AU743942B2 - Mixtures of at least two reverse transcriptase inhibitors and hydroxycarbamide, in particular for inhibiting retroviral spread - Google Patents
Mixtures of at least two reverse transcriptase inhibitors and hydroxycarbamide, in particular for inhibiting retroviral spread Download PDFInfo
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- AU743942B2 AU743942B2 AU21046/97A AU2104697A AU743942B2 AU 743942 B2 AU743942 B2 AU 743942B2 AU 21046/97 A AU21046/97 A AU 21046/97A AU 2104697 A AU2104697 A AU 2104697A AU 743942 B2 AU743942 B2 AU 743942B2
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- Prior art keywords
- reverse transcriptase
- hydroxycarbamide
- hiv
- spread
- transcriptase inhibitors
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- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 title claims description 29
- 229960001330 hydroxycarbamide Drugs 0.000 title claims description 28
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 title claims description 18
- 239000000203 mixture Substances 0.000 title claims description 12
- 230000002401 inhibitory effect Effects 0.000 title claims description 10
- 230000001177 retroviral effect Effects 0.000 title description 4
- 238000011282 treatment Methods 0.000 claims description 18
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 claims description 10
- 241001430294 unidentified retrovirus Species 0.000 claims description 9
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
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- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 3
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- XKKCQTLDIPIRQD-JGVFFNPUSA-N 1-[(2r,5s)-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)CC1 XKKCQTLDIPIRQD-JGVFFNPUSA-N 0.000 description 1
- WVXRAFOPTSTNLL-NKWVEPMBSA-N 2',3'-dideoxyadenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1CC[C@@H](CO)O1 WVXRAFOPTSTNLL-NKWVEPMBSA-N 0.000 description 1
- OCLZPNCLRLDXJC-NTSWFWBYSA-N 2-amino-9-[(2r,5s)-5-(hydroxymethyl)oxolan-2-yl]-3h-purin-6-one Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@H]1CC[C@@H](CO)O1 OCLZPNCLRLDXJC-NTSWFWBYSA-N 0.000 description 1
- FYFSTKQXVINVRW-GKROBHDKSA-N 4-amino-1-[(2r,4s,5r)-5-(hydroxymethyl)-4-sulfanyloxolan-2-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)[C@@H](S)C1 FYFSTKQXVINVRW-GKROBHDKSA-N 0.000 description 1
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- 101100063942 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) dot-1 gene Proteins 0.000 description 1
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- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 1
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- YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 description 1
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- 230000003308 immunostimulating effect Effects 0.000 description 1
- 229960001936 indinavir Drugs 0.000 description 1
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 1
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- QAGYKUNXZHXKMR-HKWSIXNMSA-N nelfinavir Chemical compound CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-HKWSIXNMSA-N 0.000 description 1
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- RXBWRFDZXRAEJT-SZNOJMITSA-N palinavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)C=1N=C2C=CC=CC2=CC=1)C(C)C)[C@H](O)CN1[C@@H](C[C@@H](CC1)OCC=1C=CN=CC=1)C(=O)NC(C)(C)C)C1=CC=CC=C1 RXBWRFDZXRAEJT-SZNOJMITSA-N 0.000 description 1
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- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
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Classifications
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- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
-
- 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
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Virology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Engineering & Computer Science (AREA)
- AIDS & HIV (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
WO 98/42349 PCT/IB97/00275 1 Mixtures of at least two reverse transcriptase inhibitors and hydroxycarbamide, in particular for inhibiting retroviral spread FIELD OF THE INVENTION The present invention relates to a combination or an association of at least two reverse transcriptase inhibitors and hydroxycarbamide wherein the combination or association is useful in inhibiting retroviral spread.
BACKGROUND OF THE INVENTION The expression "Acquired Immuno-Deficiency Syndrome" (AIDS) was first used in 1981 to describe a state of cellular immune deficiency in homosexuals, characterized by the appearance of opportunistic infections and Kaposi's Sarcoma evolving very aggressively (CDC (Center for Disease Control), MMWR, 30 305-308.DC (1981)). In 1983 a retrovirus since called HIV (Human Immunodeficiency Virus type 1) was isolated among AIDS patients (Barr6-Sinoussi F. et al Science, 220 868-870 (1983)).
Over the past several years, researchers and clinicians have gained considerable experience in studying and caring for individuals infected with HIV throughout the often prolonged course of HIV disease and AIDS. On the basis of this experience, it has become clear that the pathogenic mechanisms underlying HIV infection and disease are not unidimensional, but rather are extremely complex (Fauci AS., Science, 239, 617 (1988)). Any attempt to design a comprehensive therapeutic strategy for HIV disease must take this fact into account. (Fauci, 1993, Science, 262:1011- 1018).
After entry of the HIV virus into cells and CONFIRMATION COPY WO 98/42349 PCT/IB97/00275 2 uncoating of the HIV particle, reverse transcription of the viral RNA genome into DNA replicas occurs.
Among several forms of unintegrated viral DNA (now containing the long repeats [LTRs], at both the 5' and the 3' ends) only the two-LTR linear forms can integrate into the host genome. Such a process appears strictly dependent upon cell activation/replication of T lymphocytes, although "resting" T cells are clearly susceptible to HIV infection. (Zack J.A. et al, Cell; 61, 213-222, (1990)). Furthermore, part of the reverse transcription process also can occur in unactivated T cells, a process that results in the accumulation of incomplete DNA molecules, which may persist for several hours and remain capable of being integrated into the host genome if the cell undergoes sufficient activation (Zack J.A. et al, Cell 61, 213-222, (1990)). Therefore, infected "resting" CD4+T lymphocytes can be considered a transient viral reservoir in infected individuals (Bokrinsky M.I. et al; Science, 254, 423-427, (1991)). These observations are of particular importance in anatomic compartments such as the peripheral blood and lymphoid organs, where the CD4+ T cell subset represents the predominant infected cell type (Schmittman S M. et al, science, 245, 305-308, (1989)); (Fox CH. et al J.
Infect. Dis., 164, 1051-1057, (1991)).
The above discussion provides a sound scientific basis for blocking the initial burst of virus replication and dissemination as well as the persistent replication throughout the course of disease by treating HIV-infected individuals with anti-retroviral agents from the earliest time that HIV infection is recognized through the entire course of infection. Unfortunately, currently available agents used alone are only partially effective in suppressing virus replication and spread, and this effect is -i~li -l .I YI_-i $Q~P2A5- t 1^ WO 98/42349 PCT/IB97/00275 3 transient (Hirsch MS, et al, New Engl. J. Med. 328 1686, (1993)).
A number of reverse transcriptase inhibitors have been found to be useful for the treatment or prophylaxis of retroviral infections and especially HIV and AIDS. Examples of such materials include: 3'azido-2',3'-dideoxythymidine or azidothymidine (AZT) 2',3'-dideoxycytosine (ddC) 2',3'-dideoxy-adenosine (ddA); 2',3'-dideoxy-guanosine (ddG) and dideoxy-inosine (ddl) 2',3'-dideoxy-thymidine (ddT); 2',3'-didehydro-3'-deoxythymidine (d4T) 2'-deoxy-3'thiocytidine (3TC). See European patent application 0206497 and published PCT application number WO 87/01284.
Non nucleoside reverse transcriptase inhibitors (in abreviation NNRTI) have been also proposed, such as nevirapine (Boeringher Ingelheim), pyridinone (Merck), piperazine or atevidine, imidazobenzodiaz6pine (Tibo), delavirdine (Upjohn), loviridine.
Hydroxycarbamide (HC) was initially synthesized over 120 years ago and has been found to demonstrate activity against a broad spectrum of tumors.
(Donehower, Seminars in Oncology, Vol. 19, No. 3, Suppl. 9 (June) 1992: pp 11-19). Additionally, hydroxycarbamide has been used as a virucide. In published PCT application number WO 93/09718, hydroxycarbamide is taught to be useful in a hydrogel polymer coating of a blood bag in order to inhibit viral and HIV infectivity.
Gao et al (PNAS, USA, Vol. 900 pp. 8925-8928, October 1993) disclose that hydroxyurea (hydroxycarbamide) treatment of peripheral blood lymphocytes (PBLs) decreases dNTP levels and the DNA synthesis rate to levels comparable to quiescent PBLs.
The article alleges a possible use of hydroxyurea I L11~ WO 98/42349 PCT/IB97/00275 4 in AIDS therapy.
However, there still remains a need for more effective treatments for the suppression of retroviruses and, in particular, the prevention and/or inhibition of HIV and viral spread. By viral spread, it is intended to include the inhibition of viral replication, and also may include the ability of inhibiting the virus to infect a further host cells.
Objectives of the present invention in the search for new antiretroviral agents include: 1) the identification of treatments with less toxicity and antiviral activity greater than a combination of two reverse-transcriptase inhibitors alone, 2) the development of drug combinations or associations which potentiate the synergistic (if any) activity of at least two reverse-transcriptase inhibitors co-administered in a same treatment.
BRIEF SUMMARY OF THE INVENTION The present invention relates to a combination or association of at least two different reverse transcriptase inhibitors and hydroxycarbamide wherein the combination or association is capable of preventing and/or inhibiting the spread of retroviruses including HIV. More specifically, the present invention relates to a method of preventing and/or inhibiting the spread of retroviruses, including HIV (HIV-1 and HIV-2), HTLV-1, HTLV-2, SIV, by exposing a cell population, including cells infected by a retrovirus such as, for example, HIV, to a combination or association of at least two reverse transcriptase inhibitors and hydroxycarbamide.
Additionally, the present invention encompasses the treatment of HIV-infected and AIDS patients with a combination or association of at least two different 7-7".
WO 98/42349 PCT/IB97/00275 reverse transcriptase inhibitors and hydroxycarbamide in order to prevent and/or inhibit the spread of HIV in these patients.
In a preferred embodiment of the present invention, each reverse transcriptase inhibitor is a dideoxynucleoside, in particular at least one of AZT, ddC, ddl, ddA, ddG, ddT, and for example ddl.
In another preferred embodiment of the invention, each reverse transcriptase inhibitor is a didehydrodeoxynucleoside, in particular d4T.
In another preferred embodiment of the invention, each reverse transcriptase inhibitor is a non nucleoside reverse transcriptase inhibitor, in particular at least one of hevirapine, pyridinone or atevidine, imidazo-benzodiazdpine, delavirdine and loviridine.
In particular and in the preferred combination or association of the present invention, it has been found that the co-administration of hydroxycarbamide 2',3'-dideoxy-inosine (ddl), and didehydrodeoxythymidine (d4T) is especially effective in preventing and/or inhibiting HIV spread. The preferred embodiment of the invention encompasses a composition including a pharmaceutical composition comprising a combination of ddl, d4T and HC. The pharmaceutical composition can optionally contain a pharmaceutically acceptable carrier and/or excipient and/or vehicle. The preferred method of the instant invention comprises preventing and/or inhibiting retroviral or HIV spread by treating a cell population, including cells infected with HIV, with a combination or association of ddl, d4T and HC.
Additionally, the preferred method comprises treating an HIV infected or AIDS patient with an association or combination of ddl, d4T and HC so as to prevent and/or inhibit HIV spread in the patient.
WO 98/42349 PCT/IB97/00275 6 DETAILED DESCRIPTION OF THE INVENTION The following example of a specific embodiment of the present invention is offered for illustrative purposes only and is not limiting with respect to the scope of the disclosure or claim coverage.
Clinical evaluation of the use of hydroxycarbamide, ddI and d4T in HIV infection We evaluated 6 months' treatment of HIV-infected patients with the combination therapy hydroxycarbamide (hydroxyurea), didanosine (ddl) and didehydrodeoxythymidine (d4T). The combination or association was evaluated in asymptomatic patients. The objective was to evaluate the tolerance and the anti-viral response.
A significant decline in viral load was observed after 6 months' treatment with this combination therapy.
27 volunteers, ddl- and d4T-naive individuals classified by CDC at entry as Al or A2 (without symptoms and CD4 cell count >200 cells/Al), seropositive for HIV-1 confirmed by ELISA and Western Blot, were treated for 6 months. ddl was given at the dose of 200 mg twice daily, hydroxycarbamide at the dose of 15 mg/kg per day in two divided doses and d4T at the dose of 40 mg twice daily. Plasma viral load was evaluated for HIV-RNA by PCR using the ultrasensitive PCR Amplicor HIV Monitor (Roche Diagnostic Systems, Branchburg, NJ, USA).
Treatment was well tolerated; no patient interrupted treatment due to side-effects. A few minor transient symptoms such as digestive disorders were noted in some patients, thrombopenia in one patient, neuropathy in one patient and an increase in mean corpuscular volume was seen in all patients. After 180 days, leucopenia was observed in three patients. No changes is haemaglobin, amylases, lipases, or transaminases were recorded.
WO 98/42349 PCT/IB97/00275 7 Average plasma HIV-RNA at baseline was 172 113 copies/mi (see Table). All patients showed a very significant drop in plasma viral load and in 23 out of 27 patients evaluated at 6 months, viraemia became undetectable. 4 out of 27 patients showed an average reduction in plasma viremia of 3.17 log (from 464 312 to 318 copies/ml). After 180 days of therapy, average CD4+ lymphocytes relative to total lymphocytes remained unchanged The subject of the present invention is also a new composition or association for the treatment of a cell population in the presence of a retrovirus.
Additionally, the invention includes a pharmaceutical composition intended, in particular, for the treatment and prevention of retroviral infections, especially those linked to HIV and AIDS wherein the composition contains hydroxycarbamide (HC) and at least two different reverse transcriptase inhibitors, in particular at least two different dideoxynucleosides and hydroxycarbamide, most preferably a combination of dideoxyinosine, didehydrodeoxy-thymidine, and hydroxycarbamide as active principle, in a pharmaceutically acceptable vehicle. The composition of the invention can also contain inert or pharmacodynamically active additives, carriers and/or excipients.
The pharmaceutical composition of the invention can take the form of a lyophilized powder of the active combination, to be dissolved immediately before use in a physiological solution for the purpose of injection. The medicament can then be administered parenterally, for example intravenously, intraperitoneally, in the cerebrospinal fluid, and the like. For injection, the active principle is dissolved in a physiological solution until the desired concentration for administration is obtained.
WO 98/42349 WO 9842349PCT/IB97/00275 8
TABLE
virological data at baseline and after 6 months of treatment all HI-nfootec IndividUals; with a combination of hydroxycarbemftne, didunosino and d4T.
FO-R RNA 19NA copies/mi plasma Patient Day 0 Day 180 1 non det non det 2 336751 non dot 3 S737 non det 4 4S680 non dot S 1620 nlon dot 6 101411 non dat 7 88S28 <2130 BSis non det 9 160606 non dot 517 non doet 1 1 1645946 625 1 2 98539 non det 1s 3 3394 non det 14 216S42 non dot is 117540 non dot 16 1560 non dot 17 76895 nlon dot is 1987 non dot 1 9 52407 nlon dot 23098 266 21 1362 non dot 22 7212 nlon dot 23 116s9a6 non det 24 822913 non dot 99682 218 26 non dot non dot 27 241862 non -dot non det: non detectable (sensitivity threshold =200 RNA copies/n!) SUBSTITUTE SHEET (RULE 26) WO 98/42349 PCT/IB97/00275 9 The pharmaceutical composition according to the invention can also take a form which is suitable for oral administration. For example, suitable forms are tablets, hard gelatin capsules, dragges, powders and granules. The formation of such oral forms is wellknown to those skilled in the art. Any of the known formulations are useful in preparing the instant oral pharmaceutical compositions.
As regards the dosage of the medicament according to the invention, it will be clear to the artisan that the doses to be administered are variable according to the treatment period, and frequency of administration, the host and the nature and severity of the disease and that the dosages can be easily determined without any undue amount of experimentation.
The compositions of the invention are administered in substantially non-toxic dosage concentrations sufficient to ensure the release of a sufficient dosage unit of the present combination or association into the patient to provide the desired inhibition of the spread of the retrovirus. The actual dosage administered will be determined by physical and physiological factors such as age, body weight, severity of condition, and/or clinical history of the patient. With these considerations in mind, the dosage of the instant combination or association for a particular subject can be readily determined by the physician. It might be noted that in extreme cases a dosage approaching the toxic level may be the acceptable treatment protocol.
For example, in the treatment of HIV-infected and AIDS patients, the composition can comprise from about 1 to 66 mg/Kg/day of ddI, from 0.1 to 2 mg/Kg/day of d4T, and from about greater than 1 mg/Kg/day to about 20 mg/Kg/day of HC.
The invention also covers the use of WO 98/42349 PCT/IB97/00275 hydroxycarbamide didehydrodeoxythymidine and dideoxyinosine in combination with other medicinal compositions intended for the treatment of retroviral infections and tumors, in particular HIV protease inhibitors, such as for example indinavir, ritonavir, saquinavir, nelfinavir, palinavir, VX-478 (Vertex), and AG1343 (Agouron), immunostimulants and immunomodulators such as for example cytokines, including IL-2, IL-12 and interferon molecules can be used in combination with the present invention.
By association of compounds is meant a coadministration of these compounds, whether they are administered in a same composition comprising said compounds, or they are separately administered, so as to be available in the blood plasma almost at a same time.
All of the references cited hereinabove are expressly incorporated herein, in toto, by reference thereto.
The invention has been described with reference to specific and preferred embodiments. It will be recognized by those skilled in the art that numerous changes and substitutions may be made without departing from the spirit and scope of the invention.
Claims (3)
1. A composition as a medicament, in particular for use in inhibiting the spread of a retrovirus, comprising at least two different reverse transcriptase inhibitors and hydroxycarbamide, wherein each reverse transcriptase inhibitor is a non nucleoside reverse transcriptase inhibitor, in particular at least one of nevirapine, pyridinone, atevidine, imidazo-benzodiazepine, delavirdine and loviridine.
2. Use in association of at least two different reverse transcriptase inhibitors and hydroxycarbamide for inhibiting the replication of a retrovirus, wherein each reverse transcriptase inhibitor is a non nucleoside reverse transcriptase inhibitor, in particular at least one of nevirapine, pyridinone, atevidine, imidazo-benzodiazepine, delavirdine and loviridine.
3. An association of at least two different reverse S' transcriptase inhibitors and hydroxycarbamide for use in the treatment or prophylaxis of a human disease in relation to the S spread or replication of a retorvirus, in particular HIV, in a cell population, wherein each reverse transcriptase inhibitor is a non nucleoside reverse transcriptase inhibitor, in particular at least one of nevirapine, pyridinone, atevidine, imidazo-benzodiazepine, delavirdine and loviridine. DATED this 1 0 th Day of December 2001 The Government of The United States Of America, as Represented by The Secretary, Department Of Health And Human Services By Their Patent Attorneys CULLEN CO
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IB1997/000275 WO1998042349A1 (en) | 1997-03-20 | 1997-03-20 | Mixtures of at least two reverse transcriptase inhibitors and hydroxycarbamide, in particular for inhibiting retroviral spread |
Publications (2)
| Publication Number | Publication Date |
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| AU2104697A AU2104697A (en) | 1998-10-20 |
| AU743942B2 true AU743942B2 (en) | 2002-02-07 |
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| Application Number | Title | Priority Date | Filing Date |
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| AU21046/97A Ceased AU743942B2 (en) | 1997-03-20 | 1997-03-20 | Mixtures of at least two reverse transcriptase inhibitors and hydroxycarbamide, in particular for inhibiting retroviral spread |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0971715A1 (en) |
| JP (1) | JP2001521548A (en) |
| AU (1) | AU743942B2 (en) |
| CA (1) | CA2284483A1 (en) |
| WO (1) | WO1998042349A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995017899A2 (en) * | 1993-12-20 | 1995-07-06 | Compagnie De Developpement Aguettant | Mixtures of dideoxy-nucleosides and hydroxycarbamide for inhibiting retroviral spread |
| WO1996022777A1 (en) * | 1995-01-25 | 1996-08-01 | Compagnie De Developpement Aguettant | Mixtures of dideoxy-nucleosides and hydroxycarbamide for inhibiting retroviral spread |
-
1997
- 1997-03-20 CA CA002284483A patent/CA2284483A1/en not_active Abandoned
- 1997-03-20 AU AU21046/97A patent/AU743942B2/en not_active Ceased
- 1997-03-20 WO PCT/IB1997/000275 patent/WO1998042349A1/en not_active Application Discontinuation
- 1997-03-20 JP JP54531698A patent/JP2001521548A/en active Pending
- 1997-03-20 EP EP97906313A patent/EP0971715A1/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995017899A2 (en) * | 1993-12-20 | 1995-07-06 | Compagnie De Developpement Aguettant | Mixtures of dideoxy-nucleosides and hydroxycarbamide for inhibiting retroviral spread |
| WO1996022777A1 (en) * | 1995-01-25 | 1996-08-01 | Compagnie De Developpement Aguettant | Mixtures of dideoxy-nucleosides and hydroxycarbamide for inhibiting retroviral spread |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2104697A (en) | 1998-10-20 |
| WO1998042349A1 (en) | 1998-10-01 |
| EP0971715A1 (en) | 2000-01-19 |
| JP2001521548A (en) | 2001-11-06 |
| CA2284483A1 (en) | 1998-10-01 |
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