WO2013019221A1 - Compositions et procédés de traitement du syndrome myélodysplasique - Google Patents

Compositions et procédés de traitement du syndrome myélodysplasique Download PDF

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Publication number
WO2013019221A1
WO2013019221A1 PCT/US2011/046317 US2011046317W WO2013019221A1 WO 2013019221 A1 WO2013019221 A1 WO 2013019221A1 US 2011046317 W US2011046317 W US 2011046317W WO 2013019221 A1 WO2013019221 A1 WO 2013019221A1
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WIPO (PCT)
Prior art keywords
ezatiostat
salt
lenalidomide
administered
patient
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PCT/US2011/046317
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English (en)
Inventor
Gail L. Brown
Lixin Meng
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Telik, Inc.
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Priority to PCT/US2011/046317 priority Critical patent/WO2013019221A1/fr
Publication of WO2013019221A1 publication Critical patent/WO2013019221A1/fr
Priority to IL230689A priority patent/IL230689A0/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to compositions and methods for treating myelodysplasia syndrome.
  • MDS Myelodysplasia syndrome(s) refers to a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis (blood cell production) involving one or more cell lineages (red blood cells, white blood cells or platelets) and a variable risk of transformation to acute myeloid leukemia (AML). This syndrome becomes more common with age. It is estimated that MDS affects
  • Ezatiostat and its salts are disclosed in US Patent No. 5,763,570.
  • Ezatiostat has the IUPAC chemical name of ethyl (2S)-2-amino-5-[[(2R)-3-benzylsulfanyl-l-[[(7R)-2- ethoxy-2-oxo- 1 -phenylethyl] amino] - 1 -oxopropan-2-yl] amino] -5-oxopentanoate.
  • ezatiostat hydrochloride (USAN)
  • U.S. Patent Application No. 13/041,136 filed March 4, 2011, describes ansolvate and polymorphs of ezatiostat hydrochloride.
  • Ezatiostat hydrochloride has been evaluated for the treatment of MDS, in a Phase I-IIa study using a liposomal formulation (US Patent No.
  • this invention is a method of treating MDS in a patient wherein the patient has prior exposure to lenalidomide which method comprises treating said patient with ezatiostat or a pharmaceutically acceptable salt thereof.
  • this invention is a method of treating MDS by administration of ezatiostat or a salt thereof and lenalidomide.
  • this invention is a method of treating MDS by administration of ezatiostat or a salt thereof and lenalidomide followed by administration of ezatiostat or a salt thereof alone.
  • ezatiostat or a salt thereof is administered daily for at least 2 weeks. In some embodiments, ezatiostat or a salt thereof is administered daily for at least 3 weeks.
  • ezatiostat or a salt thereof may be administered by a dosing regimen described in U.S. Patent Application No. 13/108,752, titled
  • ezatiostat or a salt thereof may be administered in cycles of 2 gram/day orally for 3 weeks on/1 week off, or cycles of 3 gram day orally for 2 weeks on/1 week off.
  • Equivalent ezatiostat doses for ezatiostat itself or other ezatiostat salts, or for other routes of administration may also be used.
  • this invention provides use of ezatiostat or a salt thereof for the preparation of a medicament for treating a myelodysplasia syndrome in a patient who has prior exposure to lenalidomide.
  • this invention provides use of ezatiostat or a salt thereof for the preparation of a medicament for treating a myelodysplasia syndrome in a patient, wherein the ezatiostat or a salt thereof is administered with lenalidomide.
  • this invention provides a composition comprising lenalidomide and ezatiostat or a salt thereof.
  • Such compositions preferably contain a pharmaceutically acceptable excipient to facilitate administration.
  • this invention provides a kit for the treatment of MDS comprising a first composition comprising lenalidomide and a second composition comprising ezatiostat or a salt thereof.
  • compositions and methods include the recited elements, but do not exclude others.
  • Consisting essentially of when used to define compositions and methods shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention.
  • Consisting of means excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.
  • Lenalidomide (Revlimid®, also known as Revamid in the UK) is an immunomodulatory agent with antiangio genie and antineoplastic properties. It has the chemical name of 3-(4-amino-l-oxoisoindolin-2-yl)piperidine-2,6-dione or l-oxo-2-(2,6- dioxopiperidin-3-yl)-4-aminoisoindoline or 3-(7-amino-3-oxo-lH-isoindol-2- yl)piperidine-2,6-dione, and CAS registry number of 191732-72-6. Lenalidomide is indicated for the treatment of patients who are transfusion-dependent due to low- or intermediate- 1 risk MDS associated with a deletion 5q cytogenetic abnormality.
  • Lenalidomide is available in 5 milligram (mg), 10 mg, 15 mg and 25 mg capsules for oral administration.
  • the term "therapeutically effective amount” refers to the amount of either lenalidomide or ezatiostat or a salt thereof, or the combination ("together"), that is an amount sufficient to effect treatment, as defined herein, when administered to a subject in need of such treatment.
  • the therapeutically effective amount will be up to 3.5 grams (g) of ezatiostat or a salt thereof administered per day.
  • ezatiostat or a salt thereof is administered in an amount of 2 grams per day and, more preferably, is administered twice a day in equal 1 gram doses.
  • Such a therapeutically effective amount is particularly relevant when the treatment regimen is for 3 weeks of administration of ezatiostat or a salt thereof followed by a week of no administration of the drug.
  • the therapeutically effective amount will be 3 grams of ezatiostat or a salt thereof administered in a single dose, or in 2 equal daily doses of 1.5 grams.
  • Such a therapeutically effective amount is particularly relevant when the treatment regimen is for 2 weeks of administration of ezatiostat or a salt thereof followed by a week of no administration of the drug.
  • the dosing regimen employs 2 grams of ezatiostat or a salt thereof administered in an amount of 1 gram doses twice a day either under continuous administration or with administration for 3 weeks followed by a week of no administration of the drug.
  • the therapeutically effective amount will provide efficacious results in at least about 10 % of the treated population, and preferably at least about 15 %.
  • treatment means any treatment of MDS in a patient which produces one or more of the following:
  • the term "patient” refers to mammals and includes humans and non-human mammals.
  • this invention is directed to a method for treating a myelodysplasia syndrome (MDS) in a patient in need thereof wherein the patient has prior exposure to lenalidomide which method comprises treating said patient with ezatiostat or a pharmaceutically acceptable salt thereof.
  • MDS myelodysplasia syndrome
  • the response rate in patients who were not pre-treated with lenalidomide is about 22 % and in patients who were pre-treated with lenalidomide the response rate is about 46 %, an over 100 % increase in response rate.
  • the prior exposure to lenalidomide may be an administration of lenalidomide to the patient any time prior to administration of ezatiostat or a salt thereof.
  • a typical lenalidomide treatment schedule involves a 28-day-cycle, during which lenalidomide is administered once a day, every day, for 21 days (3 weeks) followed by an interruption of 7 days (1 week) when no lenalidomide is administered. This 28-day-cycle can be repeated for a duration of up to 6 months.
  • Lenalidomide capsules have four different strengths: 5 mg, 10 mg, 15 mg, and 25 mg.
  • the patient has been treated with at least one dosage of lenalidomide.
  • the patient has been treated with lenalidomide for at least 2 days, 3 days, 4 days, 5 days, or 6 days. In some embodiments, the patient has been treated with lenalidomide for at least one week, two weeks or three weeks. In some embodiments, the patient has completed 1, 2, 3, 4, 5, or 6 lenalidomide treatment cycles. In some embodiments, the patient has completed the entire 6-month lenalidomide treatment regimen.
  • lenalidomide prior to administration of ezatiostat or a salt thereof has developed intolerance to lenalidomide and stopped treatment with lenalidomide or switched to a lower lenalidomide dosage before administration of ezatiostat or a salt thereof starts. It is to be understood that a patient may stop using lenalidomide or switch to a lower lenalidomide dosage after finishing a cycle or during the cycle depending on the patient's tolerance to lenalidomide.
  • lenalidomide may cause many side effects, such as birth defects and other adverse events.
  • the reported adverse events include but are not limited to those related to:
  • blood and lymphatic system disorders such as thrombocytopenia, neutropenia, e.g., febrile neutropenia, leukopenia, anemia, hemolytic anemia, e.g., warm type hemolytic anemia, splenic infarction, bone marrow depression, coagulopathy, hemolysis, and refractory anemia; skin and subcutaneous tissue disorders such as rash, dry skin, contusion, night sweats, increased sweating, ecchymosis, and erythema;
  • neutropenia e.g., febrile neutropenia
  • leukopenia e.g., leukopenia
  • anemia e.g., hemolytic anemia, e.g., warm type hemolytic anemia, splenic infarction, bone marrow depression, coagulopathy, hemolysis, and refractory anemia
  • skin and subcutaneous tissue disorders such as rash, dry skin, contusion, night sweats, increased sweating, ecchymosis,
  • gastrointestinal disorders such as diarrhea, constipation, nausea, abdominal pain, vomiting, abdominal pain upper, dry mouth, loose stools, gastrointestinal hemorrhage, colitis ischemic, intestinal perforation, rectal hemorrhage, colonic polyp, diverticulitis, dysphagia, gastritis, gastroenteritis, gastroesophageal reflux disease, obstructive inguinal hernia, irritable bowel syndrome, melena, pancreatitis due to biliary obstruction, pancreatitis, perirectal abscess, small intestinal obstruction, and upper gastrointestinal hemorrhage;
  • respiratory, thoracic and mediastinal disorders such as nasopharyngitis, cough, dyspnea, pharyngitis, epistaxis, dyspnea exertional, rhinitis, and bronchitis;
  • musculoskeletal and connective tissue disorders such as arthralgia, back pain, muscle cramp, pain in limb, myalgia and peripheral swelling, arthritis, arthritis aggravated, gouty arthritis, neck pain, and chondrocalcinosis pyrophosphate;
  • benign or malignant neoplasms such as acute leukemia, acute myeloid leukemia, bronchoalveolar carcinoma, lung cancer, lymphoma, and prostate cancer;
  • nervous system disorders such as dizziness, headache, hypoesthesia, dysgeusia, and peripheral neuropathy;
  • infections and infestations such as pneumonia, urinary tract infection, sinusitis, cellulitis, infection, bacteremia, central line infection, clostridial infection, ear infection, Enterobacter sepsis, fungal infection, herpes viral infection, influenza, kidney infection, Klebsiella sepsis, lobar pneumonia, localized infection, oral infection, pseudomonas infection, septic shock, sinusitis acute, sinusitis,
  • metabolism and nutrition disorders such as hypokalemia, anorexia,
  • hypomagnesemia dehydration, gout, hypernatremia, and hypoglycemia
  • psychiatric disorders such as insomnia, confusional state and depression
  • renal and urinary disorders such as dysuria, renal failure, hematuria, renal failure acute, azotemia, calculus ureteric, and renal mass;
  • reproductive system and breast disorders such as pelvic pain
  • vascular and cardiac disorders such as hypertension, palpitations, cardiac failure congestive, atrial fibrillation, angina pectoris, cardiac arrest, cardiac failure, cardiorespiratory arrest, cardiomyopathy, myocardial infarction, myocardial ischemia, atrial fibrillation aggravated, bradycardia, cardiogenic shock, pulmonary edema, supraventricular arrhythmia, tachyarrhythmia, and ventricular dysfunction;
  • hepatobiliary disorders such as hyperbilirubinemia, cholecystitis acute,
  • neutropenia neutropenia
  • thrombocytopenia pneumonia, rash, anemia, leukopenia, fatigue, dyspnea, back pain, febrile neutropenia, nausea, diarrhea, pyrexia, sepsis, dizziness, granulocytopenia, chest pain, pulmonary embolism, respiratory distress, pruritus, pancytopenia, muscle cramp, respiratory tract infection, upper respiratory tract infection, asthenia, multi-organ failure, epistaxis, hypoxia, pleural effusion, pneumonitis, pulmonary hypertension, vomiting, increased sweating, arthralgia, pain in limb, headache, and syncope.
  • one or more of the adverse events are so severe that lenalidomide can no longer be administered to the patient or lenalidomide must be administered in a reduced dosage. Under such circumstances, switching from
  • lenalidomide to ezatiostat or a salt thereof or addition of ezatiostat or a salt thereof not only avoids the adverse effect, but may also provide better therapeutic effect for ezatiostat or a salt thereof.
  • lenalidomide prior to administration of ezatiostat or a salt thereof does not respond to lenalidomide or the response to lenalidomide does not continue with continued lenalidomide treatment. It is reported that about 50 % of the patient administered lenalidomide exhibit clinically recognizable response. Under such circumstances, treating patients who did not respond or stopped responding to lenalidomide with ezatiostat hydrochloride results in an unexpected better therapeutic effect and reduction of clinical symptoms. In this case, treatment with lenalidomide may continue with administration of ezatiostat or a salt thereof at the same dosage or at a reduced dosage, or treatment with lenalidomide may be completely stopped.
  • ezatiostat or a pharmaceutically acceptable salt thereof is administered daily for at least two weeks. In some embodiments, ezatiostat or a pharmaceutically acceptable salt thereof is administered daily for at least three weeks.
  • this invention provides a method treating a myelodysplasia syndrome (MDS) in a patient, which method comprises concurrently administering to said patient lenalidomide and ezatiostat or a pharmaceutically acceptable salt thereof.
  • MDS myelodysplasia syndrome
  • ezatiostat or a pharmaceutically acceptable salt thereof is administered daily for at least two weeks.
  • ezatiostat or a pharmaceutically acceptable salt thereof is administered daily for at least three weeks.
  • the patient may or may not have been treated with lenalidomide prior to administration of ezatiostat hydrochloride.
  • the former includes situations described above.
  • lenalidomide and ezatiostat or a salt thereof can be administered in any manner in which the pharmacological effects of both are manifested in the patient at the same time.
  • concurrent administration of lenalidomide and ezatiostat or a salt thereof can be administered in any manner in which the pharmacological effects of both are manifested in the patient at the same time.
  • lenalidomide and ezatiostat or a pharmaceutically acceptable salt thereof does not require that a single pharmaceutical composition, the same dosage form, the same route of administration be used for the two agents, the two agents be administered at the same time or the two agents be administered for a similar length of time.
  • a concurrent administration may be the administration of a first and second pharmaceutical composition comprising lenalidomide and ezatiostat or a pharmaceutically acceptable salt thereof, respectively.
  • concurrent includes both simultaneous delivery as well as sequential delivery wherein each drug is administered separately in a manner that provides serum levels of both drugs in the patient at the same time.
  • a clinician employing lenalidomide alone in a patient for treating MDS may, at a point in that treatment regimen, add ezatiostat or a pharmaceutically acceptable salt thereof as an additional component for treating that patient.
  • ezatiostat or a pharmaceutically acceptable salt thereof in combination with lenalidomide constitutes concurrent administration for the purposes of this invention as the effects of both will be manifested in the patient at the same time.
  • this invention is a method of treating MDS by administration of ezatiostat or a salt thereof and lenalidomide followed by administration of ezatiostat or a salt thereof alone.
  • lenalidomide when administered concurrently with ezatiostat or a pharmaceutically acceptable salt thereof, lenalidomide is administered in the typical 28-day-cycle as described above and may be given in any of the dosage strengths. In some embodiments, lenalidomide is administered at a reduced dosage and/or frequency, for example, lenalidomide may be administered once every other days, once every 3, 4, 5, or 6 days. Or it may be administered once a week or may be discontinued while treatment with ezatiostat or a pharmaceutically acceptable salt thereof continues.
  • ezatiostat or a salt thereof is administered in a therapeutically effective amount.
  • ezatiostat or a salt thereof is administered by a dosing regimen described in U.S. Patent Application No. 13/108,752, titled “COMPOSITIONS AND METHODS FOR TREATING MYELODYSPLASTIC SYNDROME,” filed May 16, 2011, which is incorporated by reference in its entirety.
  • ezatiostat or a salt thereof is administered up to about 3.5 grams per day of ezatiostat hydrochloride, or an equivalent amount (in terms of ezatiostat content) of ezatiostat itself or another salt of ezatiostat.
  • the dosing of ezatiostat or a salt thereof is a thera eutically effective amount of up to about 1.5 gram administered twice a day (b.i.d.).
  • ezatiostat or a salt thereof is administered in 1 gram dosages twice a day for three weeks followed by an interruption of one week where ezatiostat or a salt thereof is not administered. After the interruption, the regimen can be repeated as necessary. This regimen may be referred to as the "three-week regimen.”
  • ezatiostat or a salt thereof is administered in 1.5 gram dosages twice a day for two weeks followed by an interruption of one week where ezatiostat or a salt thereof is not administered. After the interruption, the regimen can be repeated as necessary. This regimen may be referred to as the "two-week regimen.”
  • the patient is treated continuously with a therapeutically effective amount of ezatiostat or a salt thereof of up to 3 grams per day preferably administered in up to 1.5 gram dosages twice a day.
  • ezatiostat or a salt thereof can be administered so long as the patient is in need of and can tolerate such treatment. It is contemplated that in this embodiment, the therapeutically effective amount of ezatiostat or a salt thereof may be less or more than that when there is an interruption in the treatment regimen. This regimen may be referred to as the
  • the treatment with ezatiostat or a salt thereof may involve one or a combination of two or more of the dosing regimens described herein.
  • the following are exemplifying dosing schedules of ezatiostat hydrochloride: • 1.5 gram ezatiostat hydrochloride administered twice per day for 2 weeks for an aggregate total dosing of 42 grams followed by a week when no ezatiostat or a salt is administered;
  • ezatiostat hydrochloride • a therapeutically effective amount of up to 3 grams of ezatiostat hydrochloride per day administered in one, two, or three divided doses for 2 weeks followed by a week when no ezatiostat or a salt is administered;
  • ezatiostat hydrochloride • a therapeutically effective amount of up to 2 grams of ezatiostat hydrochloride per day administered in one, two, or three divided doses for 3 weeks followed by a week when no ezatiostat or a salt is administered;
  • Ezatiostat hydrochloride in the above dosings can be replaced with an equivalent amount of ezatiostat itself or another salt of ezatiostat (in terms of ezatiostat content).
  • the interval between the first and second doses be from about 6 to 14 hours and preferably between about 8 and 14 hours.
  • ezatiostat or a salt thereof can be administered intravenously as a lipid formulation such as those described in U.S. Patent No. 7,029,695 which is incorporated by reference in its entirety.
  • ezatiostat or a salt thereof can be administered orally.
  • ezatiostat or a salt thereof e.g., ezatiostat hydrochloride
  • a tablet formulation is disclosed in U.S. Patent Application No. 13/075,116, filed March 29, 2011, titled "TABLET FORMULATION OF EZATIOSTAT,” which is incorporated by reference in its entirety.
  • this invention provides a composition comprising lenalidomide and ezatiostat or a pharmaceutically acceptable salt thereof.
  • the ezatiostat or the salt thereof and the lenalidomide together are in a therapeutically effective amount.
  • lenalidomide and/or ezatiostat or a salt thereof is in a therapeutically effective amount.
  • the composition comprises about 5 mg, 10 mg, 15 mg or 25 mg of lenalidomide and about 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg ezatiostat or a salt thereof.
  • lenalidomide may be added to the ezatiostat or a salt thereof lipid formulation described in U.S. Patent No. 7,029,695.
  • lenalidomide may be added to a ezatiostat or a salt thereof tablet formulation.
  • a tablet formulation is disclosed in U.S. Patent
  • this invention provides a kit for the treatment of MDS comprising a first composition comprising lenalidomide and a second composition comprising ezatiostat or a salt thereof, including those described herein.
  • the ezatiostat or the salt thereof and the lenalidomide together are in a therapeutically effective amount.
  • the kit further comprises a label with instructions to administer the first dose of lenalidomide 1 day, 2 days, 3 days, 4 days, 5 days, 6 days before the first administration of ezatiostat or a salt thereof.
  • the kit further comprises a label with instructions to administer lenalidomide 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks before administration of ezatiostat or a salt thereof.
  • the kit further comprises a label with instructions to administer lenalidomide concurrently with ezatiostat or a salt thereof.
  • the kit further comprises a label with instructions to administer lenalidomide and ezatiostat or a salt thereof according to any of the dosing schedules described herein. Examples
  • the median age was 72 years, with a patient population distribution of IPSS low risk (23 patients, 32 %) and intermediate- 1 risk (50 patients, 68 %). Patients had received a median of three prior MDS therapies including, 34 patients (47 %) with prior Revlimid® (lenalidomide) and 28 patients (38 %) with prior DNA methyltransferase inhibitors (DMTI) [azacitidine, decitabine].
  • DMTI DNA methyltransferase inhibitors
  • GI gastrointestinal
  • nausea 45%, 16%), diarrhea (25%), 7%
  • vomiting (30%>, 12%).
  • Grade 3 events were uncommon: nausea (1%), diarrhea (3%) and vomiting (2%).
  • Prior DMTI treatment was associated with an increased incidence of GI AEs.
  • Telintra® treatment may result in clinically significant hematologic improvement in patients with MDS and may offer an alternative to RBC transfusions. These results are consistent with levels of efficacy observed in prior studies with Telintra®, the first GST Pl-1 enzyme inhibitor tested in MDS patients.
  • response rate to Telintra® increased from about 22.2 % for patients who had no prior treatment with Revlimid® to about 46.2 % in patients who had treatment with Revlimid® prior to administration of Telintra®.

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Abstract

La présente invention concerne des compositions et des procédés de traitement du syndrome myélodysplasique. Dans un mode de réalisation, la présente invention concerne des procédés de traitement du syndrome myélodysplasique utilisant de l'ézatiostat ou un sel de celui-ci et un lénalidomide.
PCT/US2011/046317 2011-08-02 2011-08-02 Compositions et procédés de traitement du syndrome myélodysplasique WO2013019221A1 (fr)

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PCT/US2011/046317 WO2013019221A1 (fr) 2011-08-02 2011-08-02 Compositions et procédés de traitement du syndrome myélodysplasique
IL230689A IL230689A0 (en) 2011-08-02 2014-01-28 Preparations and methods for the treatment of myelodysplastic syndrome

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Citations (2)

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US5763570A (en) 1987-10-13 1998-06-09 Terrapin Technologies, Inc. Glutathione analogs and paralog panels comprising glutathione mimics
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