WO1998056325A1 - Drug delivery devices and methods for treatment of viral and microbial infections and wasting syndromes - Google Patents

Drug delivery devices and methods for treatment of viral and microbial infections and wasting syndromes Download PDF

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Publication number
WO1998056325A1
WO1998056325A1 PCT/US1998/011956 US9811956W WO9856325A1 WO 1998056325 A1 WO1998056325 A1 WO 1998056325A1 US 9811956 W US9811956 W US 9811956W WO 9856325 A1 WO9856325 A1 WO 9856325A1
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Prior art keywords
dmf
therapeutic composition
alkyl groups
drug delivery
methyl
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PCT/US1998/011956
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English (en)
French (fr)
Inventor
Michelle Olga Patricia Giesteira Visser
Original Assignee
Cryopreservation Technologies Cc
Handelman, Joseph, H.
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Filing date
Publication date
Priority claimed from US08/874,425 external-priority patent/US5935597A/en
Priority to EA200000011A priority Critical patent/EA200000011A1/ru
Priority to IL13339698A priority patent/IL133396A0/xx
Priority to NZ501669A priority patent/NZ501669A/en
Priority to AU78315/98A priority patent/AU7831598A/en
Priority to JP50311899A priority patent/JP4531141B2/ja
Priority to GB9929189A priority patent/GB2341319B/en
Priority to EP98926488A priority patent/EP1011567A1/en
Priority to RO99-01313A priority patent/RO121252B1/ro
Priority to PL338439A priority patent/PL196256B1/pl
Priority to SI9820040A priority patent/SI20191A/sl
Priority to BR9810095-5A priority patent/BR9810095A/pt
Priority to APAP/P/1999/001708A priority patent/AP1629A/en
Priority to CA002295176A priority patent/CA2295176A1/en
Priority to SK1722-99A priority patent/SK172299A3/sk
Priority to EEP199900562A priority patent/EE9900562A/xx
Application filed by Cryopreservation Technologies Cc, Handelman, Joseph, H. filed Critical Cryopreservation Technologies Cc
Publication of WO1998056325A1 publication Critical patent/WO1998056325A1/en
Priority to IS5289A priority patent/IS5289A/is
Priority to FI992648A priority patent/FI19992648A/fi
Priority to IL133396A priority patent/IL133396A/en
Priority to NO996117A priority patent/NO996117L/no
Priority to BG103997A priority patent/BG103997A/xx
Priority to LVP-99-182A priority patent/LV12490B/en

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    • 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
    • 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
    • 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 or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [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

Definitions

  • the present invention is directed to methods of treating an animal affected by a viral or microbial infection, particularly an infection with a retrovirus, such as HIV, or by a wasting syndrome, especially a wasting syndrome associated with HIV infection or malignancy, by administering a polar compound such as N,N'- di ethylformamide (DMF) or dimethylsulfoxide (DMSO) .
  • a polar compound such as N,N'- di ethylformamide (DMF) or dimethylsulfoxide (DMSO) .
  • the invention also provides pharmaceutical preparations and drug delivery devices comprising a polar compound such as DMF or DMSO for treatment of an animal affected by a viral or other microbial infection or a wasting syndrome.
  • HIV Human immunodeficiency virus
  • AIDS acquired immunodeficiency syndrome
  • HIV HIV-1 (Barre-Sinoussi et al . , 1983, Science 220:868-
  • HIV infection leads to depletion of this cell type and eventually to immune incompetence, opportunistic infections, neurological dysfunctions, neoplastic growth, and ultimately death.
  • Retroviruses are small enveloped viruses that contain a single- stranded RNA genome, and replicate via a DNA intermediate produced by a virally-encoded reverse transcriptase, an RNA-dependent DNA polymerase (Varmus, H., 1988, Science 240:1427-1439).
  • retroviruses include, for example, oncogenic viruses such as human T-cell leukemia viruses (HTLV-1, -II, -III), and feline leukemia virus .
  • the HIV viral particle consists of a viral core, composed in part of capsid proteins designated p24 and pl8, together with the viral RNA genome and those enzymes required for early replicative events .
  • Myristylated gag protein forms an outer viral shell around the viral core, which is, in turn, surrounded by a lipid membrane envelope derived from the infected cell membrane.
  • the HIV envelope surface glycoproteins are synthesized as a single 160 kilodalton precursor protein which is cleaved by a cellular protease during viral budding into two glycoproteins, gp41 and gpl20.
  • gp41 is a transmembrane glycoprotein and gpl20 is an extracellular glycoprotein which remains non- covalently associated with gp41, possibly in a trimeric or multimeric form (Hammerskjold, M. and Rekosh, D., 1989, Biochem. Biophys . Acta 989:269-280).
  • HIV like other enveloped viruses, introduces viral genetic material into the host cell through a viral- envelope mediated fusion of viral and target membranes.
  • CD4 cell surface protein acts as the cellular receptor for the HIV-1 virus (Dalgleish et al . , 1984, Nature 312:763-767;
  • HIV-1 isolates have revealed a heterogeneity in their ability to infect different human cell types (reviewed by Miedema et al . , 1994, Immunol. Rev.
  • T-tropic HIV-1 strains are more likely to be found in HIV-1 infected individuals during the late stages of aids (Weiss et al., 1996, Science 272:1885-1886).
  • primary HIV-1 isolates i.e., viruses not extensively passaged in culture
  • M-tropic The viral determinant of T- and M- tropism maps to alterations in the third variable region of gpl20 (the
  • V3 loop (Choe et al . , 1996, Cell 85:1135-1148; Cheng-Mayer et al., 1991, J. Virol. 65:6931-6941; Hwang et al . , 1991,
  • HIV infection is pandemic and HIV-associated diseases represent a major world health problem.
  • Therapeutics currently no curative anti- retroviral drugs against AIDS exist.
  • several stages of the HIV life cycle have been considered as targets for therapeutic intervention (Mitsuya, H., et al . , 1991, FASEB J. 5_:2369- 2381) .
  • Many viral targets for intervention with HIV life cycle have been suggested, as the prevailing view is that interference with a host cell protein would have deleterious side effects.
  • virally encoded reverse transcriptase has been one focus of drug development.
  • a number of reverse-tran ⁇ criptase-targeted drugs, including 2 , 3 -dideoxynucleoside analogs such as
  • AZT, ddl, ddC, and d4T have been developed which have been shown to been active against HIV (Mitsuya, H., et al . , 1991, Science 249.1533-1544) .
  • RT reverse transcriptase
  • ATC azidothymidine
  • ddl dideoxyinosine
  • cytotoxic therapy may also lead to suppression of CD8 + T cells, which are essential to the control of HIV, via killer cell activity (Blazevic, V., et al., 1995, AIDS Res . Hum . Retroviruses 11:1335-1342) and by the release of suppressive factors, notably the chemokines Rantes, MIP-loc and MIP-l ⁇ (Cocchi, F., et al . , 1995, Science 270 : 1811-1815) .
  • CD4 the cell surface receptor for HIV.
  • Recombinant soluble CD4 has been shown to inhibit infection of CD4 T cells by some HIV-1 strains (Smith, D.H., et al., 1987, Science 238 :1704-1707) .
  • Certain primary HIV-1 isolates are relatively less sensitive to inhibition by recombinant CD4 (Daar, E., et al., 1990, Proc . Natl . Acad . Sci . USA 8A . 6574-6579) .
  • Late stage processing is dependent on the activity of a viral protease, and drugs are being developed which inhibit this protease (Erickson, J., 1990 Science 219:527-533) .
  • drugs are being developed which inhibit this protease (Erickson, J., 1990 Science 219:527-533) .
  • chemokines produced by CD8 + T cells have been implicated in suppression of HIV infection (Paul, W.E., 1994, Cell .82:177; Bolognesi, D.P., 1993, Semin . Immunol . 5:203) .
  • chemokines RANTES , MlP-l and MlP-l ⁇ which are secreted by CD8 T cells, were shown to suppress HIV-1 p24 antigen production in cells infected with HIV-1 or HIV-2 isolates in vitro (Cocchi, F, et al . , 1995, Science 270:1811-1815) .
  • chemokines may prove useful in therapies for HIV infection.
  • the clinical outcome, however, of all these and other candidate drugs is still in question.
  • HIV-1 envelope proteins gpl60, gpl20, gp41
  • gpl60, gpl20, gp41 have been shown to be the major antigens for anti-HIV antibodies present in
  • WASTING SYDROMES Wasting syndrome is a serious clinical problem characterized by a decrease in body mass of more than 10% from baseline body weight and a disproportionate loss of body mass with respect to body fat (Weinroth et al., 1995, Infectious Agents and Disease 1:76-94; Kotler and Grunfeld, 1995, AIDS Clin . Rev. . 96 . : 229-275) .
  • wasting is distinguished from starvation in which higher levels of body fat than body cell mass are depleted (Kotler et al . , 1985, Am J. Clin . Nutr. 42 . : 1255-1265 ; Cahill, 1970, N. Engl . J. Med. 282 : 668-675) .
  • N,N' -Dimethylformamide (molecular formula : C3H7ON) is a colourless, polar, hygroscopic liquid with low volatility and a boiling point of 152.5-153.5°C . It is freely miscible with water, alcohols and some hydrocarbons. DMF is generally used as a polar solvent and is readily absorbed through the skin, by inhalation, and upon oral ingestion. DMF is rapidly metabolized, mainly in the liver, and excretion occurs principally in the urine.
  • HMMF N-hydroxymethyl-N-methylformamide
  • NMF N-methylformamide
  • AMCC N-acetyl-S- (N-methylcarbamoyl) cysteine
  • DHMF dihydroxymethylformamide
  • HMF N- hydroxymethylformamide
  • Unchanged DMF is excreted in the urine as a small fraction of an administered dose of DMF.
  • DMF has low acute dermal, oral and inhalation toxicity. It is considered to be a mild to moderate skin and eye irritant and readily permeates the skin. There is no indication of skin sensitizing properties.
  • DMF farnesoid hepatocyte necrosis
  • liver biopsies The principal toxic effect of DMF and its metabolites is on the liver; DMF is well known to cause reversible hepatic damage associated with typical clinical complaints, classical biochemical changes in the blood, and the appearance of hepatocyte necrosis in liver biopsies. DMF is teratogenic, but is not thought to be a mutagen or a carcinogen.
  • Viza et al . have reported that DMF and DMSO inhibit in vitro replication of HIV and Human Herpes Virus 6 (HHV-6) in certain cultured cell lines. (See 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 erratum at 19:179).
  • HHV-6 Human Herpes Virus 6
  • DMF has been described as an in vitro differentiating agent for certain transformed cells in culture (See Koeffler, 1983, Blood 62:709-721; Calabresi et al . , 1979, Biochem. Pharmacol. 28:1933-1941).
  • DMF has been reported to reduce their tumorigenicity upon subsequent inoculation into nude mice (See Dexter, 1977, Cancer Res. 37:3136-3140; Dexter et al., 1979, Cancer Res. 39:1020-1025).
  • DMF and NMF have been reported to slow the growth of certain human cancer xenografts (See Van Dongen et al . , 1989, Int.
  • U.S. Patent No. 3,551,154 discloses the use of DMF as a penetration enhancer to promote transdermal absorption of topically applied medications.
  • U.S. Patent No. 4,855,294 discloses the use of glycerin to mitigate the skin irritation arising from the use of DMSO and DMF as penetration enhancers to promote transdermal absorption of topically applied medications.
  • the use of DMSO as a penetration enhancer to promote transdermal absorption of antiviral agents is discussed in Woodford & Barry, 1986, J.
  • the present invention is directed to methods, compositions and drug delivery devices for treating an animal affected by a viral or other microbial infection, especially an infection with a retrovirus such as HIV.
  • the invention also provides methods, compositions and drug delivery devices for treating an animal affected by a wasting syndrome, such as wasting associated with HIV infection or malignancy.
  • N , N ' dime thyl f ormamide (dimethylformamide, DMF) ; N-hydroxymethyl N-methylformamide (HMMF) ; N-hydroxymethylformamide (HMF) ; dihydroxymethylformamide (DHMF) ; N-acetyl, S- (N- methylcarbamoyl) cysteine (AMCC); N-methylformamide (NMF) dimethylsufoxide (DMSO); formamide; acetamide methylacetamide, dimethylacetamide; diethylacetamide; isopropylace t amide ; dii sopropylacetamide ; N- acetylpiperidine; N- ( -hydroxyethyl) acetamide; N,N'-di( ⁇ - hydroxyethyl) acetamide; N-acetylmorpholine, acrylamide; propionamide; N-fluoromethyl
  • Ri and R2 are together selected from the group consisting of (CH 2 ) 4 , (CH 2 ) 5 , and (CH 2 ) 2 0 (CH 2 ) 2 and
  • R is selected from the group consisting of H, methyl, and saturated and unsaturated C2-C3 alkyl groups.
  • the therapeutic composition may comprise a mixture of any two or more of the aforementioned compounds .
  • the therapeutic regimen may optionally combine a composition of the present invention with one or more additional agents effective for treating HIV infection, including but not limited to agents selected from the group consisting of nucleoside analog reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, in any desired combination.
  • additional agents effective for treating HIV infection including but not limited to agents selected from the group consisting of nucleoside analog reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, in any desired combination.
  • the invention also extends to a vaccine prepared from antibodies that are obtained from the body of an animal after treatment with a composition of the invention for a viral infection. 4. BRIEF DESCRIPTION OF THE FIGURES
  • FIGURE 1 illustrates plasma concentrations of DMF as a function of time in 4 patients treated with 2 DMF dermal patches for 8 hours .
  • FIGURE 2 illustrates plasma concentrations of DMF as a function of time in 3 patients treated with 2 DMF dermal patches for 6 hours.
  • FIGURE 3 illustrates HIV-1 viral load as measured by quantitative PCR in a patient treated with transdermal DMF. Two DMF patches were placed against the skin of the forearm for 12 hours on days 0, 8, and 13 (indicated by arrows) .
  • FIGURE 4 illustrates the general condition of HIV infected patients before and after treatment with transdermal DMF, as assessed according to the Karnofsky performance scale. See text, Section 7, for details.
  • the infection to be treated is an infection with a retrovirus such as HIV, including an asymptomatic infection, a latent infection, an infection accompanied by one or more symptoms of the AIDS-related complex, and an infection accompanied by clinical AIDS.
  • the infection to be treated is any other viral or microbial infection, including infection with rubella, a herpesvirus such as Human Herpes Virus 6, the Epstein-Barr virus or cytomegalovirus, infection with any virus having a capsid protective coating, and any opportunistic infection associated with disease of the immune system, such as an opportunistic infection in a patient infected with HIV.
  • the present invention also provides methods, compositions and drug delivery devices for treatment or prevention of any disease or disorder characterized by a loss of body mass.
  • Particular conditions that can be treated by the methods and compositions of the invention include, but are not limited to, wasting associated with viral (e.g. HIV), bacterial, or any other types of infection or sepsis, cachexia associated with malignancy, chemotherapy or radiation therapy, wasting associated with chronic cardiovascular disease, wasting caused by exposure to toxic or radioactive substances, and wasting associated with diarrhea and other gastrointestinal disorders.
  • the subject to be treated may be any animal, including but not limited to a monkey, cow, sheep, ox, pig, horse, cat, dog chicken and the like, and is preferably a mammal, more preferably a primate, and most preferably a human adult or child, for instance a human child weighing at least 3 kg .
  • the term "patient" refers to any animal in need of treatment according to the methods or compositions of the present invention.
  • a therapeutic composition comprising DMF HMMF; HMF; DHMF; AMCC; NMF; DMSO; formamide; acetamide methylacetamide; dimethylacetamide; diethylacetamide i sopropy lacetamide ; dii sopropylace tamide ; N- acetylpiperidine, N- ( ⁇ -hydroxyethyl) acetamide; N,N'-di ( ⁇ - hydroxyethyl) acetamide; N-acetylmorpholine; acrylamide; propionamide;N-fluoromethyl-N-methyl-formamide ;pyridine-N- oxide; any agent selected from the group consisting of amides of the general formula R ⁇ -CO-NR j ⁇ , in which
  • R j and R2 are independently selected from the group consisting of H, methyl, halomethyl, saturated and unsaturated C2-C3 alkyl groups, and hydroxylated alkyl groups;
  • R3 is selected from the group consisting of H, methyl, and saturated and unsaturated C2-C3 alkyl groups; or any agent selected from the group consisting of amides of the general formula in which
  • Ri and R2 are independently selected from the group consisting of H, methyl, halomethyl, saturated and unsaturated C2-C3 alkyl groups, and hydroxylated alkyl groups; or
  • R j and R2 are together selected from the group consisting of V and
  • R is selected from the group consisting of H, methyl, and saturated and unsaturated C2 -C3 alkyl groups.
  • at least one of R j and R2 is a methyl group.
  • at least one of Ri and R2 is a fluorinated C j - C3 alkyl group.
  • the therapeutic composition may comprise a mixture of any two or more of the aforementioned compounds . Especially preferred is a composition comprising DMF.
  • the therapeutic regimen may optionally include, in addition to a composition of the present invention, one or more other agents effective for treating HIV infection, for instance one or more nucleoside analog reverse transcriptase inhibitors such as zidovudine (AZT, ZDV) , zalcitabine (ddC) , didanosine (ddl) , lamivudine (3TC) , stavudine (d4T) ; one or more non-nucleoside reverse transcriptase inhibitors such as nevirapine, delavirdine, loviride, atevirdine, pyridinone; one or more protease inhibitors such as saquinavir, indinavir, ritonavir, nelfinavir; or any combination of the aforesaid or other anti-HIV therapeutic agents.
  • the composition of the present invention and the additional anti-HIV therapeutic agent or agents may be administered simultaneously, sequentially, or in cycles of
  • compositions of the present invention may be administered by any desired enteral or parenteral route, including but not limited to transdermal, intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, intranasal, epidural, intralymphatic and oral routes.
  • the compounds may be administered by any convenient method, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral, gastric, intestinal or rectal mucosa, etc.) and may be administered together with other biologically active agents . Administration can be systemic or local.
  • intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir.
  • Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and the formulation may include an aerosolizing agent. If desired, any two or more routes of administration may be employed simultaneously, sequentially, or in cycles of treatment according to any therapeutic protocol.
  • compositions of the invention may be administered locally to the area in need of treatment; this may be achieved, for example and not by way of limitation, by topical application, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibres.
  • a composition of the invention can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990); treat et al . , in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez -Beres tein and Fidler (eds.), Liss, New York, pp. 353- 365 (1989); Lopez-Berestein, ibid . , pp. 317-327; see generally ibid . )
  • a composition of the invention can be delivered in a controlled release system.
  • a pump may be used (see Langer, supra ; Sefton, CRC Cri t . Ref .
  • polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres . , Boca Raton, Florida (1974) ; Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.) Wiley, New York (1984); Ranger and Peppas, J. Macromol . Sci . Rev. Macromol . Chem .
  • a controlled release system can be placed in proximity of the therapeutic target, thus requiring only a fraction of the systemic dose ⁇ see, e . g . , Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115- 138 (1984) ) .
  • Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990) ) .
  • the present invention also provides pharmaceutical preparations.
  • Such preparations comprise a therapeutically effective amount of a composition of the invention and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state or other government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the composition of the present invention is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • Water is a preferred carrier when the pharmaceutical preparation is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like.
  • the pharmaceutical preparation if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • preparations can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • the preparation can be formulated as a suppository, with traditional binders and carriers such as triglycerides .
  • Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Reminton' s Pharmaceutical Sciences" by E.W. Martin.
  • Such preparations will contain a therapeutically effective amount of the therapeutic, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient.
  • the formulation should suit the mode of administration.
  • compositions of the present invention may be administered transdermally .
  • a composition of the invention is directly applied to the skin.
  • a composition of the invention is applied to a reservoir (e.g. a cotton wool pad, a synthetic polymer such as Teflon , or any suitable adsorbant) that is applied to the skin, preferably under an occlusive dressing.
  • a composition of the present invention is applied to the skin by means of a dermal patch.
  • the concentration of the active therapeutic agent in the composition that is applied to the skin, contained in or adsorbed onto the reservoir, or contained in the dermal patch may be about 10-100%, preferably at least 50%, more preferably at least 90%.
  • a polar compound such as DMF is administered transdermally using any suitable drug delivery device, for example by applying one or more dermal patches.
  • the dermal patch may optionally comprise a backing, a reservoir such as an adsorbant impregnated with a polar compound of the invention, and a permeable membrane that is placed in contact with the skin.
  • the backing may be of any material, such as a natural or synthetic polymer, that resists chemical attack by the polar compound. Especially preferred is a backing of high density polyethylene.
  • the adsorbant may be a colloidal substance, for instance diatomaceou ⁇ earth or colloidal silicon dioxide.
  • the permeable membrane may be of any material that chemically resists the polar compound and may optionally be provided with pores.
  • the permeable membrane is a Teflon AM membrane having pores with a diameter of about 0.1 ⁇ m, a diameter of about 0.5 ⁇ m, or a diameter within the range of from about 0.1 ⁇ m to about 0.5 ⁇ m.
  • the patch may be self-adhesive or may be held in contact with the skin by an applicator, such as a wrapping or bandage, including without limitation an elastic bandage or an adhesive bandage; an Elastoplast ⁇ bandage is suitable for this purpose.
  • the patch contains a greater quantity of polar compound than is intended to be delivered through the skin of the patient to be treated; for instance, the patch may contain about 50% more of the polar compound than is intended to be delivered.
  • the patch may be of any desired size and shape, and may for instance take the form of a disk approximately 9cm in diameter.
  • the patch comprises a polar compound, such as DMF, and at least one other pharmacologically active agent, for instance an local anti- irritant such as glycerine.
  • the patch comprises a polar compound, such as DMF, and has no other pharmacologically active agent present.
  • the patch comprises a polar compound, such as DMF, and has present no other pharmacologically active agent that is capable of being systemically absorbed through the skin, or has present no other pharmacologically active agent in an mount that is systemically effective after transdermal absorption.
  • the patch comprises a polar compound, such as DMF, and has present no other systemically active pharmacological agent.
  • the patch comprises a polar compound, such as DMF, and has present no other antiviral agent, for instance acyclovir or arildone.
  • the present invention thus provides a dermal patch comprising a polar compound, such as DMF, in an amount that is effective for treating a viral or microbial infection (for example an infection with HIV) in a human adult or a human child.
  • the present invention further provides a dermal patch comprising a polar compound, such as DMF, in an mount that is effective for treating a wasting syndrome in a human adult or a human child.
  • the patch contains at least 0.25g of a polar compound such as DMF, preferably at least 0.5g, more preferably at least lg, and still more preferably at least 5g, for instance 5-15g of a polar compound such as DMF .
  • a polar compound such as DMF
  • the patch may optionally be stored in a sealed container, such as a sealed polymer bag. If desired, each patch may be individually sealed for convenience of use.
  • the patches may be refrigerated prior to use, for instance at about 4°C, so as to reduce evaporative loss of the polar compound.
  • the patches are prepared within 24 hours of use and are stored in a sealed container at 4°C; however, patches are stable for one or more weeks when stored in a sealed container at 4°C.
  • an area of skin Prior to applying a patch, an area of skin is preferably washed with a mild soap and water, rinsed to remove soap residue, thoroughly dried, and then hydrated with a suitable skin lubricant and moistening agent, such as KY M jelly.
  • the patch is then removed from the packing material and applied so that the permeable membrane contacts the prepared skin surface.
  • the patch may be held in place with an applicator . After a desired dosage period, the patch is removed. After removal of the patch, the treated area may be thoroughly washed with a mild soap and water to remove any residue of the polar compound.
  • compositions of the present invention may be administered at any desired interval, for instance once every two or three weeks; once, twice or three times per week; every second day; or daily.
  • a composition of the invention is administered in a dose that results in a peak plasma level of about 2-200 mg/1, more preferably about 100-200 mg/1, still more preferably about 150 mg/1 of the active ingredient of the composition, such as DMF.
  • a peak plasma level of 100-150 mg/1 or 150-200 mg/1 of DMF.
  • ppm refers to parts per million by weight, and is in practice equivalent to mg/1.
  • the rate of absorption is determined by the skin of the subject.
  • liquid DMF Upon exposure to the human skin, liquid DMF is absorbed at a steady- state rate of approximately 9.4 mg/c ⁇ r/hour (see Mraz and Nohova, 1992, Occup. Env. Health C4: 85-92) . Accordingly, the desired rate of absorption may be achieved by controlling the surface area of the skin exposed to the drug, as by determining the area of each patch and the number of patches applied to the skin. For example, two patches of diameter 9 cm will expose a total
  • a patient weighing about 72 kg is initially treated with DMF by administering two 9 cm diameter dermal patches for one hour, resulting in an initial adsorbed dose of about 1.2 g of DMF, equivalent to about 16.7 mg/kg.
  • the number of patches may be scaled up or down, and a longer or shorter initial period of exposure used, according to the body weight of the patient being treated. This starting dose may be repeated at any desired interval, as described above, and preferably is given at weekly intervals.
  • the patient is monitored for at least 72 hours after administration of DMF for signs of toxicity, such as liver toxicity, for example by monitoring the serum or plasma levels of enzymes such as aspartate aminotransferase (AST) , alanine aminotransferase (ALT) , ⁇ - glutamyl transferase ( ⁇ GT) and alkaline phosphatase, proteins such as albumin, or substances such as conjugated or unconjugated bilirubin.
  • enzymes such as aspartate aminotransferase (AST) , alanine aminotransferase (ALT) , ⁇ - glutamyl transferase ( ⁇ GT) and alkaline phosphatase, proteins such as albumin, or substances such as conjugated or unconjugated bilirubin.
  • serum or plasma levels of AST and ALT do not exceed five times the upper limit of normal as determined by the reference range of the laboratory and population in question; more preferably serum or plasma levels of AST and ALT do not exceed three times the upper limit of normal, most preferably AST and ALT are not elevated above normal levels or above pre- treatment levels .
  • the dose of DMF may be escalated by applying the patches for successively longer periods; in one embodiment the patches are applied for two hours, then four hours, then six hours, and so on; in another embodiment, the period of exposure is successively doubled.
  • the patient is monitored prior to any dose escalation, in order to detect any signs of toxicity. If desired, the dose may be escalated at weekly intervals.
  • the dose may be escalated in this manner until the dose is calculated to be about 150 mg/kg/dose; or until a desired peak plasma level, for instance 100-150 or 150-200 mg/1 is achieved; or until the period of exposure is about 6 hours or about 8 hours.
  • a desired peak plasma level for instance 100-150 or 150-200 mg/1 is achieved; or until the period of exposure is about 6 hours or about 8 hours.
  • DMF dimethylformamide
  • N-acetyl-cysteine-glutathione and/or essential phospholipids were administered (orally or intravenously) to the patients at a dosage of 250 mg to 300 mg daily as a liver booster.
  • glutamine may also be administered to the patient as a liver booster.
  • Each skin patch contained about 7,06g of gel comprising DMF (92,5 % m/m) and colloidal silicone dioxide (7,5 % m/m) .
  • the gel served to prevent leakage of liquid DMF from the patches .
  • the patches were manufactured at most 12 hours prior to use as DMF evaporates rapidly.
  • the intended level of DMF in the patient's blood was 100 ppm. For a patient weighing about 60 kg, an amount of about 14g over a period of 12 hours is required to produce a level of lOOppm. Based on studies by Marz and Nohova the surface area required to absorb this amount m about 127,2 cm 9.
  • each sticker requires about 7,064 g DMF to deliver the required amount, having a surface area of 6,36 evr (each sticker) .
  • DMF absorption rate is 9,4 mg/cm 2 /hour.
  • the stickers were thus each loaded with about 7,064 g of the gel of DMF and silicone dioxide.
  • Each patch was applied for a period of 12 hours, either once per week over a period of 12 weeks, or twice per week over a period of 6 weeks .
  • FIG. 3 shows serial quantitative PCR measurements of HIV-1 viral load in a patient prior to treatment and following three treatments with 2 dermal DMF patches for 12 hours .
  • the PCR test conducted was the Roche amplicor HIV monitor. A viral load of ⁇ 500/ml plasma is considered to be undetectable .
  • HIV-1 virological serology
  • the concentration of DMF in the patient's blood was determined hourly during the period of treatment.
  • An intravenous line was introduced each morning to take blood samples and was kept open with an infusion of Normal Saline at a rate of 20ml/hour and daily monitoring of the active metabolite AMCC (eg by 4-hourly urine sampling) derived from the DMF was also conducted.
  • Subsequent applications of DMF were adjusted in accordance with measured changes in blood level DMF concentration resulting from changes in absorption variables and daily full haematological and biochemical profiles were conducted to detect any changes in liver function. Daily full clinical and psychological evaluations were also conducted.
  • a daily virological serology workout to establish total body virus count and to monitor improvements in the immune status of the patient (CD4- T-helper cells) and prognostic factors were also conducted.
  • the serology workout was based on p24 antigen and quantitative PCR or, optionally, by other methods.
  • a weekly determination of CD4 counts and Beta-2-macroglobulin was also conducted specifically to monitor improvements in the patient's immune status and prognosis. All clinical and laboratory data were fed into a centralized data system to facilitate rapid response to any detrimental change so as to curtail treatment to maximize clinical effect and minimize potential side effects.
  • Bilirubin b) Hematology: Hemoglobin, Red cell count, Hematocrit, MCV, MCH, MCHC, RDW; c) Serum Protein Electrophoresis : Total Proteins, Albumin, Total Globulin, Alphal Globulin, Alpha2
  • AST SGOT
  • DMF acts as at least one of a reverse transcriptase inhibitor and a protease inhibitor. In vitro tests were conducted and it appears that the solvent properties of DMF dissolve the virus particles, e.g. the capsid.
  • HIV-1 HIV-1 was documented by quantitative PCR using a commercial kit (Roche Amplicor) .
  • DMF as obtained commercially (Sigma-Aldrich) and in plasma samples was analysed by mass spectroscopy/ gas chromatography (GC/MS) , using a Varian 9600 gas chromatograph, OV 351 column, carbowax-PEG capillary column, and Finnegan Mat ITS40 ion trap detector.
  • Operational parameters were as follows: GC temperature program: 60°C for 1 min. followed by a temperature gradient of 9.4°C/min. for 20 min.
  • MS ionization method electron impact; mass range: 40-80 mass units; 1 scan/sec; peak threshold: 3 counts/sec; background mass: 69 mass units.
  • a stock solution of dimethylacetamide was used as an internal standard. All samples were extracted with an organic solvent containing the internal standard, allowed to precipitate for 30 min. in a refrigerator, and centrifuged at 3000g for 5 min. before transfer to GC vials for injection. Retention time of the DMF peak relative to the internal standard was 3.26 minutes; the calibration curve showed a correlation of 0.98. Quantitation of DMF appeared linear up to 100 mg/1 and the lower limit of detection was estimate at 0.5 mg/1 based on a signal-to- background ratio of 3:1. Dermal patches 9 cm in diameter were used within 12 hours of manufacture.
  • Each patch had a backing of high density polyethylene (0.245 g) , a permeable membrane of Teflon ⁇ (pore size 0.2 ⁇ m; 0.268 g) for placement against the skin, and containing 0.573 g of colloidal silicon dioxide impregnated with 7.067 g DMF between the backing and the permeable membrane.
  • the patches were visually inspected to verify the absence of leakage and were weighed on an analytical balance to verify less than 10% deviation from a total mass of 8.153 g.
  • the patches were applied to the skin of the forearm and secured with Elastoplast bandages . Either one or two patches were used for the initial dose, as determined from the predicted skin transfer rate of 9.4 mg/crrr/hr and the patient's body weight .
  • a staged dose of DMF was used, with two-hourly blood and urine sampling to determine peak plasma DMF levels. Patients were clinically monitored for any toxic side- effects and were kept under comprehensive biochemical surveillance while the dosage was increased as necessary to achieve a peak plasma DMF level of 100-120 ppm. Once the correct dosage was established, transdermal DMF was given once a week.
  • Initial evaluation included daily determination of : a) vital signs and body weight; b) clinical checklist and Karnof ⁇ ky score,- a) full blood count and erythrocyte sedimentation rate; b) serum urea, creatinine, glucose, sodium, potassium, ALT, AST, alkyline phosphatase and total bilirubin; c) Coulter analysis of CD4+ and CD8+ counts and CD4/CD8 ratio; d) Quantitative estimates of HIV-1 load by PCR (Roche Amplicor) and analysis of antibody to p24 (Abbott); e) Urinalysis (Dipstix) .
  • Patient 1 [ADF] began the protocol in relatively good health, complaining principally of pains in the arms and legs and inability to sleep. Two DMF patches were administered once a week, for an average exposure period of 8 hours. The average weekly dose of DMF was 6.11 g and the resulting peak plasma DMF level average 75 mg/1. After 9 weeks, the patient's CD4+ T cell count had increased from 140 to 640 cells/ ⁇ l and the PCR-measured viral load had decreased from 250,000 to 50,000 copies/ml. After 10 weeks the patient's weight had increased from 81.9 to 96.0 kg, the patient was clinically well and no longer complained of pain in the limbs.
  • Patient 2 began the protocol complaining of loss of strength, inability to sleep, pains in the arms and legs, and had herpes sores in the mouth.
  • One DMF patch was administered per week, for an average exposure period of 8 hours.
  • the average weekly dose of DMF was 7.12 g and the resulting peak plasma DMF level averaged 125 m/A
  • the patient's CD4+ T cell count has increased from 460 to 720 cells/ ⁇ £
  • the PCR-measured viral load had decreased from 29,000 to 13,000 copies/ml!
  • the patient's weight had increased from 58.4 to 63.0 kg.
  • the patient's herpetic sores had resolved, the limb pains had disappeared and the patient appeared clinically well.
  • Patient 3 [SM] began the protocol with overt clinical
  • Patient 4 [EM] began the protocol with secondary infections (including herpes), anemia, diarrhea and acne. Two DMF patches were administered once weekly, for an average exposure period of 8 hours . The average weekly dose of DMF was 7.33 g and the resulting peak plasma DMF level averaged 90 mg/ . After 18 weeks, the patient's CD4+ T cell count had increased from 249 to 450 cells/ ⁇ i , the PCR-measured viral load had decreased from 13,000 to 4,000 copies/ml?, and the patient's weight had increased from 81.5 to 90.4 kg. The patient appeared clinically well and had no active medical complaints.
  • CD4+ T cell count had increased from 354 to 396 cells/ ⁇ -l?
  • the PCR-measured viral load had decreased from 156,000 to 13,000 copies/ml 1
  • the patient's weight had increased from 56.0 to 58.0 kg. The patient was clinically well, had acquired his business partner's share, and was running the business himself.
  • Patent 6 [W] began the protocol complaining of secondary infections (including herpes) , ataxia, and numbness of the left arm and left side of the face.
  • Two DMF patches were administered weekly, for an average exposure period of 8 hours .
  • the average weekly dose of DMF was 8.25 g and the resulting peak plasma DMF level averaged 110 mg/ i .
  • the patient's CD4+ cell count had increased from 260 to 450 cells/ ⁇ £
  • the PCR-measured viral load had decreased from 120,000 to 24,000 copies/m ⁇
  • the patient's weight had increased from 75.4 to 84.6 kg.
  • the secondary infections had resolved and the patient appeared clinically well.
  • Patient 7 began the protocol severely ill.
  • the patient's initial CD4+ T cell count was 29 cell/ ⁇
  • the initial PCR-measured viral load was 1,156,000 copies/mA
  • Treatment was with 1 patch, for an average exposure period of 4 hours.
  • the average weekly dose of DMF was 4.60 g and the resulting peak plasma DMF level averaged 100 mg/A
  • the patient's CD4+ T cell count decreased to 14 cells/ ⁇ i..
  • Treatment was given daily for five days and then continued at weekly intervals.
  • the patient's CD4+ T cell count had increased to 35 cells/ ⁇ £
  • the PCR-measured viral load had decreased to 9,000 copies/mi?
  • the patient's weight had increased from 46.5 kg (at commencement of DMF therapy) to 49.0 kg.
  • Patient 8 [MS] began the protocol with severe herpetic lesions in the lower back and genitalia. Two DMF patches were given once weekly, for an average exposure period of 8 hours. The average weekly dose of DMF was 6.24 g and the resulting peak plasma DMF level averaged 130 mg/ £ . After 8 weeks, the patient's CD4+ T cell count had increased from 200 to 240 cells/ ⁇ , the PCR-measured viral load had decreased from 1,200,000 to 250,000 copies/m . The patient's weight had increased from 48.1 to 52.2 kg, and the Herpes lesions had entirely resolved.
  • liver enzymes which never exceeded three times the upper limit of normal and which in most cases returned to pre-treatment levels prior to the next dose of DMF. Most instances of elevated liver enzymes were associated with at least one factor unrelated to the treatment protocol (alcohol consumption, hepatitis, and previous anti-HIV therapy with other agents) .

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PCT/US1998/011956 1997-06-13 1998-06-09 Drug delivery devices and methods for treatment of viral and microbial infections and wasting syndromes WO1998056325A1 (en)

Priority Applications (21)

Application Number Priority Date Filing Date Title
IL13339698A IL133396A0 (en) 1997-06-13 1998-06-09 Drug delivery device and methods for treatment of viral and microbial infections and wasting syndromes
APAP/P/1999/001708A AP1629A (en) 1997-06-13 1998-06-09 Drug delivery devices and methods for treatment of viral and microbial infections and wasting syndromes.
BR9810095-5A BR9810095A (pt) 1997-06-13 1998-06-09 Dispositivos para distribuição de droga e métodospara tratamento de infecções virais e microbianase de sìndromes de emaciação
AU78315/98A AU7831598A (en) 1997-06-13 1998-06-09 Drug delivery devices and methods for treatment of viral and microbial infections and wasting syndromes
JP50311899A JP4531141B2 (ja) 1997-06-13 1998-06-09 ウイルス性および微生物性感染ならびに消耗性症候群の治療に用いる薬剤供給装置および方法
GB9929189A GB2341319B (en) 1997-06-13 1998-06-09 Use of compounds in the preparation of a medicament for the therapeutic treatment of a wasting syndrome
EP98926488A EP1011567A1 (en) 1997-06-13 1998-06-09 Drug delivery devices and methods for treatment of viral and microbial infections and wasting syndromes
RO99-01313A RO121252B1 (ro) 1997-06-13 1998-06-09 Dispozitive pentru administrarea de medicamente şi utilizarea acestora pentru tratamentul infecţiilor virale şi microbiene şi a sindroamelor de scădere ponderală
PL338439A PL196256B1 (pl) 1997-06-13 1998-06-09 Układ do dostarczania leków i zastosowanie przezskórnej kompozycji terapeutycznej
CA002295176A CA2295176A1 (en) 1997-06-13 1998-06-09 Drug delivery devices and methods for treatment of viral and microbial infections and wasting syndromes
NZ501669A NZ501669A (en) 1997-06-13 1998-06-09 Dimethylformamide and other polar compounds for the treatment of wasting syndrome and HIV infections
EA200000011A EA200000011A1 (ru) 1997-06-13 1998-06-09 Средства и способы доставки лекарственных препаратов для терапии вирусных и бактериальных инфекций и синдромов истощения
SI9820040A SI20191A (sl) 1997-06-13 1998-06-09 Priprave za administracijo zdravil ter metode za zdravljenje virusnih in mikrobnih infekcij in sindroma hiranja
SK1722-99A SK172299A3 (en) 1997-06-13 1998-06-09 DRUG DELIVERY DEVICES AND METHODS FOR TREATMENT OF VIRAL ANDì (54) MICROBIAL INFECTIONS AND WASTING SYNDROMES
EEP199900562A EE9900562A (et) 1997-06-13 1998-06-09 Ravimimanustusvahendid ja meetodid viirus- ning mikroobsete infektsioonide ja kurnatusesündroomi raviks
IS5289A IS5289A (is) 1997-06-13 1999-12-08 Lyfjagjafarbúnaðir og aðferð til meðhöndlunar á veiru- og örverusýkingum og tæringarheilkennum
FI992648A FI19992648A (fi) 1997-06-13 1999-12-09 Lääkkeen luovutuslaitteita ja menetelmiä virus- ja mikrobi-infektioiden ja riutumissyndrooman hoitoon
IL133396A IL133396A (en) 1997-06-13 1999-12-09 A device for carrying a drug containing a pharmaceutical composition and the use of the said pharmaceutical composition for the preparation of a drug for the treatment of viral and bacterial infections and fatigue syndrome
NO996117A NO996117L (no) 1997-06-13 1999-12-10 Anordning for tilfoering av medikamenter samt behandling av virale og mikrobielle infeksjoner og taeringssyndrom
BG103997A BG103997A (en) 1997-06-13 1999-12-13 Drug delivery device and methods for the treatment of viral and microbial infections and wasting syndromes
LVP-99-182A LV12490B (en) 1997-06-13 2000-02-02 PHARMACEUTICAL FORM AND CONTENTS FOR VIRUS, MICROWAVE INFECTION AND SENSITIVE TREATMENT

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EA200000011A1 (ru) 2000-08-28
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