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WO2000016625A1 - Compositions medicamenteuses antivirales contenant des sels inorganiques de lithium - Google Patents

Compositions medicamenteuses antivirales contenant des sels inorganiques de lithium Download PDF

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Publication number
WO2000016625A1
WO2000016625A1 PCT/US1998/020039 US9820039W WO0016625A1 WO 2000016625 A1 WO2000016625 A1 WO 2000016625A1 US 9820039 W US9820039 W US 9820039W WO 0016625 A1 WO0016625 A1 WO 0016625A1
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lithium
azt
viral
toxicity
group
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Vincent S. Gallicchio
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University of Kentucky Research Foundation
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University of Kentucky Research Foundation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • 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
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals

Definitions

  • the present invention relates to compositions including lithium gamma-linolenate and toxic antivirals or antibiotics. Also disclosed is the use of lithium salts such as gamma- linolenate to reduce the toxicity associated with toxic antivirals or antibiotics, such as a reverse transcriptase and non-reverse transcriptase inhibitor drugs .
  • Lithium is an agent capable of influencing many aspects of blood cell production, in particular, the formation of granulocytes . Because of this property, lithium has been demonstrated to be an effective agent whenever granulocyte production is either faulty or inadequate.
  • lithium salts may possess antiviral properties against such viruses as herpes simplex virus and recently against HIV (Kinchington et al . , 1993) .
  • vi tro studies demonstrating lithium chloride, at concentrations ranging from 5 to 30 mM, inhibits herpes simplex virus replication by interfering with viral DNA synthesis (Skinner et al . , 1980) .
  • lithium was administered in order to achieve a serum lithium concentration of 0.6-1.2 mM, well within the therapeutic range observed in clinical psychiatry.
  • the monovalent cation lithium influences several functions that regulate the proliferation and differentiation of blood cells.
  • Lithium not only effectively increased the number of hematopoietic progenitor cells derived from either bone marrow or spleen following administration in vivo, but also influenced the spatial location of these progenitor cells, i.e., within the endosteal marrow of bone marrow cavity (Gallicchio et al . , 1994).
  • the opoulation of cells demonstrating the greater increase following lithium administration in MAIDS mice receiving zidovudine resided in the area of the endosteal bone marrow cavity containing the undifferentiated, i.e., pluripotential progenitor cell population, indicating lithium is capable of influencing the most undifferentiated cell population within hematopoietic tissue with the greatest proliferative potential.
  • This patent discloses a method of treatment of a condition of the body, particularly molluscum contagiosum with lithium.
  • Molluscum contagiosum is a common infectious skin disease caused by the chicken pox virus. Thus lithium acts as an anti-viral agent against this virus .
  • Lithium compounds for the treatment of this viral infection include lithium succinate, lithium chloride, lithium carbonate, lithium orotate and lithium salts of polyunsaturated fatty acids.
  • the lithium salt may be lithium gamma-linolenate or lithium dihomogamma- linolenate .
  • Lithium cyanate is used as an miticide .
  • Such auto-immune and inflammatory diseases in which excessive PGE2 synthesis have been implicated include rheumatoid and allergic arthritis; diseases induced by viruses, such as Guillain Bar syndrome, infectious mononucleosis, other viral lymphadenopathies and infections with Herpes virus; multiple sclerosis and other demyelinating diseases; hematological disorders such as hemolytic anemias and thrombocytopenias; endocrinologic disorders such as diabetes mellitus, Addison's disease, idiopathic hypoparathyroidism and chronic lymphocytic thyroiditis; collagen disorders, such as systemic lupus erythematosus ; and reproductive disorders, such as infertility and eclampsia.
  • This patent discloses the use of lithium salts of C 18 _ 22 polyunsaturated fatty acids as disinfecting compositions to combat transmission of viral diseases.
  • the fatty acids include lithium gamma-linolenate and lithium dihomogamma-linolenate .
  • the compounds are used for the treatment of Alzheimer's disease and is a biocidal agent.
  • This patent discloses the use of anti-viral agents such as AZT where a linoleyl, gamma-linolenyl or other unsaturated long chain fatty acid is born directly on a hydroxy or amino group of the sugar.
  • the patent does not disclose or suggest a lithium salt of a linolenic acid.
  • European Patent No. 615752 Al to Horrobin et al discloses a method of treating viral infections including those of the HIV group by administering unsaturated fatty acids and their lithium salts to virally infected lymphocytes.
  • Lithium salts of fatty acids include linoleic acid, gamolinolenic acid, dihomogamma-linolenic acid, arachidonic acid and adrenic acid.
  • Chemical Abstracts, Vol. 120, No. 15, abstract 182623G to Gallicchio et al . discloses the effect of lithium in murine immuno-deficiency virus infected animals. The abstract suggests that lithium may be effective in modulating murine immuno-deficiency virus infection and may play a potential role in the patho- physiological processes associated with retroviral infection.
  • Chemical Abstracts, Vol. 119, No. 3, abstract 28537E discloses the preparation of cyclodextrin polysulfates for the treatment of AIDS and lithium salts thereof.
  • Chemical Abstracts, Vol. 113, No. 11, abstract 90921E discloses methods for the synthesis of analogs of AZT. Biotechnology Business News, Vol. 4, Issue 76, March 25, 1994, pp.
  • Gallicchio, V.S., Hughes, N.K., Tse, K.F. Modulation of the hematopoietic toxicity with zidovudine in vivo with lithium carbonate." J. Intern . Med . , 233:259-268, 1993; discloses the effect of Li2C03 on AZT toxicity when treating MAIDS.
  • Gallicchio, V.S., Hughes, N.K. “Comparison of dideoxynucleoside drugs (ddl and Zidovudine) and induction of hematopoietic toxicity using normal murine bone marrow cells : effect of lithium in vi tro .
  • Li thium, 4:189-194, 1993 discloses the effect of LiCl on AZT toxicity.
  • Gallicchio, V.S., Cibull, M.L., Hughes, N.K., Tse, K.F. "Effect of lithium in murine immunodeficiency virus infected animals.”
  • composition and method of the present invention overcomes the deficiencies of prior art methods which fail to increase cell growth and reduce AZT toxicity by providing a composition comprising lithium gamma- linolenate and an anti-viral drug.
  • the present invention provides for a composition and a pharmaceutical composition comprising lithium gamma linolenate and an anti-viral or antibiotic.
  • the pharmaceutical composition includes a cell growth increasing effective amount of lithium gamma linolenate and an anti-viral or antibiotic.
  • Another object of the invention is to provide a method of treating acquired immune deficiency syndrome
  • AIDS comprising administering a cell growth increasing and AZT toxicity reducing effective amount of a composition comprising lithium gamma linolenate and zidovudine.
  • Still another object of the invention is to provide a method of decreasing the toxicity of an anti-viral or antibiotic comprising administering a toxicity reducing effective amount of a composition comprising a lithium salt with said anti-viral or antibiotic.
  • Figure 1 shows the effect of lithium on influencing peripheral blood indices from LP-BM5 MuLV- infected animals .
  • Lithium decreased the reduction in packed red cell volume (hematocrit) (Fig. la) , white blood cell count (Fig. lb) , and platelets (Fig. lc) that is associated with virus infection when compared to the virus-control group not receiving lithium.
  • Figure 2 demonstrate the effect of lithium on the WBC, the differential analysis produced absolute values for neutrophils (Fig. 2a) and lymphocytes (Fig. 2b) that indicated both were increased following lithium treatment compared to the virus control group .
  • FIG. 3 shows the effect on myeloid (CFU-GM) from bone marrow and spleen is given in Fig. 3 (bone marrow (a) spleen (b) ) .
  • Figure 4 depicts the effect of lithium on erythroid
  • BFU-E progenitors from bone marrow (a) and spleen (b) .
  • lithium-treated virus- infected mice demonstrated increased BFU-E that peaked on week 9, all other points resembled the viral control group .
  • FIG. 5 shows splenic BFU-E was increased at all time points examined from the lithium-treated virus- infected group and a similar response was observed for megakaryocyte progenitors (CFU-Meg) .
  • Bone marrow CFU- Meg(a) were increased, although not until week 17 of examination, compared to week 9 for both myeloid and erythroid progenitors, while from the spleen (b) , at all time points examined, CFU-Meg were increased significantly, in response to lithium treatment.
  • nucleoside reverse transcriptase inhibitors such as AZT, ddl , ddC, d4T
  • non-nucleoside reverse transcriptase inhibitors such as neverapine
  • the ribonuclease reductase inhibitors such as timidox and didox
  • the commercial utility of the invention achieves several objectives.
  • the composition by combining lithium gamma linolenate with anti-viral drugs the composition: 1) improves the anti-viral efficacy of such drugs while at the same time reduce their potential to develop undesirable properties and induction of viral resistance strains; 2) provides a cost-effective drug for use in those areas of the world, e.g., under-developed and/or third world areas that are now showing the greatest increases in the number of AIDS cases, since lithium gamma linolenate is relatively inexpensive to produce; and 3) by its proven psychiatric effects, also improves and/or prevents the depression that can be associated with knowing one has a potentially fatal disease.
  • the invention provides a composition and a pharmaceutical composition comprising lithium gamma linolenate and an anti-viral or antibiotic.
  • the pharmaceutical composition preferably includes a cell growth increasing effective amount of lithium gamma linolenate and an anti-viral or antibiotic.
  • the cells which experience increased cell growth may preferably be selected from bone marrow, spleen, erythroid, myeloid and megakaryocyte cells.
  • the anti-viral is preferably zidovudine.
  • the anti-viral or antibiotic may preferably be selected from zidovudine, dideoxyinosine, dideocycytidine, d4T, nervapine, protease inhibitors and others listed above.
  • the invention also encompasses a method of treating acquired immune deficiency syndrome (AIDS) comprising administering a cell growth increasing and AZT toxicity reducing effective amount of a composition comprising lithium gamma linolenate and zidovudine (and potentially others) .
  • AIDS acquired immune deficiency syndrome
  • the lithium salt may be selected from the group consisting of lithium carbonate, lithium chloride and lithium gamma linolenate. Lithium salt which is lithium gamma linolenate is preferred.
  • the anti-viral may be selected from the group consisting of zidovudine, dideoxyinosine (ddl) , dideoxycytosine (ddC) , d4T, neverapine, timidox, didox, hydroxyurea, dextran sulfate and cyclophosphamide.
  • the examples set forth below show the unexpected cell growth and AZT toxicity reduction results obtained with lithium gamma linolenate as compared to lithium carbonate and lithium chloride.
  • the examples further enable the making and use of the compositions of the invention.
  • AZT When AZT is administered with a lithium salt such as lithium gamma-linolenate or lithium carbonate, a reduction in toxicity of AZT is achieved as compared to AZT where a linoleyl, gamma-linolenyl or other unsaturated long chain fatty acid is born directly on a hydroxy or amino group of the sugar.
  • a lithium salt such as lithium gamma-linolenate or lithium carbonate
  • LiGLA lithium gamma linolenate
  • Lithium gamma linolenate (LiGLA) for this study was obtained from Enfamol, Kentville, Nova Scotia, Canada.
  • lithium gamma linolenate has been demonstrated to successfully reduce the toxicity associated with the reverse transcriptase inhibitor drug, zidovudine (AZT) following use either in vivo or in vi tro .
  • ZT zidovudine
  • Table I identifies the ability of Li-GLA to influence the toxicity of AZT and in fact, increased colony formation in the presence of AZT, which was not observed when compared to lithium chloride (Table II) .
  • Use of lithium chloride reduced AZT toxicity but was not effective in increasing cell growth and colony formation.
  • lithium gamma linolenate unexpectedly behaves differently from lithium chloride and provides an unexpected benefit of increasing healthy cell colony formation.
  • BFU-E Erythroid
  • CFU-GM myeloid
  • CFU-Meg megakaryocyte
  • lithium gamma linolenate unexpectedly and advantageously improves the immune status of such patients, since it has been demonstrated lithium significantly improves immune function status, reduces the development of lymphoma that is characteristic of immunodeficiency, and increases cell growth and survival when administered in the murine model for immunodeficiency disease (MAIDS) . Additional studies from MAIDS-infected mice administered lithium salts are provided below. Treated animals demonstrated significant hematopoiesis compared to the suppressed hematopoiesis associated with LP-BM5 MuLV infection in animals not receiving lithium.
  • MAIDS immunodeficiency disease
  • mice Female C57BL6 mice (8-10 weeks of age) were purchased from Harlan, Indianapolis, IN, USA. All animals were quarantined for a minimum of 1-week before experimental use. Animals were housed in plastic cages and fed Purina lab chow and water ad libi tum .
  • LP-BM5 MuLV isolate used in these studies was originally derived from a bone marrow stromal cell line (SC-1) harvested from animals infected with mink cell MuLV (Morse et al . , 1992) and is routinely maintained in the laboratory.
  • LP-BM5 MuLV is a retrovirus mixture containing replication-competent helper B-trophic ecotropic mink cell focus forming (MCF) virus and an etiologic 4.9-kb replication defective genome termed BM5- def, susceptibility to which depends on the presence of the FV-lb genotype permissive for B-trophic virus replication (Morse et al., 1992).
  • the viral pool permissive for B-trophic virus replication (Morse et al., 1992) consisted of a mixture of B-tropic ecotropic and B-tropic mink cell focus-inducing murine immunodeficiency virus (MuLV) .
  • the titers of ecotropic and MCF MuLV were determined by XC plaque assay in SC-1 cells or by SC-1 UV-mink assay.
  • Virus pools on average contain lO ⁇ -lO 5 - 8 XC-plaque-forming units and 10 22 -10 3 - 2 focus- forming units, respectively.
  • mice were maintained in microisolator cages and handled in accordance with the NIH Guide for the Care and Use of Laboratory Animals (NIH No.
  • mice were infected by i.p. injection of 0.25 ml of LP-BM5 MuLV virus-stock (10 ⁇ g of total protein) harvested from the SC-1 cell line following 3- day in vi tro culture. The development of MAIDS induced by virus was monitored by physical findings (Morse et al., 1992). Early stage MAIDS develops 5 weeks postinfection.
  • LP-BM5 MuLV immunodeficient mice wi th li thium
  • Lithium treatment was initiated 7 days prior to virus infection.
  • This protocol has been previously determined to provide optimum protection from LP-BM5 MuLV-induced immunodeficiency (Gallicchio and Hughes, 1993) .
  • This protocol produces an individual animal lithium dose determined to be 18 mg Li 2 C0 3 /kg/day, based upon an average daily consumption of 5.3 ml of fluid per day (Gallicchio, 1991) .
  • Lithium was initiated 7 days before virus infection and was continued for the duration of the study. Plasma lithium levels from animals bled by cardiac puncture on the days of examination were monitored by use of flame photometry (Model no. 943, IL Instruments, Lexington, MA USA) .
  • Virus-infected controls and virus-infected mice treated with lithium were serially sacrificed 1, 5, 9, 13, 17 and 21 weeks following virus inoculation for determination of lithium treatment on hematopoiesis following administration in LP-BMS5 MuLV infected animals.
  • Bone marrow and spleen cells were assayed for their progenitor cell content, i.e., erythroid (BFU-E), myeloid (CFU-GM), and megakaryocyte (CFU-Meg) using methodology as performed routinely in the laboratory (Gallicchio et al . , 1981).
  • BFU-E erythroid
  • CFU-GM myeloid
  • CFU-Meg megakaryocyte
  • lc that is associated with virus infection when compared to the virus-control group not receiving lithium.
  • the differential analysis produced absolute values for neutrophils (Fig. 2a) and lymphocytes (Fig. 2b) that indicated both were increased following lithium treatment compared to the virus control group.
  • Virus-infected mice receiving lithium maintained a plasma lithium concentration of 0.4-0.8 mM, well within the therapeutic range known for lithium activity in humans. There were no demonstrable signs of lithium toxicity, i.e., tremor, in any mice receiving lithium treatment during the course of study.
  • CFU-Meg megakaryocyte progenitors
  • HIV-induced immunodeficiency disease has been associated with several aspects of infection which results in abnormal or insufficient hematopoiesis.
  • pancytopenia can often develop and this condition can be exacerbated with the use of certain anti-viral drugs such as zidovudine.
  • certain anti-viral drugs such as zidovudine.
  • results implicated the role of the hematopoietic inductive microenvironment or stroma to be the key elements responsible for the depression of hematopoiesis associated with retroviral infection. This conclusion is based upon the observation that mice made immunodeficient as the result of LP-BM5
  • MuLV infection (MAIDS model) , fail to establish an effective stroma capable of supporting hematopoietic progenitor cell proliferation and differentiation in vitro when evaluated in the long-term bone marrow culture system (Tse et al . , 1993).
  • Progenitor cells cultured from bone marrow harvested from LP-BM5 MuLV-infected mice responded in a normal fashion compared to marrow-derived progenitor cells from non-virus-infected control animals to the growth factors that regulate their proliferation and differentiation. Therefore, the reduced capacity to maintain normal hematopoiesis as the result of virus infection was due to an effect mediated via the microenvironment rather than to a defect in the progenitor cell population.
  • the inventors next evaluated the extent of lithium' s capacity to modulate AZT toxicity by investigating the ability of lithium to influence blood cell production when administered to normal mice following an initial exposure to AZT.
  • C57BL6 were administered dose- escalation AZT (1.0 mg/ml and 2.5 mg/ml) for a period of 4 -weeks. This was followed by an additional 4 -week period during which mice received continued AZT with the addition of lithium carbonate (ImM) .
  • Animals were analyzed on a weekly basis for their peripheral blood indices. Animals receiving dose-escalation AZT demonstrated anemia, thrombocytopenia, and neutropenia which was dose-related.
  • mice C57BL6 female mice were purchased from Harlan, Indianapolis, IN, USA used at 6-12 weeks of age, and housed 5 to a cage. To minimize exogenous infection, mice were maintained in microisolator cages and handled in accordance with the NIH Guide for the Care Use of Animals (NIH No. 85-23, 1985). Cages, bedding and food were autoclaved prior to use, and all cage changes and animal handling or monitoring was performed in laminar air flow hoods. Ventilation and air flow in the animal facility is set to 12 changes/hr. Room temperatures were regulated at 72 ⁇ °F and the rooms were on automatic 12 hr light/dark cycle. Mice received Purina Autoclavable Chow and water ad libi tum until initiation of the study.
  • mice In order to evaluate the ability of lithium to influence the hematopoietic toxicity associated with AZT in mice that had already been exposed to AZT, the following protocol was established. One hundred forty- four normal mice were grouped to receive the following:
  • antivirals such as zidovudine, dideoxyinosine (ddl) , dideoxycytosine (ddC) , d4T, neverapine, timidox, didox, hydroxyurea, dextran sulfate and cyclophosphamide may be tested in a similar manner as set forth above.
  • Animals were serially sacrificed, at least three to a group, on a weekly basis, for eight consecutive weeks. Animals were bled from the tail vein (600 ⁇ l) for assessment of peripheral blood indices; i.e., packed red cell volume, white blood cell, and platelet counts. In addition, at least one femur per animal was obtained and the bone marrow cellularity was calculated using standard laboratory procedures .
  • mice receiving dose-escalation AZT i.e., 1.0 mg/ml and 2.5 mg/ml developed hematopoietic toxicity as measured by reductions in several parameters.
  • Table I shows a decrease in the hematocrit from mice receiving 1.0 mg/ml and 2.5 mg/ml. After 4-weeks of treatment, simultaneously with lithium initiation, the hematocrit levels were 82% and 62% of control, respectively, similar effects were observed for absolute neutrophils (Table III) and platelets (Table IV) . After 4 -weeks of AZT, mice receiving 1.0 mg/ml and 2.5 mg/ml, neutrophils were 72% and 21% of control, respectively.
  • the results were similar with 69% and 46% after 4 -weeks AZT treatment, 1.0 mg/ml and 2.5 mg/ml, respectively.
  • An interesting finding was a reduction in the levels of absolute eosinophils.
  • the levels were 72% and 21%, respectively, corresponding to 1.0 mg/ml and 2.5 mg/ml.
  • Lower, but less significant, levels for both lymphocytes and monocytes were also observed.
  • the control and 1 mg/ml AZT group animals consumed on average 5.3 ml of water per day. This corresponded to an AZT does of 240 mg/kg/day.
  • the 2.5 mg/ml group consumed 9% less volume, which corresponded to an AZT dose of 550 mg/ml.
  • lithium produced a neutrophilia in non-AZT treated mice (Table IV) .
  • neutrophils were 120% of control.
  • mice receiving 8-weeks AZT treatment produced neutropenia; i.e., measured 72% and 21% of control (1.0 mg/ml and 2.5 mg/ml, respectively) .
  • the level of neutrophils were 109% for 1.0 mg/ml and 90% for the 2.5 mg/ml treatment .
  • the amount of lithium consumed by animals was as follows: the lithium control (1 mM) and the 1.0 mg/ml AZT group received 18 mg lithium/kg/day, while for the 2.5 mg/ml AZT received 16 mg lithium/kg/day.
  • zidovudine has been shown to be an effective agent in prolonging life in HIV-infected patients, it has not without two undesirable effects; i.e., the development of virus resistance and bone marrow suppression.
  • the extent of marrow toxicity is often the dose-limiting factor in further therapy, and results in either dose-reduction or discontinuation of drug treatment .
  • lithium gamma linolenate also significantly improves the immune status of such patients, since the use of lithium in a murine model of AIDS (MAIDS) demonstrated a significant reduction both in the degree of lymphoma and, more importantly, increased survival.
  • MAIDS murine model of AIDS
  • the two compounds when the lithium salt and the antiviral or antimicrobial are administered in combination, in solution the two compounds form a single lithium salt compound.
  • the compounds are preformulated as a lithium salt, as a single compound.
  • the present inventors have compared two anti-viral drugs 2' , 2' -Dideoxyinosine (ddl) and 2 , 3 ' -Dideoxycytosine (ddC) in their triphosphate form as a lithium salt with the standard drug triphosphate form as a lithium salt with the standard drug fomulation not prepared as a lithium salt .
  • Triphosphate Forms of ddC and ddl Triphosphate Forms of ddc and ddi Prepared as a Lithium Salt on Bone Marrow Progenitors either Myeloid (CFU-GM) and Erythroid (BFU-E) for ID 50 Values Using Normal and Retrovirus Infected Bone Marrow Cells.
  • CFU-GM Myeloid
  • BFU-E Erythroid
  • the ID 50 concentration was increased .
  • the drug, whether ddl or ddC when formulated as a lithium salt
  • the ID 50 concentration was increased .
  • more drug, when formulated as a lithium salt was required to inhibit 50% of the target population than when the drug was analyzed not in its lithium formulation.
  • the differences were highly significant and were observed for the two types of cells analyzed, i.e., CFU-GM and BFU-E.
  • the present invention shows that the addition of lithium directly to gamma linolenate improves the anti-viral efficacy of the drug while at the same time reduces the drugs potential to induce toxicity as well as improve the solubility of the compound.
  • the present invention in a preferred embodiment, encompasses one drug, formulated as a lithium salt that would be administered not in combination, since the formulation is created as a single drug.
  • racemic mixtures of the lithium salts and the dextro and levo forms are included within the present invention.
  • the racemic mixtures and the dextro forms are preferred.
  • the compounds of the present invention are useful in pharmaceutical compositions for systemic administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile non-parenteral solutions or suspensions oral solutions or suspensions, oil in water or water in oil emulsions and the like, containing suitable quantities of an active ingredient.
  • Topical application can be in the form of ointments, creams, lotions, jellies, sprays, douches, and the like.
  • For oral administration either solid or fluid unit dosage forms can be prepared with the compounds of the invention.
  • the compounds are useful in pharmaceutical compositions (wt%) of the active ingredient with a carrier or vehicle in the composition in about 1 to 20% and preferably about 5 to 15%.
  • Either fluid or solid unit dosage forms can be readily prepared for oral administration.
  • the compounds of the invention can be mixed with conventional ingredients such as dicalciumphosphate, magnesium aluminum silicate, magnesium stearate, calcium sulfate, starch, talc, lactose, acacia, methyl cellulose and functionally similar materials as pharmaceutical excipients or carriers.
  • a sustained release formulation may optionally be used.
  • Capsules may be formulated by mixing the compound with a pharmaceutical diluent which is inert and inserting this mixture into a hard gelatin capsule having the appropriate size. If soft capsules are desired a slurry of the compound with an acceptable vegetable, light petroleum, or other inert oil can be encapsulated by machine into a gelatin capsule.
  • Suspensions, syrups and elixirs may be used for oral administration of fluid unit dosage forms.
  • a fluid preparation including oil may be used for oil soluble forms.
  • a vegetable oil such as corn oil, peanut oil or safflower oil, for example, together with flavoring agents, sweeteners and any preservatives produces an acceptable fluid preparation.
  • a surfactant may be added to water to form a syrup for fluid unit dosages.
  • Hydro- alcoholic pharmaceutical preparations may be used having an acceptable sweetener such as sugar, saccharine or a biological sweetener and a flavoring agent in the form of an elixir.
  • Pharmaceutical compositions for parenteral and suppository administration can also be obtained using techniques standard in the art .
  • compositions can be present in the reservoir alone or in combination form with pharmaceutical carriers.
  • the pharmaceutical carriers acceptable for the purpose of this invention are the art known carriers that do not adversely affect the drug, the host, or the material comprising the drug delivery device.
  • Suitable pharmaceutical carriers include sterile water; saline, dextrose; dextrose in water or saline; condensation products of castor oil and ethylene oxide combining about 30 to about 35 moles of ethylene oxide per mole of castor oil; liquid acid; lower alkanols; oils such as corn oil; peanut oil, sesame oil and the like, with emulsifiers such as mono- or di-glyceride of a fatty acid, or a phosphatide, e.g., lecithin, and the like; glycols; polyalkylene glycols; aqueous media in the presence of a suspending agent, for example, sodium carboxymethyl- cellulose; sodium alginate; poly (vinylpyrolidone) ; and the like,
  • the effective dosage for mammals may vary due to such factors as age, weight activity level or condition of the subject being treated.
  • an effective dosage of a compound according to the present invention is about 300 mg/kg/bw when administered by either oral or rectal dose from 1 to 3 times daily.
  • the required dose is when administered parenterally, preferably about 300mg/kg/bw may be administered intramuscularly or transdermally, 1 or 2 times a day for an adult human.
  • Gallicchio VS (1991) Li thium and the Blood, ed; VS Gallicchio, Lithium Therapy Monographs, Karger, Basel, pp. 1-150.
  • Boggs DR and Joyce RA (1983) The hematopoietic effects of lithium. Semin Hematol 20:123-126.
  • Gallicchio VS (1990) Lithium stimulation of granulopoiesis: mechanism of action In; Li thium and the Cell Physiology, eds ; R Bach, VS Gallicchio, Springer- Verlag, New York, 82-93. 5. Gallicchio VS (1991) Effects of lithium on the hematopoietic system. In; Li thium and the Blood, ed; VS Gallicchio, Lithium Therapy Monographs, Karger, Basel, pp. 1-17.

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Abstract

L'invention concerne une composition ainsi qu'une composition pharmaceutique comprenant un gamma linoléate de lithium et un agent antiviral ou antibiotique. L'invention concerne également un traitement du syndrome d'immunodéficience acquise (SIDA) comprenant l'administration de gamma linoléate de lithium et d'AZT. L'invention concerne en outre un procédé permettant de diminuer la toxicité d'un agent antiviral ou antibiotique, consistant à administrer à raison d'une quantité suffisante pour produire une réduction de toxicité, une composition contenant un sel de lithium et un antiviral ou un antibiotique.
PCT/US1998/020039 1998-09-23 1998-09-23 Compositions medicamenteuses antivirales contenant des sels inorganiques de lithium Ceased WO2000016625A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008019968A1 (fr) 2006-08-16 2008-02-21 F. Hoffmann-La Roche Ag Inhibiteurs de la transcriptase inverse non nucléoside
US20220105128A1 (en) * 2020-10-05 2022-04-07 United States Government As Represented By The Department Of Veterans Affairs Methods of treating viral infections affecting the respiratory tract using topically administered lithium agents

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US4724232A (en) * 1985-03-16 1988-02-09 Burroughs Wellcome Co. Treatment of human viral infections
US4978655A (en) * 1986-12-17 1990-12-18 Yale University Use of 3'-deoxythymidin-2'-ene (3'deoxy-2',3'-didehydrothymidine) in treating patients infected with retroviruses
US5026687A (en) * 1990-01-03 1991-06-25 The United States Of America As Represented By The Department Of Health And Human Services Treatment of human retroviral infections with 2',3'-dideoxyinosine alone and in combination with other antiviral compounds
US5116822A (en) * 1986-10-24 1992-05-26 Stichting Rega Vzw Therapeutic application of dideoxycytidinene
US5216142A (en) * 1989-04-17 1993-06-01 Efamol Holdings Plc Anti-virals
US5252333A (en) * 1987-04-27 1993-10-12 Scotia Holdings Plc Lithium salt-containing pharmaceutical compositions
US5262174A (en) * 1983-07-27 1993-11-16 Efamol Limited Anti-viral compositions

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Publication number Priority date Publication date Assignee Title
US5262174A (en) * 1983-07-27 1993-11-16 Efamol Limited Anti-viral compositions
US4724232A (en) * 1985-03-16 1988-02-09 Burroughs Wellcome Co. Treatment of human viral infections
US5116822A (en) * 1986-10-24 1992-05-26 Stichting Rega Vzw Therapeutic application of dideoxycytidinene
US4978655A (en) * 1986-12-17 1990-12-18 Yale University Use of 3'-deoxythymidin-2'-ene (3'deoxy-2',3'-didehydrothymidine) in treating patients infected with retroviruses
US5252333A (en) * 1987-04-27 1993-10-12 Scotia Holdings Plc Lithium salt-containing pharmaceutical compositions
US5216142A (en) * 1989-04-17 1993-06-01 Efamol Holdings Plc Anti-virals
US5026687A (en) * 1990-01-03 1991-06-25 The United States Of America As Represented By The Department Of Health And Human Services Treatment of human retroviral infections with 2',3'-dideoxyinosine alone and in combination with other antiviral compounds

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008019968A1 (fr) 2006-08-16 2008-02-21 F. Hoffmann-La Roche Ag Inhibiteurs de la transcriptase inverse non nucléoside
US20220105128A1 (en) * 2020-10-05 2022-04-07 United States Government As Represented By The Department Of Veterans Affairs Methods of treating viral infections affecting the respiratory tract using topically administered lithium agents
US11850259B2 (en) * 2020-10-05 2023-12-26 The United States Government As Represented By The Department Of Veterans Affairs Methods of treating viral infections affecting the respiratory tract using topically administered lithium agents

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