WO1999003350A1 - Substance therapeutique convenant au traitement du sida et d'affections immuno-allergiques - Google Patents

Substance therapeutique convenant au traitement du sida et d'affections immuno-allergiques Download PDF

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Publication number
WO1999003350A1
WO1999003350A1 PCT/IL1998/000042 IL9800042W WO9903350A1 WO 1999003350 A1 WO1999003350 A1 WO 1999003350A1 IL 9800042 W IL9800042 W IL 9800042W WO 9903350 A1 WO9903350 A1 WO 9903350A1
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Prior art keywords
pharmaceutical composition
components
fractions
prevention
control
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PCT/IL1998/000042
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English (en)
Inventor
Eli Kaplan
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New Era Biotech Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from IL12133697A external-priority patent/IL121336A0/xx
Priority claimed from IL12168097A external-priority patent/IL121680A0/xx
Application filed by New Era Biotech Limited filed Critical New Era Biotech Limited
Priority to AU57780/98A priority Critical patent/AU5778098A/en
Publication of WO1999003350A1 publication Critical patent/WO1999003350A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/742—Spore-forming bacteria, e.g. Bacillus coagulans, Bacillus subtilis, clostridium or Lactobacillus sporogenes

Definitions

  • the present invention relates to the treatment of AIDS and immuno- allergical diseases. More particularly, the present invention relates to a therapeutic substance for use in the treatment of AIDS, HIV+ related infections and immuno- allergical diseases, and to pharmaceutical compositions for the treatment of same.
  • the search for effective means of treating the acquired immuno deficiency syndrome (AIDS), HIV+ related infections and immuno-allergical diseases is intense due to the potentially devastating effect that such diseases can have on civilization.
  • Epidemiological statistics show an ever increasing prevalence of such diseases, with global and regional health organisations predicting catastrophic consequences on a mass scale, unless effective and easily apphcable means are provided and implemented, for the control of such diseases.
  • the present invention involves the use of the total culture, extracts, filtrates, dialyzates, filtration or dialysis residues, either individually or in combination, in liquid form or as the dried solids, of an initially protein-free culture medium comprising bacillus subtilis var. indolasus, in the treatment, prevention and control of AIDS, HTV+ related diseases and immuno-allergical diseases, and in the preparation of improved pharmaceutical compositions for the treatment, prevention and control of AIDS, HIV+ related diseases and immuno-allergical diseases.
  • the new treatment includes the use of one or more components or fractions of an initially protein-free culture medium comprising bacillus var. indolasus, including the total culture, extracts, filtrates, dialyzates, filtration or dialysis residues, either individually or in combination, in liquid form or as the dried solids, in the preparation of pharmaceutical compositions for the treatment, prevention or control of AIDS, HIV+ related diseases and immimo-allergical diseases in humans as well as veterinary applications (where applicable), said compositions comprising at least one or more components of the initially protein- free culture medium comprising bacillus subtilis var. indolasus.
  • the initial protein-free culture medium comprising bacillus subtilis var. indolasus, for treatment, control or prevention of AIDS, HIV+ related diseases and immuno-allergical diseases, such as Systemic Lupus Erythematosus, Bronchial Asthma, Allergic RJ initis, Autoimmune Thyroiditis, Psoriasis and Crohn's Disease.
  • the pharmaceutical composition further comprising at least one pharmaceutically acceptable inactive component selected from the group consisting of carriers, coatings, diluents and adjuvants.
  • the pharmaceutical composition is used for the tieatments prevention or control of AIDS. According to still further features in the described preferred embodiments the pharmaceutical composition is used for the tieatments prevention or control of HIV infection.
  • the pharmaceutical composition is used for the treatments prevention or control of Systemic Lupus Erythematosus.
  • the pharmaceutical composition is used for the tieatments prevention or control of Bronchial Asthma. According to still further features in the described preferred embodiments the pharmaceutical composition is used for the treatments prevention or control of Allergic Rhinitis.
  • the pharmaceutical composition is used for the treatments prevention or control of Autoimmune Thyroiditis.
  • the pharmaceutical composition is used for the tieatments prevention or control of Psoriasis.
  • the pharmaceutical composition is used for the treatments prevention or control of Crohn's Disease.
  • the component, components and fractions have been dried and milled prior to preparation of the pharmaceutical composition.
  • said pharmaceutically acceptable inactive component includes at least one member of the group consisting of silica gel, starch, cellulose, silicon dioxide, talc and fibers.
  • said starch is selected from the group consisting of corn starch and potato starch.
  • the pharmaceutical composition is formulated for oral or parenteral administration.
  • the pharmaceutical composition is formulated as uncoated tablets, coated tablets or capsules.
  • the pharmaceutical composition is formulated in liquid form to be administered parenterally.
  • the liquid form includes one or more purified components or fractions of an initially protein-free culture medium compiismg bacillus subtilis var. indolasus, in solution suitable for therapeutic administration
  • the pharmaceutical composition is formulated for rectal administration.
  • the pharmaceutical composition is formulated for ttans-dermal administration.
  • the pharmaceutical composition is fab ⁇ cated as a transdermal device.
  • the pharmaceutical composition is formulated ointment, cream of gel form for external administration.
  • the one or more components oi fi actions consist mainly or exclusively of the insoluble protein fraction of the culture
  • FIG 1 shows plots of HIV- 1 p24 antigen levels (m O D units) m culture media of T-cell line cultures which wei e cultui ed in the indicated concentrations of Antiviran and thereafter subjected to infection with the HIV- 1 vims
  • FIG. 2 shows plots of HIV- 1 p24 antigen levels (in O D units) m culture media of T-cell line cultures which weie subjected to infection with the HIV-1 virus and were treated with the indicated substances at the indicated times postinfection DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • the present invention is of a therapeutic substance for use in the treatment of AIDS, HIV+ related infections and immuno-allergical diseases, and to pharmaceutical compositions for the treatment of same, which can be used to cure or relieve such conditions.
  • the present invention can be used for treating AIDS, HIV+ related diseases and a variety of immuno-allergical diseases in human and in veterinary applications (where applicable) with rninimal, negligible or no negative side effects.
  • one or more components or products of an initial protein-free culture medium comprising bacillus subtilis var. indolasus including the total culture, extracts, filtrates, dialyzates, filtration or dialysis residues, either individually or in combination, in liquid form or as the dried solids, are used in the treatment, prevention and control of AIDS, HIV+ related diseases and a variety of immuno-allergical diseases, as well as in the preparation of pharmaceutical compositions for the treatment, prevention and control of AIDS, HIV+ related diseases and a variety of immuno-allergical diseases.
  • the compositions comprising at least one or more components of the initially protein-free culture medium comprising bacillus subtilis var.
  • indolasus and optionally in addition, one or more pharmaceutically acceptable inactive components selected from, carries, coatings diluents and adjutants.
  • IM immuno-allergical diseases
  • AV Antiviran
  • the substances of the present invention can be used alone or in combination with other therapeutic substances and methods known for the treatment of AIDS, HIV+ related diseases, or immuno-allergical diseases.
  • Antiviran or Imumodulan has been known previously as Subtiltryptasin. Its preparation and certain of its properties are described in - German Patent No 873,732, whose teachings are included herein by reference.
  • Antivnan is effective agamst HIV-1 type viruses. Its efficacy is manifested both theiapeutically, i.e , allowing infected T- cells to recover, as well as preventively, I e , preventing the infection of T-cells by the virus. While the mechanism of action of AV is not fully clarified, it appears to be related to a dual function of mteicellulai lmmunostimulation and lntracellular regulation.
  • Imumodulan is effective against a very wide variety of immuno-alleigical diseases and conditions. Imumodulan has been tested for effectiveness in the tieatment of the following immuno-allergical diseases: Systemic Lupus Erythematosus, Bionchial Asthma, Allergic Rhinitis, Autoimmune Thyroiditis, Psoriasis and Ciohn's Disease In every case dramatic recovery was observed, thus cleaily demonstrating that it is effective agamst all such diseases
  • Imumodulan Its efficacy is manifested both as thei apeutic, I e , facilitating recovery in immuno-allergical diseases, as well as pieventive, l e , preventing the immuno- allergical condition. While the mechanism of action of Imumodulan is not fully clarified, it appears to be related to one or moie of the following functions, namely, intercellular immunostimulation, immunomodulation and lntracellular regulation.
  • Imumodulan or Antiviran can be admmisteied in various forms, such as but not limited to, solid or liquid, powdeis, tables, capsules, suppositones, solutions, suspensions, ointments, creams, gels, etc and in vanous ways of administration, such as, but not limited to, oral, parenteial. lectal, de ⁇ nal, tiansdermal, nasally, in the eyes(s), etc.
  • Pharmaceutically acceptable lnactn e components for pharmaceutical compositions comprising Imumodulan oi Antivnan can include, but are not limited to, silica gel, starch, cellulose, silicon dioxide, talc, fibeis, and other substantially inert, acceptable pharmaceutical components Typical examples of starches for such purposes mclude, com starch, potato staich oi othei edible starches
  • Tablets may be uncoated oi coated w ith gelatin oi other suitable coating materials.
  • the efficacy of Antiviran to inhibit the replication of HIV- 1 in a T-cell line was evaluated by the measurement of the p24 antigen in the growth media.
  • the p24 antigen is a marker of HIV- 1 expression, which reflects the presence of the vims in the cells.
  • An increase of the vims load directly conelates with an increase in the p24 antigen level, as measured in optical density (O.D.) units.
  • the OD values of the negative control decreased from day 0 to day 7, as expected, reflecting the death of cells
  • Table 3 denotes the results of a microscopic inspection for a cytopathic effect (CPE), which confi ⁇ ns the sprout of the vims and the validity of the experiment.
  • CPE cytopathic effect
  • Antiviran has a protective or recovery effect on the T-cells, since their number increased as compared to the control.
  • Antiviran has a presumable protecting effect on a T-cell that is already infected with HIV-1, since, at higher concentiations a cultured T-cell line did recover after the addition of Antiviran to the culture, as compared to the control.
  • the efficacy of Antiviran to inhibit HIV- 1 infection was evaluated by measurements for HIV-1 p24 antigen in the medium of a T-cell line infected with HIV-1 after cultnring in a medium containing the substance.
  • the replaced media were collected for p24 antigen determinations as described for Example 1 above. Cultures were divided into two equal parts.
  • the p24 antigen appeared in increasing concentrations, as expected. However, in the 3 lowest concentrations (0.5 ⁇ g/ml; 0.05 ⁇ g/ml and 0.005 ⁇ g/ml) there was substantially no expression of the p24 antigen, and only a slight increase over the lower cut-off value of p24 antigen in the two highest concentrations (5 and 50 ⁇ g/ml) was detected.
  • Table 7 shows that there is no difference in the viability between the control cells and all the cells grown in Antiviran containing media. That means that there is no cytotoxic effect imposed by Antiviran on normal cells.
  • Preliminary anti-HIV-1 lesults obtained with Antivnan show activity against HIV-1 (Illg strain) with an EC50 of 24 4 ⁇ g/ml of pure substance while it was toxic for the host cells at a concent ation of 172 4 ⁇ g/ml, resulting in a selectivity index of 7, as was detennined by an MTT-assay.
  • MT-4 cells were grown in RPMI 1640 medium (Life Technologies, Merelbeke, Belgium), supplemented with 10 % (v/v) heat-inactivated fetal calf scrum (FCS), 2 mM L-glutamine, 0.1 % sodium bicaibonate and 20 ⁇ g/ml gentamicin (Life Technologies, Merelbeke, Belgium)
  • FCS heat-inactivated fetal calf scrum
  • FCS heat-inactivated fetal calf scrum
  • 2 mM L-glutamine 2 mM L-glutamine
  • 0.1 % sodium bicaibonate 20 ⁇ g/ml gentamicin
  • Solubilization of the formazan ciystals was achieved by adding 100 ⁇ l of 10 % (v/v) Triton X-100 in acidified lsopropanol (2 ml concentrated HC1 per 500 ml solvent) using the Biomek 2000 robot Complete dissolution of the formazan crystals could be obtained after the frays had been placed on a plate shaker for 10 min (ICN Biomedicals Flow Laborato ⁇ es) Finally, the absorbance were read in an eight-channel computerconti oiled Titertek Mici opiate reader and stacker (Multiskan MCC, ICN Biomedicals - Flow Laboratories) at two wavelengths (540 and 690 run).
  • the absorbance measured at 690 nm was automatically subtracted from the absorbance at 540 nm, so as to eliminate the effects of non-specific absorption. Blanking was carried out dnectl on the macotiter trays with the first column wells which contained all leagents except MT-4 cells, virus and compounds. All data represent the aveiage values foi a minimum of three wells.
  • the 50 % cytotoxic concentration (CC50) was defined as the concentration of compound that reduced the absorbance (OD540) of the mock-mfected control sample by 50 %
  • the percent protection achieved by the compounds m HIV- infected cells was calculated by the following formula
  • (OD r p)HIV is the optical density measuied with a given concentration of the test compound in HlV-mfected cells
  • (OD ⁇ )HIV is the optical density measured for the control untreated HlV-mfected cells
  • (ODc)mock is the optical density measured for the control untieated mock-infected cells
  • all OD values were determined at 540 nm.
  • the concentiation achieving 50% piotection accordmg to the above formula was defined as the 50 % effective concentration (EC50)
  • Antiviran has been compared to the binding inhibitor dextran sulfate, to the reverse transcriptase inhibitor AZT and the protease inhibitor Saquinavir (Ro31-8959) as controls.
  • Antiviran like dextran sulfate, need to be present at the time of infection, in order to be active against the replication of HIV. It is believed that Antiviran interacts with the binding of HIV to the target cells. A slight inhibitory effect on the binding of gp l20 to MT-4 cells has been noticed. However, the exact mechanism has not yet been elucidated and expeiiments are still currently in progress.
  • MT-4 cells were infected with HIV- 1 (Hlg) at a multiplicity of infection (moi) of >1 and Antiviran, the binding inhibitor dextran sulfate (DS), the reverse transcriptase inhibitor AZT and the protease inhibitor Ro31-8959 (Saquinavir), were added at different times (0, 1, 2, 3 . . 22, 23, or 24 h) after infection (the last 3 compounds served as controls). Viral p24 antigen production was determined as described hereinabove 29 h postinfection and is expressed in O.D. units. The compounds were added at a standardized concentration - that is, 100 times their EC50 required to reduce by 50 % the cytopathicity of HIV-1 (Ill ⁇ ) (moi, 0.01) in MT-4 cells.
  • Antiviran has been separated into 3 distinct components, namely (i) fraction 8a which contains polysaccharides and purines, (ii) fraction 3b which contains insoluble proteins and (iii) fraction 2b which contains soluble proteins. Each of these fractions has been tested against HIV, as in Example 3 above, and has been found to be active against HIV-1 infection. The same MT-4/MTT assay (as in Example 3) has been applied in duplicates at the present test.
  • Table 9 below shows the activity of the 3 components against HIV-1 (Illg) infection.
  • Fraction 2b shows activity as EC50 of 3 and 1.5 mg/ml; EC90 of 5.1 and 2.3 mg/ml; CC50 of > 10 and 15.5 mg/ml with a selectivity index (SI) of > 3 and 10, respectively.
  • Fraction 3b shows activity as EC50 of 2.7 and 9.5 mg/ml; EC90 of 4.1 and > 25 mg/ml; CC 50 of > 10 and > 25 mg/ml with a SI of > 4 and >
  • fraction 8a shows activity as EC50 of 2.4 and 2.7 mg/ml; EC90 of 3.6 and 4.1 mg/ml; CC50 of > 10 and > 10 mg/ml, with a SI of > 4 and >
  • Antiviran was found to have no antibiotic action against pathogenic gram- positive or gram-negative organisms.
  • Cytokines consist of a broad class of glycoproteins which regulate intercellular communication. They play an important role in hematopoiesis, immune reactions and inflammation, both in physiological and pathological conditions. When stimulated, the cytokines are secreted by a variety of cells ubiquitously distributed in the body, such as lymphocytes, macrophages, fibroblasts and endothelial cells.
  • PBMCs peripheral blood mononuclear cells
  • IL-6 Interleukin 6
  • IL-12 Interleukin 12
  • TNF ⁇ Tumour Necrosis Factor- ⁇
  • cytokine levels as low as 18 pg/ml " for IL-6, 5 pg/ml for IL-10, 10 pg/ml for IL-12 and 20 pg/ml for TNF ⁇ .
  • Polymyxin B (Polymyxin B has been shown to block in vitro effects of endotoxin).
  • Imumodulan is a strong IL-6 inducer and the coactivation of IL-10 may have beneficial effects on the imbalance between humoral and cellular immunity observed at allergic and autoimmune diseases, mainly those diseases
  • Diabetes Mellitus type 1 Autoimmune Thyroid Diseases, Crohn's Disease, Acute
  • Imumodulan cytotoxicity The cytotoxic effects of Imumodulan were examined in two cell systems.
  • the effect Imumodulan has on human K-562 leukemia and murine YAC-1 lymphoma cells after 72 h in culture was measured with a calorimetric assay, based on the cleavage of the tetiazolium salt WST-1 by mitochondrial dehydrogenases in viable cells.
  • Cells were cultured in microtiter plates in a final volume of 100 ⁇ l/well culture medium (serumfree low protein hybridoma medium purchased from Life Technologies. Basel) in a humidified atmosphere (37 °C, 5 % CO2) for 72 h, at a cell concentration of 2 x 1 Orwell. After 72 h incubation of the cells in the presence of various concentiations of Imumodulan, as indicated in
  • PBMC cell membrane The change in the permeability of PBMC cell membrane during culture was used to differentiate living from dead cells by flow cytometiy.
  • Cells (10 ⁇ ) were treated with various concentrations of Imumodulan for 24 h. Then they were collected by centrifugation, resuspended in 0.5 ml phosphate buffered saline (PBS) containing 5 ⁇ g/ml propidium iodide, and incubated for 15 min at room temperature. Results were obtained as dot plots of forward scatter versus fluorescence intensity obtained with a FACscan (Becton Dickinson) Lysis II program.
  • FACscan Becton Dickinson
  • the percentage of propidium iodide containing (dead) cells was 17.07 % at negative control. This value was practically the same observed at various concentrations of Imumodulan indicating that up to 10 mg/ml concentration did not affect viability of PBMC cultured cells (10 mg/ml - 19.92 % dead cells; 1 mg/ml - 18.02 % dead cells; 0.5 mg/ml 19.88 % dead cells; 0.1 mg/ml 19.42 % dead cells; 0.01 mg/ml - 1 8.42 % dead cells).
  • Erythematosus was initially treated with Meticorten. Slight improvement was observed, but the Meticorten had to be discontinued because of severe side effects. Recurrence of high fever, discomfort, rush and joint aches ensued.
  • Imumodulan treatment was initiated. (No other drug was used in addition). Subsequently, the skin cleared, the msh was eliminated, as well as the fever and chills. The patient experienced only mild joint aches.
  • Imumodulan treatment was continued (eveiy 2-3 months) for several years. There was no recurrence of acute symptoms, such as fever or msh. Only occasional mild joint aches were experienced, during changes of weather. The patient was able to resume her regular work routine and normal life style.
  • EXAMPLE 11 Imumodulan used for relieving Bronchial Asthma symptoms
  • Psoriasis localized mainly on both legs. Different cycles, with corticosteroids and non-corticosteroids containing ointments and creams, were administered. Tentative treatment at the dead sea was also experienced. No improvement was observed. In August first dose of Imumodulan was administered. Three weeks later, there was a complete disappearance of all the typical lesions characteristic for the disease (i.e., complete remission). The patient continued treatment with 4 additional doses of Imumodulan with 4-6 week intervals and then stopped the treatment. No side effects were experienced. The complete remission lasted for one year, when a relapse was noted.

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Abstract

La présente invention concerne un traitement du SIDA, d'affections liées au VIH+ et d'affections d'ordre immuno-allergiques. Ce traitement consiste à utiliser un ou plusieurs composants ou fractions d'un milieu de culture initialement aprotéique comprenant une souche bacillus var. indolasus, et à inclure dans une préparation pharmaceutique la culture totale, les extraits, les filtrats, les dialysats, et les restes de filtration et de dialyse, soit individuellement, soit par combinaison, et ce, sous forme liquide ou de solides séchés. Cette préparation de compositions pharmaceutiques, qui est destinée au traitement curatif, préventif ou thérapeutique du SIDA, d'affections liées au VIH+ et d'affections d'ordre immuno-allergiques chez l'homme, peut également convenir, dans certains cas, en médecine vétérinaire. Ces compositions comprennent au moins un ou plusieurs composants du milieu de culture initialement aprotéique comprenant une souche bacillus var. indolasus, et, éventuellement en plus, un ou plusieurs composants passifs pharmaceutiquement admis tels que des excipients, des enrobages, des diluants et des adjuvants.
PCT/IL1998/000042 1997-07-18 1998-01-29 Substance therapeutique convenant au traitement du sida et d'affections immuno-allergiques WO1999003350A1 (fr)

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AU57780/98A AU5778098A (en) 1997-07-18 1998-01-29 Therapeutic substance for use in the treatment of aids and immuno-allergical diseases

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IL12133697A IL121336A0 (en) 1997-07-18 1997-07-18 Therapeutic substance for use in the treatment of AIDS and in the preparation of pharmaceutical compositions for the treatment of AIDS
IL121336 1997-07-18
IL121680 1997-09-01
IL12168097A IL121680A0 (en) 1997-09-01 1997-09-01 Therapeutic substance for use in the treatment of and in the preparation of pharmaceutical compositions for the treatment of immuno-allergical diseases

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6619027B1 (en) 2000-10-13 2003-09-16 General Electric Company Gas turbine having rotor overspeed and overboost protection

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE873732C (de) * 1948-12-12 1954-06-21 Heinrich Dr Med Sprung Verfahren zur Herstellung eines Heilmittels, insbesondere fuer Leber-, Gallen-, Magen- und Darmkrankheiten
JPS62434A (ja) * 1985-06-25 1987-01-06 Ss Pharmaceut Co Ltd 新規化合物ｓｓ７３１３ａ及びその製造法並びにこれを含有する免疫調節剤
JPS6248633A (ja) * 1985-08-27 1987-03-03 Microbial Chem Res Found 抗アレルギ−剤及び気管支拡張剤
JPH0840903A (ja) * 1994-07-29 1996-02-13 Synthelabo Sa 抗癌剤により誘発される末梢神経障害を予防するための医薬組成物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE873732C (de) * 1948-12-12 1954-06-21 Heinrich Dr Med Sprung Verfahren zur Herstellung eines Heilmittels, insbesondere fuer Leber-, Gallen-, Magen- und Darmkrankheiten
JPS62434A (ja) * 1985-06-25 1987-01-06 Ss Pharmaceut Co Ltd 新規化合物ｓｓ７３１３ａ及びその製造法並びにこれを含有する免疫調節剤
JPS6248633A (ja) * 1985-08-27 1987-03-03 Microbial Chem Res Found 抗アレルギ−剤及び気管支拡張剤
JPH0840903A (ja) * 1994-07-29 1996-02-13 Synthelabo Sa 抗癌剤により誘発される末梢神経障害を予防するための医薬組成物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
REDINBO M. R., ET AL.: "CRYSTALLIZATION AND PRELIMINARY STRUCTURAL ANALYSIS OF BACILLUS SUBTILIS ADENYLOSUCCINATE LYASE, AN ENZYME IMPLICATED IN INFANTILE AUTISM.", PROTEIN SCIENCE, WILEY, US, vol. 05., 1 April 1996 (1996-04-01), US, pages 786 - 788., XP002914659, ISSN: 0961-8368 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6619027B1 (en) 2000-10-13 2003-09-16 General Electric Company Gas turbine having rotor overspeed and overboost protection

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