
United States Patent (USP) 3,551,154 disclose use DMF absorbs with the percutaneous that promotes local application as penetrating reinforcing agent.United States Patent (USP) 4,855,294 disclose and use glycerol to relax owing to use DMSO and DMF does that short percutaneous absorbs local application penetrates reinforcing agent caused skin irritation.Woodfood and Barry, 1986 deliver and paper (J.Toxicol.Cut.﹠amp; OcularToxicol5:167-177) percutaneous that uses DMSO to penetrate reinforcing agent promotion antiviral agent being discussed absorbs.
The list of references that the application quotes and authenticates in second joint (or other parts) does not constitute and admits that this is with reference to can be used as technology formerly of the present invention.3. summary of the invention
The present invention relates to treat by virus or other infected by microbes, especially as the doser of method, compositions and the medicine of the animal of the retroviral infection of HIV.The present invention also is subjected to provide as the animal that the syndrome of becoming thin relevant with HIV infection or malignant tumor influences the doser of method, compositions and medicine for treatment.
According to the present invention; animal to the needs treatment is used a kind of compositions; said composition comprises N; N '-dimethyl formamide (DMF); N-methylol-N-methylformamide (HMMF); N-hydroxymethyl Methanamide (HMF); dihydroxy methylformamide (DHMF); N-acetyl group S-(N-methylamino formoxyl) cysteine (AMCC); N-methylformamide (NMF); dimethyl sulfoxine (DMSO); Methanamide; acetamide; methylacetamide; dimethyl acetylamide; diethyl acetamide; the isopropyl acetamide; the diisopropyl acetamide; N-acetyl group piperidines; N-(beta-hydroxy ethyl) acetamide; N, N '-two (beta-hydroxy ethyl) acetamide; N-acetyl group morpholine; acrylamide; propionic acid amide.; N-fluoro methyl-N-methyl-Methanamide; pyridine-N-oxides; perhaps any being selected from by general formula R 3-CO-NR 1R 2In the group formed of amide of expression, R wherein 1And R 2For being independently selected from by H, methyl, halogenated methyl, full close and C is closed in insatiable hunger 2-C 3In the group that alkyl and hydroxylated alkyl are formed; Or
R 1And R 2For being selected from by (CH together 2) 4, (CH 2) 5, and (CH 2) 2O (CH 2) 2In the group of being formed; With
R 3Be selected from by H, methyl, full close and C is closed in insatiable hunger 2-C 3In the group that alkyl is formed.The mixture that can contain any two and a plurality of above-claimed cpds in the therapeutic composition.
In the patient of infected by HIV, therapeutic scheme alternatively combines compositions of the present invention and is used for the treatment of the HIV infection effectively with one or more additives, additives include but not limited to be selected from by nucleoside simulation reverse transcriptase inhibitors, non-nucleoside simulation reverse transcriptase inhibitors and protease inhibitor, the reagent in the group of being formed with any desired combination.
The present invention also expands to by from the vaccine with the Antibody Preparation that obtains in the animal body behind the combination treatment of viral infection resisting of the present invention.4. the simple description of accompanying drawing
With reference to following detailed description of the present invention, the embodiment of the specific specific embodiment of the present invention and accompanying drawing, can understand the present invention more fully:
Fig. 1 represents to use 4 of 2 DMF skin grafts and is treated 8 hours DMF of patient treatment plasma concentration-time function curve.
Fig. 2 represents to use 3 of 2 DMF skin grafts and is treated 6 hours DMF of patient treatment plasma concentration-time function curve.
Fig. 3 represents the HIV-1 viral load of a patient with percutaneous DMF treatment, with the PCR quantitative measurement.At the 0th, 8,13 day (shown in the arrow), two DMF skin grafts were affixed on upper arm skin 12 hours.
Fig. 4 represents that the ordinary circumstance of HIV infected patient is assessed with Ka Shi performance scale with before and after the percutaneous DMF treatment.See textbook the 7th joint for details.5. detailed description of the present invention
The invention provides the method, compositions and the doser that are used for the treatment of virus and infected by microbes.In a specific embodiment, the infection that treat is the infection that has as the HIV retrovirus retrovirus, comprise symptomless infection, incubation period infect, with the infection of the relevant comprehensive symptom of one or more AIDS with the infection of clinical AIDS.Perhaps; the infection for the treatment of is any other virus or infected by microbes, comprises rubella, the herpesvirus as human herpes virus 6, E-BShi virus or cytomegalovirus infection, any viral infection with housing protective layer and the patient's of any opportunistic infection relevant with disease of immune system such as infected by HIV opportunistic infection.
The present invention also is provided for treating or prevents by weight loss is any disease or disorderly method, compositions and the doser of feature.The disease specific of available the inventive method and combination treatment includes but not limited to relevant with the infection of virus (as HIV) and antibacterial or any other form or septicemia to become thin, with tumor, chemotherapy or emitting treatment relevant cachexia, be correlated with chronic cardiovascular diseases become thin, be exposed to that toxicity or radioactive substance cause becomes thin, and with suffer from diarrhoea or other gastrointestinal disease is correlated with becomes thin.
The object of treatment can be any animal, includes but not limited to monkey, cattle, sheep, pig, horse, cat, Canis familiaris L., chicken etc., preferred mammal, and more preferably primate, most preferably the people comprises adult and child, as the child of at least 3 kilograms of body weight.This civilian patient's one speech refers to the animal of any needs with method of the present invention or combination treatment.
According to the present invention; have and use a kind of therapeutic composition; said composition comprises DMF, HMMF, HMF, DHMF, AMCC, NMF, DMSO, Methanamide, acetamide, methylacetamide, dimethyl acetylamide, diethyl acetamide, isopropyl acetamide, diisopropyl acetamide, N-acetyl group piperidines, N-(beta-hydroxy ethyl) acetamide, N, N '-two (beta-hydroxy ethyl) acetamide, N-acetyl group morpholine, acrylamide, propionic acid amide., N-fluoro methyl-N-methyl-Methanamide, pyridine-N-oxides, any being selected from by general formula R 3-CO-NR 1R 2The group that the amide of expression is formed, wherein R 1And R 2For being independently selected from by H, methyl, halogenated methyl, full close and C is closed in insatiable hunger 2-C 3In the group that alkyl and hydroxylated alkyl are formed; With
R 3Be selected from by H, methyl, full close and C is closed in insatiable hunger 2-C 3In the group that alkyl is formed, or any being selected from by general formula R 3-CO-NR 1R 2The group that the amide of expression is formed, wherein
R 1And R 2For being independently selected from by H, methyl, halogenated methyl, full close and C is closed in insatiable hunger 2-C 3In the group that alkyl and hydroxylated alkyl are formed; Or
R 1And R 2For being selected from by (CH together 2) 4, (CH 2) 5, and (CH 2) 2O (CH 2) 2In the group of being formed; And R 3Be selected from by H, methyl, full close and C is closed in insatiable hunger 2-C 3In the group that alkyl is formed.
In a specific specific embodiment, R 1And R 2At least one be methyl.In another specific specific embodiment, R 1And R 2At least one be fluorizated C 2-C 3Alkyl.Therapeutic composition can be the mixture of any two kinds or the multiple chemical compound of above-claimed cpd.Especially preferred a kind of compositions that comprises DMF.
Animal for the treatment infected by HIV, except that compositions of the present invention, this therapy can comprise arbitrarily that one or more other reagent are used for the treatment of the infection of HIV effectively, one or more nucleoside reverse transcriptase inhibitors for example, as zidovudine (AZT, ZDV), zalcitabine (DDC), didanosine (ddI), come Mi Fuding (3TC), Si Tafuding (d4T), one or more non-nucleoside reverse transcriptase inhibitors, as how fertile sharp flat (nevirapine), delaviridine (delavirdine), Luo Woride (loviride), Aunar fertile fixed (atevirdine), pyrrole is decided ketone (pyridinone), one or more protease inhibitor, as Sa Kuinawo (saquinavir), Yin Dingnawo (indinavir), day is with receiving fertile (ritonavir), that branch is received fertile (nelfinavir), or the combination of any said medicine, or other anti-HIV therapeutic agent.Compositions of the present invention and additional anti-HIV therapeutic agent or other reagent can be simultaneously, in succession or by the administration course of treatment of other any desired treatment regulation.
Compositions of the present invention can include, but are not limited to through skin, intradermal, subcutaneous, muscle with any desirable through intestinal or parenteral administration, intraperitoneal, intravenous, intranasal, epidural, interior, the oral route of lymph.These chemical compounds can be with the method administration of any routine, for example transfusion or bolus injection, through epithelium or mucosa (for example mouth, stomach, intestinal or mucous membrane of rectum etc.) and can with other bioactivator while administration.
But also topical can be administered systemically.In addition, may require Pharmaceutical composition of the present invention with any suitable approach to comprise the injection in intraventricular and the sheath to the nervus centralis administration; Intraventricular injection can for example, be connected to the conduit of a reservoir such as the conduit of Ommaya reservoir by means of intraventricular conduit.Also can for example use inhaler or nebulizer, and contain the aerosolization agent in the prescription through the lung administration.As needs, the two or more route of administration of any usefulness can be simultaneously, in succession or with the administration course of treatment of any therapeutic scheme.
In a specific specific embodiment, may wish that with compositions of the present invention at needs treatment place topical, this can reach, such as but not limited to local dispenser, tube injection, suppository or implant.Described implant is porous, atresia or gel rubber material, comprises film, for example silastometer film or fiber.
In another embodiment, compositions of the present invention can send in especially a kind of adipose capsule at a kind of folliculus.(see Langer, Science, 249:1527-1533), liposomes in the therapy of infectious Disease and Cancer such as treat, Lopez-Berestein and Fidler edit, Liss, New York, P353-365 1989, and Lopez-Berestein is 317-327 as above).
In another embodiment, compositions of the present invention can send with the system of a control release.
In a specific embodiment, can (see Langer, Supra, Sefton, CRC Crit.Ref.Biomed.Eng.14:201 1987 with a pump; Surgery 88:507 1980 such as Buchwald; N.Engl.J.Med.321:547 such as Saudek, 1989).In another embodiment, (see the application of sustained release medicine, Langer and Wise edit CRC printing Boca Raton, Florida 1974 to available polymeric material; The biological availability of control medicine, the design of drug products and sign Smolen and Ball edit Wiley, New York1984; Ranger and Peppas, J.Macromal.Sci.Rev.Macromol.Chem.23:611983; See Science such as Levy, 228:190 1985 years; Ann.Neurol.25:351 such as During J.Neurosurg.71:105 such as Howard in 1989 1989).In another embodiment, a control medicine-releasing system can be placed near the therapeutic goal place, so only need the sub-fraction (seeing the application supra of the sustained release medicine of Goodson, 1984 2 volume 115-138 pages or leaves) of system's dosage.
Other control medicine-releasing system (Science 249:1527-1533,1990) in the summary of Langer obtains discussing.
The present invention also provides pharmaceutical preparation.This pharmaceutical preparation comprises the compositions of the present invention and the medicine acceptable carrier of effective therapeutic dose.In a specific specific embodiment, " medicine can be accepted " speech be meant use by federal government or continent government or the approval of other government bodies or list in American Pharmacopeia or other generally acknowledges the officinal animal that is used for, particularly human." carrier " speech is meant diluent, adjuvant, excipient, vehicle, and compositions of the present invention is with these carrier administrations.These pharmaceutical carriers can be disinfectant liquid, and Ru Shui and oil comprise oil, animal, plant or artificial oil, as Oleum Arachidis hypogaeae semen, Oleum Glycines, mineral oil, Semen Sesami wet goods.Water is preferred carrier when the pharmaceutical formulation intravenous administration.Saline and D-glucose aqueous solution and glycerol also can be used as liquid-carrier, especially as injection.The pharmaceutical excipient that is fit to comprises starch, glucose, lactose, sucrose, gelatin, maltose, rice, flour, hundred chalks, silicon gel, sodium stearate, glyceryl monostearate, Talcum, sodium chloride, dry milk sheet, glycerol, propylene glycol, water, ethanol etc.If desired, described pharmaceutical preparation also can comprise wetting agent or emulsifying agent or PH buffer agent in a small amount.Described pharmaceutical preparation can be solution, suspension, emulsion, sheet, ball, capsule, powder and slow release prescription etc.Described pharmaceutical preparation can be used conventional binding agent and make as the carrier of triglyceride and fasten agent.Formula of oral can comprise the carrier of standard, as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharinate, cellulose, magnesium carbonate etc.The appropriate drug carrier obtains describing in " pharmaceutical science of Reminton " that E.W.Martin writes.This pharmaceutical preparation meeting comprises dose therapeutically effective, and preferably form and the appropriate carriers with pure medicine is patient's administration with suitable form together.The agent shape administering mode that should suit.
Compositions of the present invention can percutaneous dosing.In a concrete embodiment example, compositions of the present invention directly imposes on skin.In another concrete embodiment example, compositions of the present invention imposes on a reservoir, and (as, cotton pad, synthetic polymer is as Ta Fulong TM, or any suitable assimilate) in be used for skin, preferably under big envelope.In a specific concrete embodiment example, compositions of the present invention imposes on skin with skin graft.Be contained in or be absorbed in the reservoir or be contained in the effective therapeutic component that acts on the compositions on the skin in the skin graft, its concentration can reach 10-100%, is preferably at least 50%, and more preferably at least 90%.
In a preferred specific embodiment example, as applying one or more skin graft, percutaneous carries out the polar compound administration as DMF with suitable doser.This skin graft selectively contains a back side, and the reservoir of an adsorbent that is soaked with polar compound of the present invention and one place the permeable membrane with contact skin.The back side can be any material, as the natural or erosive polymer of synthetic anti-polar compound.The particularly preferred back side is high density polyethylene (HDPE).Adsorbent can be colloid, as kieselguhr or colloidality silicon dioxide.Permeable membrane can be any erosive polymer of anti-polar compound with holes of selecting.In a preferred specific embodiment, permeable membrane be have 0.5 micron of the hole of 0.1 micron of diameter and diameter the hole carry the husband dragon TMFilm, or the hole of diameter between 0.1 to 0.5 micron.Skin graft can be self-adhesion, or keeps and contact skin with a cover or binder applicator, comprises the not plastic bandage or the cohesive bandage of belt restraining, Elastoplast TMBinder is suitable for this usefulness.Preferably, described skin graft contains than planning more to be measured the amount of the polar compound of quilt treatment patient administration through skin, contains more than the amount of plan through the amount about 50% of the polar compound of patient skin administration as skin graft.Skin graft can be any desired size and dimension, and can, for example take diameter to be about 9 centimetres disk sample form.
In a specific embodiment, skin graft contains a kind of polar compound and at least a other pharmacologically active reagent as DMF, as the counteirritantia glycerol in part.In another embodiment, skin graft contains a kind of polar compound as DMF, and does not have other pharmacologically active reagent.In a further specific embodiment, skin graft contains a kind of polar compound as DMF, and not having perhaps, not to have to act on effectively the amount of other pharmacologically active reagent of whole body through other pharmacologically active reagent of skin whole body absorption after skin absorbs.In another embodiment, skin graft contains a kind of polar compound as DMF, does not contain the pharmacologically active reagent that other acts on whole body.In another further specific embodiment, skin graft contains a kind of polar compound as DMF, does not contain other antiviral agent, as acyclovir or arildone.
Therefore, the invention provides a kind of skin graft, this skin graft contains a kind of polar compound as DMF, and its amount is for effectively treating adult or child virus and infected by microbes (for example HIV infects).The present invention also provides a kind of skin graft, and this skin graft contains a kind of polar compound as DMF, presents in an amount at least sufficient to effectively treat adult or child's the syndrome of becoming thin.In a specific embodiment, skin graft contains at least 0.25 gram, and preferably at least 0.5 gram more preferably at least 1 restrains, and more preferably at least 5 restrains, for example a kind of polar compound as DMF of 5-15 gram again.
Be to reduce the evaporation loss of polar compound, skin graft is selectively deposited in the container of sealing as in the polymer pouches of sealing.If desired, each skin graft can seal respectively so that use.Alternatively, skin graft can leave in the refrigerator before use, and for example 4 degrees centigrade, to reduce the evaporation loss polar compound.Preferably, described skin graft prepared within 24 hours that use and leaves in the sealed container in 4 degrees centigrade.Yet, skin graft 4 degrees centigrade of sealings deposit one the week or be stable more than the week.Before the use skin graft, the skin that the most handy green soap and water washing are used washes away remaining soap, and bone dry is used suitable emollient and wetting agent such as KY then TMFreeze and carry out hydration.The packaging material that tear skin graft off impose on skin then, face toward the skin surface of getting ready with penetrating film.Available a kind of applicator is fixing on the throne skin graft.After the administration time that requires, remove skin graft.Use green soap and the washing remnants of all polar compounds only after taking skin graft away.
Compositions of the present invention can be in any desirable interval administration, as per two weeks or per three weeks once, weekly, twice or three times, two days are once, or once a day.Preferably, compositions of the present invention reaches 2 to 200 milligrams every liter dosage approximately with the effective ingredient that reaches the compositions in the blood plasma such as the peak value of DMF, and preferably approximately 100 to 200 milligrams every liter, more preferably from about 150 milligrams every liter.The peak value that particularly preferably is the content in the blood plasma of DMF is every liter of 100-150 or 150-200 milligram.Ppm herein refers to the weight of 1,000,000/volume unit, actually equals every liter of milligram.
The skin absorbs speed of polar compound administration depends on subject's skin.To human skin, DMF with about 9.4 milligrams/square centimeter/hours stable speed absorb (see Mraz and Nohova, 1992, Occup.Env.Heath, 64:85-92).Therefore, desired absorption rate can be exposed to long-pending the reaching of skin surface of medicine by control, promptly reaches by the area of determining every skin graft and the skin graft number that imposes on skin.For example, the skin graft that two diameters are 9 centimetres can be the gross area that 127 square centimeters skin is exposed to polar compound, can produce the per hour absorption rates of 1.2 grams for DMF.The predose of every kilogram of 15 milligrams of DMF is particularly preferred.
In a specific embodiment, the about 72 kilograms patient of body weight initially uses two skin graft DMF administration one hour of 9 centimetres of diameters, and the initial absorbed dose of result are about 1.2 gram DMF, are equivalent to every kilogram about 16.7 milligrams.According to the body weight of being treated the patient, the quantity of skin graft and the time of initial exposure can be adjusted up and down.This initial dose can repeat at any desirable interval, as mentioned above, and preferably in the week administration.Preferably the patient monitors at least 72 hours poisoning sign after the DMF administration, as liver poisoning, as concentration by the enzyme in monitoring serum or the blood plasma, shift enzyme (AST), alanine transaminase (ALT), γ-glutamine transferring enzyme (γ GT) and alkali formula phosphatase as glutamic acid, with albumen such as globulin, or material such as combination and unconjugated bilirubin.Preferably, AST in serum or the blood plasma and ALT are no more than 5 times by the laboratory term of reference and the determined normal value upper limit of crowd that relates to, more preferably AST in serum or the blood plasma and ALT are no more than 3 times of the normal value upper limit, the value before most preferably AST in serum or the blood plasma and ALT are no more than the normal reference value upper limit or are no more than treatment.The dosage of DMF can skin graft edges up by using enough for a long time; In a kind of specific embodiment, this skin graft was used two hours, and 4 hours then, then 6 hours again, by that analogy; Open-assembly time is doubled continuously in the another kind of specific embodiment; Monitored patient before dosage edges up preferably is to discover the sign of poisoning.If desired, this dosage can be cumulative at interval with the week.This dosage can edge up in this way and be approximately every dose every kilogram 150 milligrams until calculating this dosage; Or until desirable plasma peaks, as reach every liter of 100-150 or 150-200 milligram; Or it is about 6 hours or about 8 hours until the time that exposes.Being increased to every dose every kilogram 240 milligrams at dosage is engaged in the care should be used to of going forward.6. embodiment: by N, the percutaneous dosing of N '-dimethyl formamide (DMF) treatment HIV infects
By patient's body being used patient with skin graft dimethyl formamide (DMF) the treatment infected by HIV of dimethyl formamide gel dipping.The patient gives the N-acetyl group-cystine-glutathion of 250 milligrams to 300 milligrams (oral or intravenous administrations) and/or phospholipid every day as hepatoprotective.As an alternative or supplement, make hepatoprotective with glutamic acid also can for the patient.
Zones of different such as forearm at patient body paste two skin grafts.Each skin graft contain about 7.06 the gram contain DMF (92.5%, m/m) and colloidal silica (7.5%, gel m/m).This gel works to prevent that liquid D MF from spilling from skin graft.Because the DMF evaporation is very fast, this skin graft should be made in 12 hours at most before use.The concentration of the DMF that will reach in patient's blood plasma is 100ppm.For the patient of 60 kilograms of body weight, need be at 12 hours to the concentration of 14 doses that restrain with generation 100ppm.According to the research of Marz and Nohova, absorbing the needed surface area of this dosage is 127.2 square centimeters.For reaching in the blood 100 milligrams concentration, per hour should absorb the DMF of about 1.272 grams.Therefore the every subsides that have 6.36 square centimeters of surface areas (every subsides) need about 7.06 gram DMF to discharge needed amount.The absorbance of DMF is per hour 9.4 milligrams every square centimeter.This treatment can discharge 125-135ppm in theory, but because the evaporation of DMF only obtains the release of 100ppm.Patient's absorbability has nothing in common with each other, and depends on the factors such as thickness of skin type and skin.For making the patient reach desired DMF concentration, monitor every patient's plasma D MF concentration, and therefore treat by every patient's DMF concentration adjustment.Fig. 1 represents the plasma D MF concentration with 4 patients of 6 hours of two DMF skin graft treatments.
Every subsides are loaded with the DMF of about 7.06 grams and the gel of silicon dioxide.Every subsides are used 12 hours, or use for 12 weeks once in a week, or secondary used for 6 weeks weekly.
Some patients' blood test points out, CD4 T cell number is increased to 1000 from 350, and in three weeks, and PCR drops to 500 (polymer link enzyme reaction) (viral loads) very soon from every milliliter 12000 in three treatments only.Fig. 3 represents that a patient is before treatment and carry out the serial quantitative PCR measured value that the HIV-1 virus after three times 12 hours the treatment is carried with two DMF skin grafts.The measurement of PCR uses Roche applicator HIV monitor to carry out.Every milliliter of blood plasma carries less than 500 virus and is considered as and can not detects.
Some is treated the patient has serious acne or shows the German measles syndrome before treatment.When making patient's DMF blood level reach 50-100ppm with the DMF treatment, German measles syndrome and serious acne disappeared in 7 days or disappear.
Before with the dimethyl formamide treatment, the patient has been carried out complicated basic clinical and psychological assessment.This assessment provides basic biochemical hematology's data of patient.Also the patient has been made detailed virusology serum test (HIV-1), to determine patient's total virus counting, these checks are carried out when treating weekly or at every turn.
During treating, per hour measure DMF concentration in a patient's the blood.Insert a duct of Arantius every morning with blood sampling, and keep open and have an intravenous drip of physiological saline, and monitor every day by the deutero-active metabolite AMCC of DMF (for example per 4 hours adopt urine sample) with 22 milliliters speed per hour.According to regulating using of follow-up DMF, and carry out whole blood every day and resemble inspection with biochemical indicator to detect the change of liver function by the variation that absorbs DMF concentration in the blood that variable causes.Also carry out comprehensively clinical and psychological assessment every day.
Carry out the virusology examination of serum every day to detect overall viral count and to be used for the improvement (CD4-T lymphocyte) of monitored patient immune state, also carry out the judgement of prognostic factor.Serology detects according to P24 antigen and quantitative PCR, or alternatively, carries out with other method.The mensuration of also carrying out CD-4 counting and β-2 macroglobulin weekly is with the improvement of monitored patient immune state and carry out the prognosis judgement.All clinical and laboratory datas are all sent into central data system so that reaction is fast made in any nocuity change, to reach maximum clinical cure the disease effect and minimum side effect.
Detection comprises:
A) serum: sodium, potassium, chlorine, carbon dioxide, urea, urate, creatinine, calcium, magnesium, phosphate, total bilirubin and conjugated bilirubin;
B) hematology: globulin, red blood cell count(RBC), blood flow specific volume, MCV, MCH, MCHC, RDW;
C) serum protein electrophoresis; Total protein, folding albumen, total globulin, alpha globulin, alpha2 Globulin, beta Globulin, gamma Globulin;
D) analysing leucocyte: differential blood count, absolute neutrophilic leukocyte, lymphocyte, single a tree, used in making timber for boats cell, have a liking for erythrocyte and basophil counting;
E) liver enzyme: Alk, Phos, γ-GT, ALT (SGPT), AST (SGOT), LDH;
F): other: cell marking, PCR, β 2 macroglobulin, P24 antigen, C activated protein, CK-MB concentration;
G) DMF concentration analysis in the blood;
H) AMCC concentration analysis in the urine
Obviously, DMF plays one of reverse transcriptase inhibitors and protease inhibitor effect at least.Experiment in vitro shows that DMF has the particulate characteristic of lytic virus, for example dissolves housing.7. by N, the percutaneous dosing of N '-dimethyl formamide (DMF) treatment HIV infects
Carried out pilot study to estimate the curative effect that percutaneous DMF treats the patient who is infected by HIV.Every patient has been done state of an illness consulting.Adopt commercially available medicine box to get ready and detect P24 antibody act confirmation seropositivity (Abbott diagnostics), with the existence of commercially available medicine box (RocheAmplicor) by PCR quantam of proof HIV-1 by Western.
DMF in commercially available DMF (Sigma-Aldrich) and the blood sample analyzes with mass spectrum/gas chromatogram coupling instrument (GC/MS), adopt Varian 9600 gas chromatograpies, the OV351 chromatographic column, detector is obtained in polyethylene glycol-PEG capillary column and Finnegan Mat ITS40 ion shop.Running parameter is as follows: the chromatography of gases temperature program(me) is: 60 ℃ of constant temperature 1 minute, heated up 20 minutes with 9.4 ℃/minute thermograde then.The mass spectrum ioning method is electronic impact; Mass range: 40-80 mass unit; The per second run-down; Peak threshold value: per second 3 times; Background quality: 69 mass units.Make interior mark with common dimethyl formamide solution.All samples is all used and is contained target organic solvent extraction in this, makes it precipitate 30 minutes in refrigerator, then be transferred to be used for bottle that GC injects before with the centrifugal acceleration of 3000G centrifugal 5 minutes.The DMF peak is 3.26 minutes with respect to interior target retention time; Calibration curve shows that correction factor is 0.98.100 milligrams up to every liter of the amounts that linear DMF occurs, detecting rolls off the production line is estimated as 0.5 milligram every liter under 3: 1 signal to noise ratio.
The skin graft that the diameter that employing was made in 12 hours is 9 centimetres.Every teflon (Teflon that high density polyethylene (HDPE) liner (0.245 gram) is arranged and be affixed on skin TM) (0.2 micron in aperture; 0.268 permeable membrane gram), and between backing and permeable membrane, contain the silica sol that 0.573 gram is soaked with 7.067 gram DMF.This skin graft is with the naked eye checked the leakage of confirmation nothing and is confirmed 8.135 its deviations of gross mass that restrain less than 10% with analytical balance.This skin graft is applied to skin of forearm and uses Elastoplast TMBinder is fixed.On the estimation 9.4 milligrams/square centimeter/hours skin transfer rate and weight in patients can be used a slice or two as predose.
Use fractionated DMF dosage, every two hours adopt blood sample and urine sample to detect the peak value of DMF plasma concentration.Clinical monitoring patient's toxic and side effects, and in the time must increasing dosage, carry out complicated biochemistry monitoring for the serum peak value that reaches 100-120.Initial assessment comprises detection every day:
A) general situation and body weight;
B) clinical examination harmony in the exterior Carlow Paderewski scoring;
A) full blood count and erythrocyte sedimentation rate;
B) serum urea, flesh chloric acid, sugar, sodium, potassium, ALT, AST, alkali phosphatase and total bilirubin;
C) CD4+ and CD8+ counting and CD4+/CD8+ ratio;
D) quantitative analysis (Roche Amplicor) and the P24 antibody analysis (Abbott) of the HIV-1 that loads with by PCR;
E) urinalysis (Dipstix).
Analyze patient's untoward reaction when making the rounds of the wards weekly, in fact all experiments are all repeated, and collect blood and urine measurement DMF and metabolite thereof.
Patient 1[ADF] relative health status is better when begin the course of treatment, main suit's pain in hand skelalgia and insomnia.The administration of weekly two DMF sheets, average open-assembly time is 8 hours.Average DMF weekly dose is 6.11 grams, and plasma D MF peak concentration average out to is 75 milligrams every liter as a result.9 week these patients' of back CD+T cell counting increases to 640 cells of every microlitre from 140 cells of every microlitre, and the viral load that PCR measures drops to 50000copies/ml from 250000.10 week back patient's body weight are increased to 96.0 kilograms from 81.9 kilograms, and patient's clinical manifestation is good, no longer main suit's extremity pain.
Patient 2[AM] main suit is weak when begin the course of treatment, and insomnia and pain in hand skelalgia have herpes ulcer in mouthful.A slice DMF sheet administration weekly, average open-assembly time is 8 hours.Average DMF weekly dose is 7.12 grams, and plasma D MF peak concentration average out to is 125 milligrams every liter as a result.9 week these patients' of back CD+T cell counting rises to 720 cells of every microlitre from 460 cells of every microlitre, and the viral load that PCR measures drops to 13000copies/ml from 29000.Weight in patients is increased to 63.0 kilograms from 54.8 kilograms.Herpes ulcer disappears in mouthful, main suit's extremity pain no longer, and patient's clinical manifestation is good.
Patient 3[SM] tangible AIDS, main suit's dyspnea arranged when begin the course of treatment.The administration of weekly two DMF sheets, average open-assembly time is 8 hours.Average DMF weekly dose is 8.97 grams, and plasma D MF peak concentration average out to is 121 milligrams every liter as a result.7 week these patients' of back CD+T cell counting rises to 138 every microlitre cell from 39 cells of every microlitre, and the viral load that PCR measures drops to 160000copies/ml from 222000.Weight in patients is increased to double centner from 72.4 kilograms.Patient's appetite is improved, and dyspnea solves, and clinical manifestation is good, and setting in motion again.
Patient 4[EM] secondary infection (comprising herpes) is arranged when begin the course of treatment, anemia is suffered from diarrhoea and rubella is arranged.Two DMF sheets administration weekly, average open-assembly time is 8 hours.Average DMF weekly dose is 7.33 grams, and plasma D MF peak concentration average out to is 90 milligrams every liter as a result.18 these patients' of week back CD+T cell countings rise to 450 every microlitre cell from 249 cells of every microlitre, and the viral load of PCR measurement drops to 4000copies/ml from 13000, and weight in patients is increased to 90.4 kilograms from 81.5 kilograms.Patient's clinical manifestation is good, no longer includes the internal medicine main suit.
Patient 5[SV] course of treatment is when beginning, main suit's off feed, poor memory, stomachache and extremely tired is consequently abandoned business.Two DMF sheets administration weekly, average open-assembly time is 6 hours.Average DMF weekly dose is 3.75 grams, and plasma D MF peak concentration average out to is 67 milligrams every liter as a result.5 these patients' of week back CD+T cell countings rise to 396 cells of every microlitre from 354 cells of every microlitre, and the viral load that PCR measures drops to 13000copies/ml from 156000, and weight in patients is increased to 58.0 kilograms from 56.0 kilograms.Patient's clinical manifestation is good, has obtained its business partner's share, and manages voluntarily.
Patient 6[VV] secondary infection (comprising herpes) is arranged when begin the course of treatment, left arm and left face numbness are withered in the motion mistake.Two DMF sheets administration weekly, average open-assembly time is 8 hours.Average DMF weekly dose is 8.25 grams, and plasma D MF peak concentration average out to is 110 milligrams every liter as a result.19 these patients' of week back CD+T cell countings rise to 450 cells of every microlitre from 260 cells of every microlitre, and the viral load that PCR measures drops to 24000copies/ml from 120000, and weight in patients is increased to 84.6 kilograms from 75.4 kilograms.Secondary infection disappears, and patient's clinical manifestation is good.
Patient 7[AJF] be in a bad way when begin the course of treatment.The initial CD+T cell counting of patient is 29 cells of every microlitre, and the viral load that initial PCR measures is 1156000copies/ml.With the treatment of a slice DMF sheet, average open-assembly time is 4 hours.Zhou Pingjun DMF dosage is 4.60 grams, and plasma D MF peak concentration average out to is 100 milligrams every liter as a result.This patient's CD+T cell counting drops to 14 cells of every microlitre after first course of treatment, and every day, drug treatment was 5 days, administration every other week then.After 9 treatments, this patient's CD+T cell counting rises to 35 cells of every microlitre, and the viral load that PCR measures drops to 9000copies/ml, and weight in patients is increased to 49.0 kilograms since 46.5 kilograms (during the treatments of DMF sheet).The patient feels good, and returns to full-time employment.
Patient 8[MS] back and penis had serious herpes lesion when began the course of treatment.Two DMF sheets administration weekly, average open-assembly time is 8 hours.Average DMF weekly dose is 6.24 grams, and plasma D MF peak concentration average out to is 130 milligrams every liter as a result.8 week these patients' of back CD+T cell counting rises to 240 cells of every microlitre from 200 cells of every microlitre, and the viral load that PCR measures drops to 250000copies/ml from 1200000.Weight in patients is increased to 52.2 kilograms from 48.1 kilograms.The herpes lesion complete obiteration.
Two patients withdraw from test, and one is spilt because of having a liking for, and another name is because of hepatitis B.
The most of patients sensation is pasted the medicine place after taking skin graft away has slight local skin to stimulate; And maculopapule appears pasting medicine place skin, this may be because the strong hydration under the sheet.The patient has slight blister in one example, disappears in 24 hours, does not cause patient's significant discomfort.Most of patients generally after treatment 3 days, of short duration mild nausea occurs, and with gradually moving back the course of treatment, a patient reports that moderate is of short duration nauseating.Four each patients show of short duration liver enzyme and raise, and do not surpass 3 times of upper limits of normal value, and return to the level before the treatment before many infra potion DMF medication.Most liver enzymes raise at least with one therewith the irrelevant factor of test (drink spills, hepatitis, and before carried out anti-HIV treatment with other medicines) relevant.
In fact all patients show clinical improvements at treatment 2-3 after week.As shown in Figure 4, according to this disjunction mark chi assessment of Boris Karloff, each patient's general situation all has improvement after with the DMF treatment, and by this standard, every patient's general situation gives following scoring: 100=is normal, NC; 90=can carry out normal activity, and seldom disease resembles or symptom; 80=is through making great efforts to make normal activity; 70=can take care of oneself, and can not carry out normal activity, maybe can not do and work hard; The 60=idol must help, and also can take care of oneself when majority needs; 50=needs significantly to take care of, and often need seek medical advice; 40=can not take care of oneself, and need provide special care to; 30=seriously can not take care of oneself, although be not critically ill, needs hospitalization; The 20=severe disease, the hospitalization and the positive supporting treatment of need acting speedily and vigorously; 10=is critically ill, and death makes much progress; 0=death.(see Kanofsky etc., 1984, Cancer 1:634-656).The improvement of the sick viral infection of nervous symptoms and herpes is obvious.Seldom require additional secondary infection antibiotic therapy.14 days general fatigues and appetite in DMF treatment are significantly improved.All weight in patients increase.From viral load and the Cytometric assessment of CD+T, clinical improvements and morbid state are closely related.Eight are tried to have among the patient five relative PCR viral loads to meet the Gompertz curve; This analyzes explanation PCR viral load after DMF treats 42 days and moves down 88.8%.Eight are tried to have among the patient seven CD+T cell countings to meet the Gompertz curve; This analyzes explanation in DMF treatment CD+T cell counting rising 73.4% after 42 days.
The invention is not restricted to the scope of listed embodiment, they are only with explaining details of the present invention.In fact, those of ordinary skills can do various modifications from above-mentioned explanation and accompanying drawing shown in of the present invention.These modifications can fall within the scope of appended claims.
The document that this paper drew is all recorded and is reference.

Claims (26)

1. drug release device that is used for the treatment of the percutaneous dosing of medicament, this device comprises:
One contains or has the storage part that is adsorbed with therapeutic combination; said composition contains N-methylol-N-methylformamide (HMMF); N-hydroxymethyl formamide (HMF); dihydroxymethyl Methanamide (DHMF); N-acetyl group-S-(N-methylamino formoxyl) cysteine (AMCC), dimethyl sulfoxine (DMSO) or pyridine-N-oxides.
2. drug release device that is used for the treatment of the percutaneous dosing of medicament, this device comprises:
A liner;
A permeable membrane that is suitable for being placed on the animal skin of being treated; With
Adsorbate between this liner and permeable membrane is adsorbed with therapeutic combination on this adsorbate, and said composition contains N; N '-dimethyl formamide (DMF), N-methylol-N-methylformamide (HMMF), N-hydroxymethyl formamide (HMF); dihydroxymethyl Methanamide (DHMF), N-acetyl group-S-(N-methylamino formoxyl) cysteine (AMCC), N-methylformamide (NMF); dimethyl sulfoxine (DMSO); Methanamide, acetamide, methylacetamide; dimethyl acetylamide; diethyl acetamide, isopropyl acetamide, diisopropyl acetamide; N-acetyl group piperidines; N-(beta-hydroxyethyl) acetamide, N, N '-two (beta-hydroxyethyl) acetamide; N-acetyl group morpholine; acrylamide, propionic acid amide., N-methyl fluoride-N-methylformamide; pyridine-N-oxides, or general formula is R 3-CO-NR 1R 2A kind of amide, wherein
R 1And R 2Be independently selected from by H methyl, halogenated methyl, saturated and undersaturated C 2-C 3Alkyl, and in the group formed of hydroxylating alkyl; Or
R 1And R 2Be selected from by (CH together 2) 4, (CH 2) 5And (CH 2) 2O (CH 2) 2In the group of being formed; With
R 3Be selected from by H methyl and saturated and undersaturated C 2-C 3In the group that alkyl is formed; This drug release device be suitable for placing with by the treatment animal contact skin.
3. according to the drug release device of claim 2, therapeutic combination wherein contains DMF.
4. according to the drug release device of claim 3, therapeutic combination wherein contains the DMF of at least 0.25 gram.
5. according to the drug release device of claim 4, therapeutic combination wherein contains the DMF of at least 5 grams.
6. according to any one drug release device in the claim 3 to 5, therapeutic combination wherein contains DMF, and the amount of this DMF is enough to treat effectively adult or child's virus or the infected by microbes or the syndrome of becoming thin.
7. according to any one drug release device in the claim 3 to 6, this device does not contain other active agents except DMF.
8. according to any one drug release device in the claim 3 to 7, this device does not contain other the active agents that can absorb through the skin whole body except DMF.
9. according to any one drug release device in the claim 3 to 8, adsorbate wherein is a colloidal silica, and permeable membrane is to have about 0.1 Teflon to the hole of about 0.5 micron diameter TMFilm.
10. the treatment method of syndrome of becoming thin, this method comprises uses a kind of therapeutic combination to the animal of need treatment, and this therapeutic combination contains N; N '-dimethyl formamide (DMF), N-methylol-N-methylformamide (HMMF), N-hydroxymethyl formamide (HMF); dihydroxymethyl Methanamide (DHMF), N-acetyl group-S-(N-methylamino formoxyl) cysteine (AMCC), N-methylformamide (NMF); dimethyl sulfoxine (DMSO); Methanamide, acetamide, methylacetamide; dimethyl acetylamide; diethyl acetamide, isopropyl acetamide, diisopropyl acetamide; N-acetyl group piperidines; N-(beta-hydroxyethyl) acetamide, N, N '-two (beta-hydroxyethyl) acetamide; N-acetyl group morpholine; acrylamide, propionic acid amide., N-methyl fluoride-N-methylformamide; pyridine-N-oxides, or general formula is R 3-CO-NR 1R 2A kind of amide, wherein
R 1And R 2Be independently selected from by H methyl, halogenated methyl, saturated and undersaturated C 2-C 3Alkyl, and in the group formed of hydroxylating alkyl; Or
R 1And R 2Be selected from by (CH together 2) 4, (CH 2) 5And (CH 2) 2O (CH 2) 2In the group of being formed; With
R 3Be selected from by H methyl and saturated and undersaturated C 2-C 3In the group that alkyl is formed.
11. according to the method for claim 10, it is R that therapeutic combination wherein contains general formula 3-CO-NR 1R 2A kind of amide, wherein
R 1And R 2Be independently selected from by H methyl, halogenated methyl, saturated and undersaturated C 2-C 3Alkyl, and in the group formed of hydroxylating alkyl; Or
R 1And R 2Be selected from by (CH together 2) 4, (CH 2) 5And (CH 2) 2O (CH 2) 2In the group of being formed; With
R 3Be selected from by H methyl and saturated and undersaturated C 2-C 3In the group that alkyl is formed.
12. according to the method for claim 10 or claim 11, it is R that therapeutic combination wherein contains general formula 3-CO-NR 1R 2A kind of amide, wherein
R 1And R 2Be independently selected from by H methyl, halogenated methyl, saturated and undersaturated C 2-C 3Alkyl, and in the group formed of hydroxylating alkyl; With
R 3Be selected from by H methyl, saturated and undersaturated C 2-C 3In the group that alkyl and hydroxylating alkyl are formed.
13. according to any one method in the claim 10 to 12, therapeutic combination wherein contains DMF, HMMF; HMF, DHMF, AMCC; NMF, DMSO, Methanamide; acetamide, methylacetamide, dimethyl acetylamide; diethyl acetamide; the isopropyl acetamide, diisopropyl acetamide, N-acetyl group piperidines; N-(beta-hydroxyethyl) acetamide; N, N '-two (beta-hydroxyethyl) acetamide, N-acetyl group morpholine; acrylamide; propionic acid amide., N-methyl fluoride-N-methylformamide, or pyridine-N-oxides.
14. according to the method for claim 13, therapeutic combination wherein contains DMF, HMMF, HMF, DHMF, AMCC, or NMF.
15. according to any one method in the claim 10 to 14, this method further comprises using and other at least a treatment HIV is infected efficacious agents.
16. according to the method for claim 15, this method further comprises uses at least a nucleoside analog reverse transcriptase inhibitors, at least a non-nucleoside counter-rotating transcripting enzyme inhibitor, or at least a protease inhibitor.
17. according to any one method in the claim 14 to 16, therapeutic combination wherein contains DMF.
18. according to any one method in the claim 13,15 or 16, therapeutic combination wherein contains DMSO.
19. according to any one method in the claim 10 to 18, therapeutic combination applied dermally wherein.
20. treat virus or infected by microbes method for one kind; this method comprises uses a kind of therapeutic combination to the animal of need treatment; this therapeutic combination contains N-methylol-N-methylformamide (HMMF); N-hydroxymethyl formamide (HMF); dihydroxymethyl Methanamide (DHMF); N-acetyl group-S-(N-methylamino formoxyl) cysteine (AMCC), dimethyl sulfoxine (DMSO) or pyridine-N-oxides.
21. according to the method for claim 20, using of therapeutic combination wherein is to be used for the treatment of at retroviral infection.
22. according to the method for claim 21, wherein be that a kind of HIV infects at retroviral infection.
23. according to any one method in the claim 20 to 22, this method further comprises using and at least aly other treatment HIV is infected efficacious agents.
24. according to any one method in the claim 20 to 23, this method further comprises uses at least a nucleoside analog reverse transcriptase inhibitors, at least a non-nucleoside counter-rotating transcripting enzyme inhibitor, or at least a protease inhibitor.
25. according to any one method in the claim 20 to 24, therapeutic combination applied dermally wherein.
26. the vaccine from Antibody Preparation, this antibody obtains from the animal body that viral infection has been carried out treatment according to the method for claim 20.
CN98806085A 1997-06-13 1998-06-09 Drug delivery device and method for treating viral and microbial infections and wasting syndromes Pending CN1260703A (en)

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