IES20020719A2 - Therapy with agents for the enhancement of the antigenicity of endogenous infectious organisms. - Google Patents

Abstract

There is provided the use of 2-Deoxy-D-glucose compounds, including Glucosamine, as well as derivatives, metabolites and precursors of such compounds, and pharmaceutically acceptable salts of any of these compounds, collectively defined herein as the "compounds of the present invention", in the treatment of infected patients, in order to enhance, by a combination of administration of the compounds of the within inventions combined with appropriate non-cabrohydrate diet, the immune response to the infection. An infected patient may be, or have been, infected or exposed to or with an infectious organism, including virus, bacteria, micro-organism or prion. The present invention is further directed to the use of such compounds in the treatment of the immune system of patients infected with, or exposed to, or suffering from the diseases associated with infection with any of the following infectious agents, one or more kind of parasites or viruses and/or one or more diseases caused by such parasites, against one or more kind of Mycoplasma and/or one or more diseases caused by such Mycoplasmas and/or against one or more of the following indications or infections: (a) hairy Leukoplakia, (b) oral candidosis, (c) mouth ulcerations-aphthous/herpetic/bacterial, (d) fungalcandida, (e) human papilloma virus, (f) molluscum contagiosum, (g) squamous oral carcinoma, (h) Kaposi's sarcomaoral lesions,(i) periodontitis, (j) necrotizing gingivitis, (k) orafacial herpes zoster, and (1) rotaviruses, retroviruses and all types of viruses and other infectious agents and foreign agents, as well as all other indications and infections.

Description

“Therapy with agents for the enhancement of the antigenicity of endogenous infectious organisms.” This patent presents a novel method for the prophylaxis and therapy of infectious organisms. The present invention is directed to the use of an anti-metabolite and related compounds, as well as derivatives, and precursors of such compounds, and pharmaceutically acceptable salts of any of these compounds, collectively defined herein as the “compounds of the present invention”, optionally together with one or more additional administration and/or treatment (as described below) in the treatment of infectious diseases. The compounds of the present invention are agents for the enhancement of the antigenicity of endogenous infectious organisms. Such diseases may including viral and or bacterial or malaria or African Trypanosomiasis or American Trypanosomiasis or microbial organisms, this list is not complete but is included for demonstration purposes. The present invention is further directed to the use of such compounds (and combinations) in the treatment of one or more kind of parasites or viruses or prion and/or one or more diseases caused by such organisms. One such antimetabolite is a non-metabolizable analogue of glucose e.g. 2-deoxy-glucose and/or 2 amino-2deoxy-glucose.

By subjecting the patient to a carbohydrate free diet and the substitution of carbohydrate intake by non-metabolizable analogues of glucose the immune system of the infected patient is exposed to distorted infectious organisms, and as a consequence an immune response is generated. These non-metabolizable analogues will be incorporated into the glycoproteins and oligosaccharides of the reproducing disease organism. This incorporation produces for the patient’s immune system defective infective organisms with distorted outer coat structures and these distorted structures elicit both a neutralising antibody cascade, and a cell mediated immune response, which works to remove the infection-causing organism while also enhancing cell mediated immunity.

The compounds of the present invention are agents for the enhancement of the antigenicity of endogenous infectious organisms. The compounds of the present invention also reduce the respiration rate and as a consequence reduce the infectious organisms reproductive rate and create a greater percentage of perturbed or outer coat distorted infectious organisms which will again enhance immune system production of neutralising antibodies to clear infection and provide long term immune protection from future exposure to the organism after the compounds of the present invention are removed from the system.

By means of this substantial substitution in the diet of compounds of the present invention it is possible to distort and rebalance the dynamic equilibrium in favour of the immune system and teach the bodies own immune system to recognise the disease causing agent which may IE 0 2 07 1 9 have previously undermined the normal vigilant immune system and present the immune system with a more distorted and vulnerable infectious target which is less efficient at replication and infection.

Embodiments of the compounds of the present invention are the non-metabolizable glucose analogues 2-deoxy glucose and also 2-Amino-2-deoxy-glucose. A number of three and five day courses of these non-metabolizabie glucose analogues have demonstrated the ability to elicit a large neutralising antibody response which clears infection. Because this therapy targets an essential energy molecule such as glucose it is not subject to mutation escape by the infectious organism and therapy can be repeated numerous times as required to facilitate control and avoidance of disease progression. j OPEN TO PUBLIC INSPFl'Tim Background of the Invention j OPEN TO PUBLIC INSPECTION ; UNDER SECTION 28 ANL RULE 23 j JNLNoJ&aSViruses and bacteria are important etiological agents Ί5Τ While specific antibody of classes IgG, IgM and IgA can bind with reasonably high avidity to particular epitopes on a particular protein in the outer coat of bacterial or viral envelopes only a certain number of these anti-bodies are capable of neutralising the infectivity of the virus, bacteria or infecting agent.

It may be necessary to prepare the immune system to enhance its ability to produce a competent immune response in advance of therapy with compounds of the present invention.. This may be achieved by treatment with IL-2 or other cytokines on conventional prescription therapies known to enhance both humoral immunity and cell mediated immunity.

Another embodiment of this invention would be to administer an adjuvant to the patient immediately following their course of therapy with compounds of the present invention. The patient may be administered an adjuvant while on or after a strict carbohydrate free diet in which all carbohydrate is replaced by non metabolisable carbohydrate. Such diets may include the administration of such compounds as a glycosylation inhibitor, tunicamycin, strephlovrudins and/or glycosidase inhibitors such as carbohydrate analogues, e.g. 2-deoxy-D-glucose, 2Amino-2deoxy-D Glucose or any non-metabolizable analogues of glucose or fructose or any of the family of such carbohydrate molecules.

A typical carbohydrate free diet will consist of consuming only protein and fat, no intake of processed foods or fruits juices, which may contain sugars and starches are allowed for they will severely limit the effectiveness of the therapy as outlined in this invention.

It is envisaged that anyone skilled in the art may be able from following this therapy method to substitute molecules which would interfere with amino acid or lipid metabolism to achieve a similar distortion or corruption of viral or infectious organism lipid layer, or peptides that would make these infectious organisms more exposed to immune clearance.

Passive transfer of antibodies from carbohydrate anti-metabolite treated patients, or patients treated with compounds of this invention, to other patients incapable of generating their own antibodies or immune response is also envisaged in the present invention, eg. Baby, bone marrow or organ transplant recipients.

In one embodiment of this invention, we have administrated a compound of the invention to a HIV patient. - see in-vivo example below. This therapy regime cleared infected cells and viruses from the patient’s circulation and the consequential lowering of viral load created an opportunity for the immune system to regenerate. The patient experienced a return of normal markers of T4 (CD4) cells which in HIV infection are depleted both by direct viral infection and from the effect of viral peptides which create T4 cell apoptosis and death.

Protocol for the administration of a compound of this invention to a HIV or Hep. C infected patient. 2-deoxyglucose and 2amino-2 deoxy -D-Glucose (LDG) PROTOCOL FOR CLINICAL PHASE l/ll TRIAL IN HIV PATIENTS TITLE A Phase l/ll, Open-label, single centre study following oral administration of 2amino-2 deoxy -D-Glucose as 8 capsules of 500mg under a strict carbohydrate free diet in volunteers with HIV infection. INDICATION Treatment of HIV-1 infection OBJECTIVES Dosing schedule To determine the efficacy, safety and tolerance of 8 orally administered LDG capsules of 500mg every four hours for a period of 72 hrs combined with a diet restriction excluding all carbohydrates during the 72hrs period of therapy (2amino2deoxy -D-Glucose 24g/day) with extended monitoring for a further 4 weeks in volunteers with HIV disease. To determine 2amino-2 deoxy -D-Glucose’s ability to reduce viral load levels and improve immune function when IE 0 2 0 7 1 9 administered under a strict carbohydrate free diet at 24g daily for a total period of 72 hrs.

TRIAL DESIGN Open label study, Medication will be administered every 4 hours in equally divided doses and dispensing will take place for a maximum period of 72 hrs. During the period of therapy the volunteers will be maintained on a strict diet excluding all forms of carbohydrates, starches and hydrocarbons. They will be maintained on a high protein diet such as chicken and cheese. A blood sample will be drawn at the beginning of therapy at the 72hrs period of treatment and every five days thereafter for a period of 4 weeks. LENGTH OF STUDY Screening period: None Treatment period: Open-label, daily administration of 2amino-2 deoxy -D-Glucose under strict carbohydrate free diet conditions, at dosing schedules of 24g per volunteer, with review of assessment of the dosage schedules and efficacy after therapy for 3 Days and extended monitoring for a further 28 days. INVESTIGATIONAL DRUG DOSE/ROUTE/REGIMEN Dosing schedule: 2amino-2deoxv-D-Glucose administered orally as 8 capsules of 500mg every 4 hours under a diet restriction excluding carbohydrates for a period of 72 hours, and extended monitoring for a further 4 weeks ASSESSMENTS OF: • EFFICACY Primary: • Reduction in HIV or Hep C viral load as measured by HIV-RNA -PCR Amplicor assay.

Secondary: • Improvements in immune response will be measured by increase in CD4 absolute count and percentage change in CD4/CD8 ratio. Clinical benefit will be assessed by changes in total body weight, Karnofsky performance score, and amelioration of signs and symptoms of disease present at baseline including the remission or occurrence of opportunistic infections.

• The dose response effect on the above parameters will be evaluated and the dose and dose scheduling for the volunteers treatment cycles will then be determined.

• Improvements in immune response will be measured as changes from baseline CD4/CD8 ratio, clinical lymphocyte counts, percent WBC.

• The remission or incidence of new opportunistic infections will be summarised at all times.

• SAFETY PROCEDURES (summary) Vital signs, laboratory tests, clinical adverse events (AEs) Complete pre-treatment medical history; general physical and laboratory exams, prior to therapy then weekly after end of therapy; symptom-directed physical and vital signs during 4 weeks of follow-up after therapy. Ε 0 2 0 7 1 9 STATISTICAL ANALYSES The primary objectives of the study are to assess the efficacy at viral load clearance of 2amino-2 deoxy -DGlucose administered orally under a strict carbohydrate free diet as capsules on HIV-1 viral load reduction. Percentage change in HIV-1 viral load over each cycle of therapy. The number of patients who show a decline in HIV-1 viral load greater than 90% will then be calculated. All efficacy and safety analyses data will be compiled by the Biostatistician and Principle physician in weekly interim reports and in a final report following the completion of the trial.

STUDY FLOW CHART Day B A S E Ll N E s T A R T 1 2 48 hr 3 72 hrs 7 14 21 28 Days 0 1 2 3 4 5 6 7 Medical History, X X X X X X X X Full Physical Exam X X X X X X X X Weight X X X X X X X X Biochemistry : Creatinine X X X X X X K X X X X X X UREA X X X X X X ALP X X X X X X GGT X X X X X X GOT X X X X X X GPT X X X X X X Na+ X X X X X X BIL X X X X X X Haematology :FBC WBC X X X X X X RBC X X X X X X HGB X X X X X X HOT X X X X X X PLT X X X X X X MCV X X X X X X MCH X X X X X X MCHC X X X X X X Immunology CD4 X X X X X X CD8 X X X X X X CD4/CD8 X X X X X X IgA X X X X X X igG X X X X X X ig e X X X X X X IE Ο 2 07 1 9 IgM X X X X X X Virotoav PCR (RNA) HIV Viral Loads X X X X X X RFS1HTS T4 Cell Numbers HIV-PCR & T4 Cell Variations with administration of PRENDERGAST Diet IE 02 07 1 9 The present invention relates to the field of medicine generally, in particular to the treatment of infectious diseases.

The present invention is directed to the use of an anti-metabolite and related compounds, as well as derivatives, and precursors of such compounds, and pharmaceutically acceptable salts of any of these compounds, collectively defined herein as the “compounds of the present invention”, optionally together with one or more additional administration and/or treatment (as described below) in the treatment of infectious diseases, caused by viruses, virons, parasites, microbes and other organisms, including HIV, Hepatitis, Herpes, all viruses, malaria, African Trypanosomiasis and American Trypanosomiasis. The present invention is further directed to the use of such compounds (and combinations) in the treatment of one or more kind of viruses and or parasites and/or one or more diseases caused by such parasites or viruses.

The present invention is directed towards providing an improved method in the prophylaxis and therapy of infectious diseases or a complication or consequence thereof. In particular the invention relates to the use of anti-metabolites in the prophylaxis and therapy of viral infections. Most particularly the anti-metabolites are 2-Deoxy-D-ribose and/or 6-Deoxy-D-ribose.

In accordance with one aspect of the present invention, it now has been discovered that surprisingly, malaria may be treated with anti-metabolites (or pharmaceutically acceptable salts thereof, analogues and precursors thereof).

According to the invention there is provided a pharmaceutical formulation for use in the prophylaxis and therapy of HIV or a complication or consequence thereof comprising a prophylactically or therapeutically effective amount of carbohydrate anti-metabolite as an active ingredient in association with a specific dietary regiem.

According to the invention there is provided a pharmaceutical formulation for use in the prophylaxis and therapy of hepatitis C or a complication or consequence thereof comprising a prophylactically or therapeutically effective amount of a carbohydrate anti-metabolite as an active ingredient.

In accordance with one aspect of the present invention, the anti-metabolites are sugar anti-metabolites. In another embodiment the anti-metabolite is a 6 carbon compound.

In another embodiment the carbohydrate anti-metabolites are selected from the group consisting essentially of: IE 0 2 0 7 1 9 2-Deoxy-D-Glucose; 6-Deoxy-D-Glucose; 2-Deoxy-D-Fructose; 6-Deoxy-D-Fructose; 2-Deoxy-DSucrose; 6-Deoxy-D-Sucrose; D-glucose; 2-Deoxy-D-galactose; 6-Deoxy-D-galactose; 2-DeoxyD-lyxohexose; 6-Deoxy-D-lyxohexose; D-Fructose; D-Levulose; D-Fructose-1,6-diphosphate; DSucrose; D-Saccharose; D-Succrose octaacetate; 2-Deoxy-D-glucose; 2-Deoxy-D-galactose; 2Deoxy-D-ribose; 6-Deoxy-D-ribos; 2Amino-2Deoxy-D-glucose, Glucosamine, Tunicamycin, Fluoroglucose, Benzhydrazone, Deoxyglucose, 2-deoxy-D-arabinohexose,2-deoxy-2-fluoro-Dglucose. or from any salt or L forms of these molecules and also other sugar molecules not glucose, of these listed compounds, but members ofthe carbohydrate family from which glucose belongs. The halogens which form part of any molecule refers to in the above list can be selectively exchanged with other members ofthe halogen group and the D and L forms of each molecule referred to can be exchanged to provide useful compounds ofthe invention..

Additionally compounds of the invention include inhibitors of glycosylation of proteins on the immune presenting surfaces of any infectious agent.

Additionally, the invention provides a pharmaceutical formulation for use in the prophylaxis and therapy of infectious diseases or a complication or consequence thereof comprising a prophylactically or therapeutically effective amount of at least an anti-metabolite and/or a glycosylation inhibitor as an active ingredient.

Additionally non-metabolizable analogues of the following carbohydrates are compounds of the present invention: D-Glyceraldehyde; D- Glyceraldehyde,3-deoxy-3,3-C-bis-(hydroxymethyl)(Cordycepose);D-Glyceraldehyde, 3,3-bis(C-hydroxy-methyl)-(Apiose); beta-D-Arabinose; DArabinose, 2-O-methyl- ;Alpha-L-Arabinose; Beta-L- Arabinose; DL- Arabinose; alpha-L-Lyxose; LLyxose,5-deoxy-3-C-formyl-(Streptose); L- Lyxose, 3-C-formyl-(Hydroxy-Streptose); Pentose, 4,5anhydro-5-deoxy-D-erythro-; Pentose, 2-deoxy-D-erythro-; D-Ribose; D-Ribose,2-c-hydroxymethyl(Hamamelose); alpha-D-Xylose; D-Xylose, 5-deoxy; beta-D-Xylose,2-O-methyl-; alpha-D-Xylose, 3O-methyl- ; D-Allose, 6-deoxy-; D-Allose,6-deoxy-2, 3-di-O-methyl-(Mycinose); Amicetose; Antiarose; alpha-D-Galactose; beta-D-Galactose; D-Galactose,3,6-anhydro-; alpha-D-Galactose, 6deoxy-(D-Fuctose:Rhodeose) ; D-Galactose, 6-deoxy-3-O-methyl- ; D-Galactose,6-deoxy-4-0methyl-; D-Galactose, 6-deoxy-2, 3-di-O-methyl-;Alpha-D-Galactose, 3-O-methyl-;Alpha-D-Galactose, 6-0methyl-;L-Galactose;Alpha-L-, 3,6,-anhydro-;Alpha-L-Galactose6-deoxy- (l-Fucose);L-Galactose, 6deoxy-2-O-methyl-;L-Galactose,6-sulfate;DL-Galactose;Alpha-D-Glucose;Beta-D-Glucose;DGlucose,6-acetate;D-Glucose, 2,3-di-O-methyl-;D-Glucose 6-O-benzoyl-;Alpha-D-Glucose, 6deoxy; IE 0 2 07 1 9 Alpha-D-Glucose, 6-deoxy-3-O-methly-;D-Glucose, 6-sulfonic acid, 6-deoxy-;D-Glucose ,3-0methyl-Alpha-L-Glucose;L-Glucose, 6-deoxy-3-O-methyl-;D-Glucose, 6-deoxy-;Hexose,2-deoxy-Darabino; Hexose, 2, 6-dideoxy-3-O-methyl-D-arabino-; Hexose, 3,6-dideoxy-D-arabino- ;Hexose, 2,6dideoxy-3-O-methyl-L-arabino-;Hexose, 3,6-dideoxy-L-arabino-;Hexose, 2,6-dideoxy-3-O-methyl-Dlyxo-; Hexose, 2,6-dideoxy-L-lyxo-;Hexose, 2,6-dideoxy-3-O-methyl-L-lyxo-;Hexose, 2,6-dideoxy-D-ribo;Hexose, 2,6-dideoxy-3-O-methyl-D-ribo-;Hexose,3,6-dideoxy-D-ribo-;Hexose, 4,6-dideoxy-3-Omethyl-D-ribo;Hexose,2,6-dideoxy-D-xylo-; 2,6-dideoxy-3-O-methyl-D-xy/o; 3,6-dideoxy-D-xy/o-; 2,6dideoxy-3-C-methyl-L-xy/o-; 2,6-dideoxy-3-C-methyl-3-O-methyl-L-xy/o-; 3,6-dideoxy-L-xy/o-; DIdose; L-ldose, 1,6-anhydro-; a-D-Mannose; β-D-Mannose; D-Mannose, 6-deoxy-; a-L-Mannose, 6deoxy-monohydrate; β-L-Mannose, 6-deoxy-; L-Mannose, 6-deoxy-2-O-methyl-; L-Mannose, 6deoxy-3-O-methyl-; L-Mannose, 6-deoxy-2,4-di-O-methyl-; L-Mannose, 6-deoxy-5-C-methyl-4-Omethyl-; Rhodinose (a 2,3,6-trideoxyhexose); D-Talose; D-Talose, 6-deoxy-; L-Talose, 6-deoxy-; LTalose, 6-deoxy-2-O-methyl-; Heptose, D-glycero-D-galacto-; Heptose, D-glycero-D-manno-; Heptose, D-g/ycero-L-manno-; Dihydroxyacetone; Tetrulose, t-glycero-; Pentulose, D-etythro-; Pentulose, L-erythro-; Pentulose, D-threo-; Pentulose, 5-deoxy-D-ibreo-; Pentulose, L-threo-;; Hexulose, fi-D-arabino-; Hexulose, 6-deoxy-D-arab/no-; Hexulose, D-/yxo-; 5-Hexulose, D-/yxo; Hexulose, 6-deoxy-D-/yxo-; Hexulose, D-ribo-; Hexulose, L-xy/o-; Hexulose, 6-deoxy-L-xy/o-; Heptulose, D-altro-; Heptulose-hemihydrate, L-galacto-; Heptulose, L-gulo-; Heptulose, d-/'c/o-; Heptulose, D-manno-; Heptulose, D-ia/o-; Octulose, D-glycero-L-galacto-; Octulose, D-glycero-D— manno-·, D-Ribose, 3-amino-3-deoxy-; D-Galactose, 2-amino-2-deoxy-; α-L-Galactose, 2-amino-2,6dideoxy-; α-D-Glucose, 2-amino-2-deoxy-; β-D-Glucose, 2-amino-2-deoxy-; D-Glucose, 3-amino-3deoxy-; D-Glucose, 3-amino-3-deoxy-; D-Glucose, 6-amino-6-deoxy-; D-Glucose, 2,6-diamino-2,6dideoxy-; D-Glucose,3,6-dideoxy-3-dimethyl-amino-; D-Glucose, 4,6-dideoxy-4-dimethyl-amino-; LGlucose, 2-deoxy-2-methylamlno-; D-Gulose, 2-amino-1,6-anhydro-2-deoxy-; D-Gulose, 2-amino-2deoxy-; Hexose, 3,4,6-trideoxy-3-dimethyl-amino-D-xy/o-; Hexose, a 4-acetamido-2-amino-2,4,6trideoxy-; Hexose, an amino-deoxy-3-O-carboxy- ethyl-; Hexose, a 2,6-diamino-2,6-dideoxy-; Hexose, a 3-dimethylamino-2,3,6-Trideoxy-; D-Mannose, 2-amino-2-deoxy-; D-Mannose, 3-amino3,6-dideoxy-; D-Talose, 2-amino-2-deoxy-; L-Talose, 2-amino-2,6-dideoxy-; Pentulose, 1-ocarboxyanilino)-1-deoxy-D-erytf?ro-; Hexulose, 1-(o-carboxyanilino)-1- deoxy-D-arab/no-; Hexulose, 5-amino-5-deoxy-L-xy/o-; Hexulose, 6-deoxy-6-(/V-methyl-acetamido)-L-xy/o-; Glycerol; Glycerol, 1deoxy-; Erythritol; Erythritol, 1,4-dideoxy-; D-Threitol, 1,4dideoxy-; L-Threitol, 1,4-dideoxy-; dlThreitol, 1,4-dideoxy-; D-Arabinitol; L-Arabinitol; Ribitol; Galactitol; D-Glucitol; D-Glucitol, 1,5anhydro-; L-lditol; D-Mannitol; D-Mannitol, 1,5-anhydro-; Heptitol, D-glycero-D-galacto-; Heptitol, dglycero-D-gluco--. Heptitol, D-glycero-D-manno-·, Octitol, D-erythro-D-galacto-; Betitol; Bioinosose; hBornesitol; /-Bornesitol; Conduritol; Cordycepic acid; Dambonitol; DL-lnositol; d-lnositol; /-Inositol; Laminitol; Liriodendritol; muco-lnositol monomethyl ether; myo-lnositol; of-myo-lnosose-1; Mytilitol; IE 0207 ,9 neo-lnosamine-2; d-Ononitol; b-Pinitol; /-Pinitol; /-Quebrachitol; d-Quercitol; c/-Quinic acid;/-Quinic acid; Quinic acid, 5-dehydro-; Seyllitol; Sequoyitol: Shikimic acid; Shikimic acid, 5-dehydro-; Streptamine; Streptamine, 2-deoxy-; Streptadine; Viburnitol; D-Glyceric acid; L-Glyceric acid; DArabinonic acid; L-Arabinonic acid; L-Arabinonic-1,4-lactone; D-Ribonic acid; D-Xylonic acid; lXyionic acid; D-Altronic acid; D-Galactonic acid; D-Gluconic acid; L-Gulonic acid; Hexsonic acid, 2deoxy-D-arab/no-; 2-Hexulosonic acid, Darabino-, 2-Hexulosonic acid, 3-deoxy-D-eryibro-; 2Hexulosonic acid, D-lyxo-: 5-Hexulosonic acid, D-arabino-: 5-Hexulosonic acid, D-xylo-: D-Mannonic acid; D-Gluconic acid,0-p-D-galactopyranosyl-; L-Lyxuronic acid; β-D-Galacturonic acid; a-DGalacturonic acid monohydrate; D-Galacturonic acid, 2-amino-2-deoxy-; β-D-Glueuronic acid; DGlueuronic acid, 2-amino-2-deoxy-; D-Glueuronic acid, 3-O-methyl-; L-Guluronic acid; L-lduronic acid; β-D-Mannuronic acid; α-D-Mannuronic acid monohydrate; D-Tartaric acid; L-Tartaric acid; lMalic acid.

In addition, as discussed above, the present invention is directed to the treatment of sleeping sickness and the treatment of Chagas disease by administering one or more of the compounds of the present invention. Also, the present invention relates to the use of the compounds of the present invention in the treatment of one or more kind of parasites and/or one or more diseases caused by such parasites. The compounds of the within invention are administrated in order to activate a therapeutic vaccination of the patients own immune response with transformed infectious organism, by creating such immune activation to the altered infections organism is the infection treated and prevented. The disturbing of the outer coat of the infectious organism or virus is greatly attenuated by combining the administration of the compounds of the invention with a non-carbohydrate diet. The greater the disruption of the outer coat, or parts of the infectious organism and/or agents which interact with the immune system the greater will be the immune response against the infected organism.

Further, the invention provides use of anti-metabolites in the manufacture of a medicament for use in the prophylaxis or therapy of infectious diseases or a complication or consequence thereof. Where reference is made to administration of anti-metabolites, within this patent, it is implied at all times that such administration is in conjunction with or combination with an appropriate non-carbohydrate diet. Such diet is administrated to the infected patient in order to accentuate the bio-availability of the anti-metabolite to the infected organism. This dietary aspect of the therapy disclosed in the present patent is essential.

Additionally, the invention provides use of anti-metabolites to provide protection against viral infections. These compositions may be used prophylactically or therapeutically to protect animals or patients, by improvements to immune responses, from the consequences of infection by pathogenic organisms.

IEO 2 0 7 1 9 Further, the invention provides use of anti-metabolites in veterinary medicine in animal populations that are subject to malarial infection and tsetsy fly infestation.

The invention also provides a method for treating an infection or a complication or consequence thereof in a human or a non-human patient, comprising administering a therapeutically effective amount of carbohydrate anti-metabolite to the patient in combination with an appropriate non-carbohydrate diet.

The invention further provides a method for the prophylaxis of a malarial infection or a complication or consequence thereof in a human or non-human patient, comprising administering a prophylactically effective amount of a pharmaceutical formulation comprising carbohydrate anti-metabolite to the patient.

According to a further aspect of the invention there is provided a method for the prophylaxis and therapy of malaria, comprising administering a prophylactically or therapeutically effective amount of carbohydrate anti-metabolite to the patient.

According to a further aspect of the invention there is provided a method for the prophylaxis and therapy of an infectious organism, comprising administering a prophylactically or therapeutically effective amount of an carbohydrate anti-metabolite to the patient in combination with a non-carbohydrate diet.

According to a further aspect of the invention there is provided a pharmaceutical formulation for the prophylaxis and therapy of an infectious organism comprising administering an effective amount of an anti-metabolite to the patient in combination with a non-carbohydrate diet.

According to a further aspect of the invention there is provided a method for the prophylaxis and therapy of an infectious organism comprising administering a prophylactically or therapeutically effective amount of a carbohydrate anti-metabolite to the patient in combination with a noncarbohydrate diet.

According to a further aspect of the invention there is provided a pharmaceutical formulation for the prophylaxis and therapy of infectious agents , comprising administering an effective amount of a carbohydrate anti-metabolite to the patient in combination with a noncarbohydrate diet.

IE 0 2 0 7 1 9 Accordingly, the present invention provides a method for treating parasitic infections which comprises administering to an afflicted host a therapeutically effective amount of an antimetabolite (or a pharmaceutically acceptable salt thereof), as well as derivatives, and precursors thereof, as defined herein in combination or other organised time frame with a non-carbohydrate diet.

The present invention provides a new pharmaceutical formulation for treating malaria, sleeping sickness, Chagas disease, or one of the other conditions described above by administering glucose anti-metabolite (or a pharmaceutically acceptable salt thereof), as well as derivatives, and precursors thereof, as defined herein in association with a strict dietary regime.

In accordance with another preferred aspect of the present invention, there is provided a pharmaceutical formulation for treatment of one or more of the conditions described above, including viral infections, comprising administering a combination therapy including one or more of the compounds of the present invention administered simultaneously or sequentially with a anti metabolite glucose, a compound known to inhibit malaria, plant extracts known to inhibit malaria, antidiabetic compounds or one or more macrophage stimulating factor (and optionally further co-administering an oxidation), or anti-viral compounds or immune boosting compounds. Macrophage stimulating factors are well known to those of skill in the art, examples including GM-CSF (see, e.g., Callard et al., The Cytokine Facts Book, Academic Press, 1994, p. 139) and lnterleukin-4 (sold by Immunex as “Leukine” and by Schering Plough as “Prokine”.

In another preferred aspect of the present invention, to enhance destruction of parasite infected erythrocytes, the compounds of the present invention can be co-administered with one or more oxidation agent (optionally further together with a macrophage stimulating factor), or the patient may be given oxygen ventilation to increase oxidative stress in the plasma.

In another preferred aspect of the present invention to the compounds of the invention are administered under specific dietary instructions enhance destruction of infectious agents, unidentifiable or identified, which are utilised or distributed as a weapon, or accidentally released into the environment. The compounds of the present invention can be administrated in order to assist and teach the immune system to challenge these infectious organisms, the compounds of the present invention administrated in combination with an appropriate non-carbohydrate diet can enhanced the antigenicity of these unidentified endogenous infectious organisms.

In one embodiment the compounds previously shown to inhibit HIV or malaria can be selected to be administered simultaneously with the compounds and dietary methods disclosed in this Patent, IE 0 2 07 1 9 In one embodiment of the invention lipo-polysaccharide is administrated at the concluding stage of the treatment and diet in order to enhance the immune surveillance of the patients immune system. It will be obvious to those skilled in the art than any and all combinations of suitable adjuvants can be so administrated.

In another embodiment the plant extracts co-administered with the anti-metabolite are selected from the families comprising: Acanthaceae; Agavasceae; Asteraceae; Bignoniaceae; Chenopodiaceae; Clusiaceae; Cucurbitaceae; Euphorbiaceae; Fabaceae; Iridaceae; Lamiaceae; Moraceae; Musaceae; Myriacaceae; Myrsinaceae; Myrtaceae; Onagraceae; Pedaliaceae; Poaceae; Polygonaceae; Polygalaceae; Primulaceae; Ranunculaceae; Rosaceae; Rubiaceae; Solanaceae; Tiliaceae; Verbenaceae; and Vitaceae.

In another embodiment the plant extracts co-administered with the anti-metabolite are selected from the group comprising: Aspila pluriseta Schweinf; Blumea alata (D.Don) DC; Cajanus cajan (L.) Millsp; Cissus petiolata Hook f.; Clematis hirsute Perr. Et Guill. Var. hirsute; Conyza sumairensis (Retz) E.K. Walker; Crassocephalum vitellinum (Benth.) S. Moore; Dalbergia lacteal Vatke; Gardenia temifolia Schum et Thonn. Subsp. jovis-tonatis (Welw.) Verde.; Gynura scadens O. Hoffm.; Harungana madagascariensis (Lam.) ex Poir; Lablab purpureus (L.) Sweet subsp. uncinatus Verde.; Lantana camara L.; Ludwigia abyssinica A. Rich; Lysimachia ruhmeriand Vatke; Maesa lanseolata Forsskal; Markharnia lutea (Benth.) Schum.; Mormordica foetida Schum.; Monechma subsessile (Oliv.) C.B. Clarke; Myrica kandtiana Engl.; Orthosiphon Suffrutescens (Thonn.) J.K. Morton; Pavieta ternifolia (Oliver) Hiern; Polygala luteo-viridis Chodat; Rumex bequaertii De Wild.; Rytigynia beniensis De Wild. Robyns; Senecio mannii Hook, f.; Sesamum agolense Welw.; Tetradernia riparia (Hochst.) Codd.; Triumfetta cordifolia A. Rich.; Chenopodium procerum Hochst. ex Moq; Chenopodium ugandae (Aellen) Aellen; Clerodendrum myricoides (Hochst.) R. Br. Vatke Clerodendrum myricoides (Hochst.) R. Br. Vatke; Erythrina abyssinica Lam. ex DC; Dracaena afromontana Mildb; Ficus thonningii Blume; Gladiolus psittacinus Hook;. Leucas martini censis (Jacq.) R. Br.; Musa acuminata Colla; Phyllanthus bequaertii Rob.; Psidium guajava L.; Rubus rigidus Sm.; Senecio cydoniifolius O. Hoffm.; Solanum dasyphyllum Schum. et Thom; Sporobolus pyramidalus P. Beauv.; Tragia brevipes Pax; Vernonia pogosperma Klatt; and and Vernonia amygdaline Del.. ΙΕΟ 2 07 1 9 In another embodiment, the antidiabetic compounds are thiazolidinediones. Preferably selected from the group comprising: troglitazone, pioglitazone and/or rosiglitazone. In another embodiment, the antidiabetic compounds are sulfonylureas. In another embodiment, the antidiabetic compounds are biguanides. Preferably metformin.

In another embodiment, the antidiabetic compounds are alpha-glucosidase inhibitors. Preferably, acarbose and/or miglitol. In another embodiment, the antidiabetic compounds are alpha-glucosidase inhibitors. Preferably, acarbose and/or miglitol. In another embodiment, the antidiabetic compounds are meglitinides. Preferably, Repaglinide.

By combining the anti-metabolite with an anti-diabetic compound is that the system is starved of glucose and therefore will only have access to the carbohydrate anti-metabolite as a source of sugar.

The components of any of the combination therapies can be administered with anti-diabetic compounds such as those listed above to patients who have developed insulin resistance due to previous administrations of the anti-metabolite diet or from any other medical reason. Drugs for the therapy of insulin resistance can be administered with compounds of the present invention.

The components of any of the combination therapies disclosed herein can be administered simultaneously (in a combination formulation), essentially simultaneously (e.g., administration of each compound a few minutes or a few hours apart), or can be administered sequentially, e.g., several days apart, or more than a week apart. For example, a compound of the present invention and a glucose anti-metabolite compound (and/or a macrophage stimulating factor) can be administered together, or essentially simultaneously, e.g., administration of each compound a few minutes or a few hours apart, or can be administered sequentially, e.g., several days apart, or more than a week apart (optionally together with simultaneous or sequential administration of oxidating agent or oxygen ventilation). All such variations in administration of the combination therapy are encompassed within the scope of the invention.

Further, the pharmaceutical formulation according to the present invention may be administered intermittently. The advantage of this is that it allows the patient to suspend therapy for periods without the worry of inactivity of the drug resulting from the development of a resistant strain.

The invention also includes pharmaceutical formulations containing any such combination as described herein.

IE 0 2 07 1 9 The invention also includes the use of combinations of compounds as disclosed herein in the manufacture of a medicament for use in the treatment of a condition selected from malaria, African Trypanosomiasis, American Trypanosomiasis, as well as one or more kind of parasites and/or one or more diseases caused by such parasites.

The present invention is also directed to the use of compounds of the present invention in the manufacture of a medicament for treatment as described herein.

The present invention is also directed to administering of compounds of the present invention to provide a prophylactic treatment of a patient against liver parasites.

The present invention also provides articles of manufacture comprising, for example, packaging material, at least one unit-dosage of a compound of the present invention (optionally together with one or more unit-dosage of a compound which can be administered in a combination therapy, and a label or package insert indicating that the compound can be used in a method disclosed herein.

The compounds of the present invention can be administered to a patient in any of a wide range of routes. The pharmaceutical formulation according to the present invention may be administered locally or systemically.

By systemic administration means any mode or route of administration which results in effective amounts of active ingredient appearing in the blood or at a site remote from the route of administration of the active ingredient.

The compounds of the present invention may be formulated for enteral, parenteral or topical administration. Indeed all three types of formulations may be used simultaneously to achieve systemic administration of the active ingredient.

For oral administration, the compounds can be formulated into solid or liquid preparations. Suitable formulations for oral administration include hard or soft gelatin capsules, dragees, pills, tablets, including soft coated tablets, troches, lozenges, melts, powders, solutions, emulsions, elixrs, suspensions, syrups or inhalations and controlled release forms thereof.

In one embodiment, the compounds are dissolved in the drinking water.

IE 0 2 07 1 9 Solid dosage forms in addition to those formulated for oral administration include rectal suppositories.

The compounds of the present invention may also be administered in the form of an implant.

Suitable formulations for topical administration include creams, gels, jellies, mucilage’s, pastes and ointments. The compounds may be formulated for transdermal administration, for example in the form of transdermal patches so as to achieve systemic administration.

Suitable injectable solutions include intravenous, subcutaneous and intramuscular injectable solutions. Examples of injectable forms include solutions, suspensions and emulsions. Typically the compound(s) is injected in association with a pharmaceutical carrier such as normal saline, Ringers solution, anti-metabolite dextrose solution and other aqueous carriers known in the art. A preferred carrier is a 5% 2 deoxy dextrose or a 5% 2 amino-2-deoxy dextrose in saline. Frequently, it is desirable to include additives in the carrier such as buffers and preservatives or other substances to enhance isotonicity and chemical stability.

The compounds may also be administered in the form of an infusion solution or as a nasal inhalation or spray. It is important aspect of this invention that the glucose, fructose or any sugar or carbohydrate content of any excipient used in any delivery mechanism be maintained at a minimum.

With regard to dosage and duration of treatment according to any aspect of the present invention, it is recognised that the ability of an artisan skilled in pharmaceutical administration of drugs to determine suitable dosages depending on many inter-related factors is well known, and skilled artisans are readily able to monitor patients to determine whether treatment should be started, continued, discontinued or resumed at any given time. For example, dosages of the compounds are suitably determined depending on the individual cases taking symptoms, age and sex of the subject, dietary carbohydrate intake, and the like into consideration. The amount of the compound to be incorporated into the pharmaceutical composition of the invention varies with dosage route, solubility and chemical properties of the compound, administration route, administration scheme and the like. An effective amount for a particular patient may vary depending on factors such as the condition being treated, the overall health of the patient, the dietary carbohydrate intake of the patient and the method route and dose of administration. Determination of the appropriate dose is made by the clinician using parameters known in the art. Generally, the dose begins with an amount somewhat less than the optimum dose and it is increased by small increments thereafter until the desired or optimum effect is achieved.

IE Ο 2 Ο 7 1 9 Suitable dosages can be determined by further taking into account relevant disclosure in the known art.

These and other features and advantages of the present invention will be more clearly 5 understood with reference to the following description of some embodiments thereof in the example of the treatment ofa HIV positive patient presented above and table 3 below.

The terms “comprise, comprised and comprising” and the terms “include, included and including” are used interchangeably in this specification and are to be afforded the widest interpretation.

The invention is not limited to the embodiments described above, but may be varied in both construction and detail within the scope of the claims. Note in the text or claims of this invention reference to glucose is defined to encompass all or any molecules similar to glucose and which are anti-metabolites of the Natural and synthetic Monosaccharides, including Aldoses, Ketoses, Amino sugars, Alditols and Inositols

Claims (71)

1. I CLAIM

1. A method of therapy to enhance or initiate immune clearance of a disease causing organism in a human or animal which involves a period of absence from all forms of carbohydrate in the diet while concomitantly administering every one hour to twenty four hours glucose antimetabolites as a carbohydrate substitution.

2. A method of therapy according to claim one in which the patient is infected with a virus selected from the group consisting of: adenoviridae, herpesviridae, orthomyxoviridae, hepadnaviridae, parvoviridae, togaviridae, paramyxoviridae, flaviviridae, rhabdoviridae, bunyviridae, reoviridae, picornaviridiae and retroviridae.

3. A method of therapy according to claim one in which the glucose anti-metabolite used is selected from any one or a combination of the following non inclusive list: Glucosamine, Tuncamycin, Deoxyglucose, Fluoroglucose and Benzhydrazone, 2deoxy-glucose, 2Amino-2deoxy-glucose.

4. A method of therapy according to claim one in which the glycosidase inhibitor compounds used are for example only:- Deoxymannojirimycin, Castanospermine and Deoxynojirimycin.

5. A method of therapy according to claim one in which the patient is infected with the immunodeficiency virus HIV.

6. A method of therapy according to claim one in which the patient is infected with the hepatitis A, B or C virus.

7. A method of therapy according to claim one in which a patient has been suspected of being exposed to an unknown disease causing agent in order to accentuate the disease agents clearance by the immune system and provide the patient with immune protection from future exposure.

8. A method of therapy according to claim one in which the patient human or animal is also co-administrated Prescription. Anti-viral or anti-bacterial or anti-fungal medications. IE 0 2 01 1 9

9. A pharmaceutical formulation for use in treating an infected patient in need of such treatment, comprising administering to said patient an effective amount of at least one compound selected from the group consisting of the compounds of the present invention-;

10. A pharmaceutical formulation as claimed in any preceding claim, further comprising administering to said patient at least one macrophage stimulating factor.

11. A pharmaceutical formulation as claimed in any preceding claim, further comprising administering to said patient one or more oxidation agent and/or oxygen ventilation.

12. A pharmaceutical formulation as claimed in any preceding claim, wherein said patient is a mammal.

13. A pharmaceutical formulation as claimed in claim 7, wherein said patient is a human.

14. A pharmaceutical formulation as claimed in any preceding claim, wherein the compounds of the present invention are administered orally.

15. A pharmaceutical formulation as claimed in claim 9, wherein the compounds of the present invention are administered sub-lingual.

16. A pharmaceutical formulation as claimed in any preceding claim, wherein the compounds of the present invention are administered by injection.

17. A pharmaceutical formulation as claimed in any preceding claim, wherein the compounds of the present invention are administered by infusion.

18. A pharmaceutical formulation as claimed in any preceding claim, wherein the compounds of the present invention are administered by intravenous injection.

19. A pharmaceutical formulation for use in treating sleeping sickness in a patient in need of such treatment, comprising administering to said patient an effective amount of a compound of the present invention while maintaining a total carbohydrate free diet.

20. A pharmaceutical formulation for use in treating sleeping sickness in a patient in need of such treatment, comprising administering to said patient an effective amount of a compound of the present invention. IE 0 2 07 1 9 21.

A pharmaceutical formulation as claimed in claim 20, wherein said patient is a human.

A pharmaceutical formulation as claimed in as claimed this patient wherein the compounds of the present invention are administered orally.

A pharmaceutical formulation as claimed in claim 22, wherein the compounds of the present invention are administered sub-lingual.

A pharmaceutical formulation as claimed in as claimed in claims compounds of the present invention are administered by injection.

A pharmaceutical formulation as claimed in as claimed in claims compounds of the present invention are administered by infusion. 14 - 23, wherein the 14 - 24, wherein the

A pharmaceutical formulation as claimed in as claimed in claims 14 - 25, compounds of the present invention are administered by intravenous injection. wherein the

A pharmaceutical formulation for use in treating Chagas disease in a patient in need of such treatment, comprising administering to said patient an effective amount of a compound of the present invention.

A pharmaceutical formulation as claimed previously, further comprising administering to said patient at least one glucose anti metabolite compound.

A pharmaceutical formulation as claimed previously, wherein said at least one compound of the present invention and said at least one glucose anti metabolite.compound are administered simultaneously.

A pharmaceutical formulation as claimed previously, wherein said at least one compound of the present invention and said at least one glucose anti metabolite compound are administered sequentially.

A pharmaceutical formulation as claimed in as claimed previously, further comprising administering to said patient at least one macrophage stimulating factor.

A pharmaceutical formulation as claimed in as claimed previously, further comprising administering to said patient one or more oxidation agent and/or oxygen ventilation. ΙΕΟ 2 07 18

33. A pharmaceutical formulation as claimed in as claimed previously, wherein said patient is a mammal.

34. A pharmaceutical formulation as claimed previously, wherein said patient is a human.

35. A pharmaceutical formulation as claimed in as claimed in previous claims wherein the compounds of the present invention are administered orally.

36. A pharmaceutical formulation as claimed in previous claims, wherein the compounds of the present invention are administered sub-lingual.

37. A pharmaceutical formulation as claimed in as claimed in previous claims, wherein the compounds ofthe present invention are administered by injection.

38. A pharmaceutical formulation as claimed in as claimed in previous claims, wherein the compounds of the present invention are administered by infusion.

39. A pharmaceutical formulation as claimed in as claimed in previous claims, wherein the compounds ofthe present invention are administered by intravenous injection.

40. A pharmaceutical formulation for use in treating one or more kind of parasites and/or one or more diseases caused by such parasites, against one or more kind of Mycoplasma and/or one or more diseases caused by such Mycoplasmas and/or against one or more of the following indications or infections: (a) hairy Leukoplakia, (b) oral candidosis, (c) mouth ulcerations-aphthous/herpetic/bacterial, (d) fungal Candida, (e) human papilloma virus, (f) molluscum contagiosum, (g) squamous oral carcinoma, (h) Kaposi’s sarcoma oral lesions, (i) periodontitis, 0) necrotizing gingivitis, (k) orafacial herpes zoster, and (I) rotaviruses in a patient in need of such treatment, comprising administering to said patient an effective amount of a compound of the present invention.

41. A pharmaceutical formulation as claimed earlier, further comprising administering to said patient a glucose anti metabolite compound.

42. A pharmaceutical formulation as claimed in previous claims, wherein said at least one compound of the present invention and said glucose anti metabolite compounds are administered simultaneously. IE 0 2 07 19

43. A pharmaceutical formulation as claimed in previous claims, wherein said at least one compound of the present invention and said glucose anti metabolite compounds are administered sequentially.

44. A pharmaceutical formulation as claimed in previous claims, further comprising administering to said patient at least one macrophage stimulating factor.

45. A pharmaceutical formulation as claimed in previous claims, further comprising administering to said patient one or more oxidation agent and/or oxygen ventilation.

46. A pharmaceutical formulation as claimed in previous claims, wherein said patient is a mammal.

47. A pharmaceutical formulation as claimed earlier, wherein said patient is a human.

48. A pharmaceutical formulation as claimed in as claimed in previous claims, wherein the compounds of the present invention are administered orally.

49. A pharmaceutical formulation as claimed earlier, wherein the compounds of the present invention are administered sub-lingual.

50. A pharmaceutical formulation as claimed in as claimed in previous claims, wherein the compounds ofthe present invention are administered by injection.

51. A pharmaceutical formulation as claimed in as claimed in previous claims, wherein the compounds ofthe present invention are administered by infusion.

52. A pharmaceutical formulation as claimed in as claimed in previous claims, wherein the compounds ofthe present invention are administered by intravenous injection.

53. A composition as claimed earlier, further comprising at least one macrophage stimulating factor.

54. A composition as claimed in previous claims, further comprising an oxidation agent.

55. A composition comprising: -at least one of the compounds of the present invention, and -at least one macrophage stimulating factor. IE 0 2 07 U

56. A composition as claimed earlier, further comprising at least one oxidation agent.

57. A composition comprising: -at least one of the compounds of the present invention, and -at least one an oxidation agent.

58. A kit comprising unit dosage of each compound of the present invention.

59. A kit as claimed in claim 57, further comprising unit dosages of at least one macrophage stimulating factor.

60. A kit as recited in claim 57, 58, further comprising unit dosages of an oxidation agent.

61. A kit comprising: -unit dosages of at least one of the compounds of the present invention, and -unit dosages of at least one macrophage stimulating factor.

62. A kit as recited in above claim, further comprising unit dosages of at least one oxidation agent.

63. A kit comprising: -unit dosages of at least one of the compounds of the present invention, and -unit dosages of at least one an oxidation agent.

64. Generating antibody (immunoglobulin) in animals against an infective organism or enhancing/neutralising immunoglobulin production in such vaccinated or naturally challenged animals.

65. Treatment of severe viral infections where the immune system would not have enough time to mount an attack on the infectious organism itself such as small-pox, ebola and other agents. The patient is administered the compounds of the present invention preferably by continuous intravenous administration for 72 hours and this will allow very high levels of neutralising antibodies to be achieved and the viral replication to be curtailed to allow recovery and immunity to develop in the patient.

66. A method of therapy according to the present invention in which inhibitors of N-glycosylation such as Tunicamycin, Castanospermine, 1-Deoxynojirimycin and 1-Deoxymannojirimycin are IE Ο 2 07 1 9 used in place of the anti metabolites of glucose.

67. A method of therapy according to the present invention in which compounds that inhibit the enzymes of N-glycosylation such as Tunicamycin, Castanospermine, 1-deoxynojirimine, 15 deoxymannojirimycin are used in association with anti-metabolites of glucose and combined with a carbohydrate free diet during therapy.

68. A claim for use of the antibiotic Tunicamycin in a patient to enhance the antigenicity of endogenous or administered infections organisms.

69. A claim for use of the compound CASTANOSPERMINE to enhance the antigenicity of administered or endogenous infectious organism.

70. A claim for use of the compound Deoxynojirimine to enhance the antigenicity of administered 15 or endogenous infectious organism.

71. A claim for use of the compound Deoxymannojirimcin to enhance the antigenicity of administered or endogenous infectious organism.