WO2003063857A1 - A novel dosage form of l-methionine s-sulfoximine - Google Patents
A novel dosage form of l-methionine s-sulfoximine Download PDFInfo
- Publication number
- WO2003063857A1 WO2003063857A1 PCT/US2003/002513 US0302513W WO03063857A1 WO 2003063857 A1 WO2003063857 A1 WO 2003063857A1 US 0302513 W US0302513 W US 0302513W WO 03063857 A1 WO03063857 A1 WO 03063857A1
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- WO
- WIPO (PCT)
- Prior art keywords
- methionine
- sulfoximine
- amount
- glutamine
- mso
- Prior art date
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- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 title claims abstract description 45
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Classifications
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
Definitions
- the MSO was given in divided doses every 6 or 8 hours. The result of this experiment was no change in hepatic or renal function or in hematological status. Further, no evidence of tumor regression was discovered. It was noted that MSO impacted the central nervous system in the form of hallucinations, disorientation, and marked agitation. The author suggested that the symptoms were related to the size of the daily dose rather than a cumulative dose. In the reported experimentation, each patient was given a laboratory evaluation of their hepatic, renal, and hematologic status before the experimentation began. These evaluations were continued at regular intervals during the course of the experimentation and each subject was watched for evidence of tumor regression, measurable either enterogenographically or by direct observation of tumor masses. No evidence of tumor regression was noted.
- the Wada reference entitled "The Susceptibility to Auditory Stimuli of Animals Treated with Methionine Sulfoximine” disclosed that cats and rats treated with MSO and subjected to repeated sounds responded to the sounds with episodic running behavior and that the most effective dosage of MSO was 7.5 mg/kg. It was also disclosed that these effects were completely reversible. It was noted that amounts less than 5 mg/kg did not render cats susceptible whereas 10 mg/kg tended to produce early convulsive episodes that often ended in status epilepticus. Wada, "The Susceptibility to Auditory Stimuli of Animals Treated with Methionine Sulfoximine, " Experimental Neurology 15: 157-163 (1966).
- the Lamar reference entitled "The Duration of the Inhibition of Glutamine Synthetase by Methionine Sulfoximine” disclosed the duration of inhibition of glutamine synthetase and glutamine transferase activities in liver, brain and kidney cells after a single injection of MSO. Lamar disclosed that the maximal inhibition in the brain was 24 hours, but that the inhibition remains to a considerable degree for 72 hours, and that at the end of one week, the activity had not returned to normal levels. Lamar, "The Duration of the Inhibition of Glutamine Synthetase by Methionine Sulfoximine," Biochemical Pharmacology 17: 636-642 (1968).
- the Richman reference entitled "Inhibition of ⁇ -Glutamylcysteine Synthetase by L-Methionine-S-Sulfoximine" disclosed that MSO was an effective inhibitor of y- glutamylcysteine synthetase. MSO is disclosed as binding to the glutamate site of the enzyme and is converted into methionine sulfoximine phosphate in the presence of ATP and either JvlG + or Mn 2+ ions. It was taught in this reference as well that only L- methionine-S-sulfoximine inhibits the enzyme and causes convulsions in mice.
- the article also disclosed a Table on page 6685 which set forth the inhibition percentage of y-glutamylcysteine synthetase for each methionine derivative.
- MSO y-glutamylcysteine synthetase
- the inhibition in this case is a matter of hours, as compared to the days of inhibition of glutamine synthetase. Richman, "Inhibition of ⁇ -Glutamylcysteine Synthetase by L- Methionine-S-Sulfoximine," J. Biological Chemistry 248:19, 6684-6690 (1973).
- the Hawkins reference entitled "Hyperammonaemia Does Not Impair Brain Function in the Absence of Net Glutamine Synthesis” disclosed a series of experiments in which different doses of MSO, ranging from 5 to 200 mg/kg body weight, were injected into the peritoneal cavity of rats. It was noted that the metabolic changes seen in hyperammonaemia, whether caused by injections of urease or portacaval shunting, occurred within the first two days. It was also noted that a single intraperitoneal injection of MSO raises the brain concentration of ammonia within 2 hours. The response to the range of doses was disclosed in Figure 1 of the Hawkins reference. This data has been reproduced in the attached Figure 3 as percent inhibition rather than percent normal.
- glutamine synthetase activity was decreased in proportion to the dose and that the decrease in enzyme activity was accompanied by a parallel decrease in the brain content of glutamine.
- the plasma ammonia values increased as a function of dose and there was no evidence of toxicity except at the highest dose of 200 mg/kg body weight. It was also disclosed that a smaller dose of MSO, given intravenously, decreased brain glutamine synthetase activity as much as the larger intraperitoneal dose.
- the IV drug administered to the rats in this paper was at a dosage of 30 mg/kg, the toxicity of which to primates is unknown.
- the administration of 100 and 50 mg/kg to primates had not adverse effect on the test subject.
- the effect a lower dosage (such as 30 mg/kg) is not disclosed by Gershoff and Hawkins' testing of rats does not aid in this determination.
- the Hawkins reference does not disclose the MSO isomer used, one of ordinary skill could conclude that the LSMSO isomer was used given the congruity of the Hawkins data and the present invention's data.
- the Takahashi reference entitled “Inhibition of Brain Glutamine Accumulation Prevents Cerebral Edema in Hyperammonemic Rats” disclosed that the inhibition of glutamine synthetase activity by pre-treatment with L-methionine S-sulfoximine prevented both the increase in brain glutamine levels and the increase in brain water content despite elevated plasma ammonium levels. It was determined that cerebral edema during hyperammonemia is associated with glutamine accumulation. It was also disclosed that within the brain, MSO pretreatment produced a 64% inhibition of glutamine synthetase activity, in agreement with others. It was also noted that cortical glutamine levels were increased 3.3-fold in group III hyperammonemic rats compared with group I control rats.
- the Blei reference entitled "Ammonia-Induced Brain Edema and Intracranial Hypertension in Rats After Portacaval Anastomosis” disclosed that when portacaval anastomosis rats were infused with ammonium acetate and pretreated with 150 mg/kg MSO, brain edema was ameliorated and intracranial pressure did not rise. A dose-dependent reduction in brain glutamine levels was seen with increasing doses of MSO, but brain edema did not decrease beyond the 150 mg/kg dose. The article posited that the increase in brain water was not solely a result of the glutamine accumulation.
- the Hirata reference entitled "Impaired Pial Arteriolar Reactivity to Hypercapnia During Hyperammonemia Depends on Glutamine Synthesis” disclosed the depressed CBF response to hypercapnia could be prevented by glutamine synthetase inhibition with MSO. It was also determined that MSO can inhibit ⁇ -glutamylcysteine synthetase reversibly. It will not decrease glutathione in the brain, though.
- MSO inhibited, in this model of acute hyperammonemia, cortical glutamine synthetase by 64%, prevented 13-mmol/kg increase in cortical glutamine concentration, prevented the increase in tissue water content, prevented the increase in cisterna magna pressure, and prevented the loss of the CBF response to hypercapnia. It was also demonstrated that MSO prevents loss of the pial arteriolar dilator response to hypercapnia. Hirata, "Impaired Pial Arteriolar Reactivity to Hypercapnia During Hyperammonemia Depends on Glutamine Synthesis," Stroke 27:4, 729-736 (1996).
- Willard-Mack "Inhibition of Glutamine Synthetase Reduces Ammonia- Induced Astrocyte Swelling in Rat," Neuroscience 71 :2, 589-599 (1996).
- the Sugimoto reference entitled "Methionine Sulfoximine, A Glutamine Synthetase Inhibitor, Attenuates Increased Extracellular Potassium Activity During Acute Hyperammonemia” disclosed that hyperammonemia causes glutamine accumulation and astrocyte swelling, and that the inhibition of glutamine synthesis would reduce the ammonia-induced edema formation and watery swelling in astrocyte processes. The article concluded that acute hyperammonemia impairs astrocytic control of [K + ] e and that his impairment is linked to glutamine accumulation rather than ammonium ions per se.
- Cerebral edema, brain stem compression and death are the inevitable consequences of uncontrolled clinical hyperammonemia. It is well established that the pathophysiology of hyperammonemic encephalopathy consists of cerebral edema. There is also considerable and increasing evidence to suggest that the cerebral edema consists exclusively of swollen astrocytes. It has been shown that astrocytes swell as a result of hyperammonemia-induced glutamine synthesis, and that the accumulated glutamine serving as an intracellular osmolyte which causes water to shift into the cell.
- Brusilow offered the hypothesis that cerebral edema associated with hyperammonemia was a consequence of astrocyte brain glutamine accumulation catalyzed by glutamine synthetase, the principal brain sites of which are astrocytes. Accordingly, the inhibition of brain glutamine synthetase should prevent astrocyte glutamine accumulation and thereby prevent astrocyte swelling and cerebral edema in hyperammonemic states.
- MSO is a well-known and potent inhibitor of glutamine synthetase that possesses inhibitory effects that may persist in the brain for a long as seven days. Lamar at page 638. However, there have been no published dose response studies of L-Methionine S-Sulfoximine's effect on glutamine synthetase in primates.
- Circ Res 71 :1220-1230, 1992 causes inhibition of glutamine synthesis, causes reduced ammonia induced astrocyte swelling in the rat (See Willard-Mack reference), causes inhibition of glutamine synthesis, attenuates increased extracellular potassium activity during acute hyperammonemia (See Sugimoto H, Koehler RC, Wilson DA, Brusilow, Traystman RJ. Methionine Sulfoximine, a Glutamine Synthetase Inhibitor, Attenuates Increased Extracellular Potassium Activity during Acute Hyperammonemia.
- the mean rat brain glutamine level (an indirect measure of GS activity) decreased to the same degree at MSO doses (mg/kg) of 200, 100, and 50; however the rats receiving the two lower doses "did not differ in any way from the control animals" whereas the animals receiving the highest dose had seizures (see Folbergrova, "Free Glutamine Level in the Rat Brain In Vivo After Methionine Sulphoximine Administration," Physiologia Bohemoslovenica 13:21-26 (1963)).
- MSO doses mimethyl-N
- the Sellinger reference also demonstrated that L-methionine protected rats from the convulsant effect of MSO, but did not affect MSO's inhibition of GS. Additionally, Sellinger disclosed the effect of MSO when administered intraventricularly.
- the clinical effect of mixed isomers of MSO has been evaluated in two primate studies. Monkeys were found to tolerate doses of mixed MSO isomers in the range of 50 and 100 mg/kg "without observable effect"; GS activity, though, was not measured (see Krakoff). Also, when mixed isomers of MSO were given in daily doses to terminally ill cancer patients, significant side effects such as agitation, disorientation and hallucinations were noted after two days (see Krakoff).
- Cerebral edema in hyperammonemia is a consequence of hyperammonemia induced intracellular glutamine synthesis.
- Glutamine serves as an osmolyte, causing water to enter the cell and cause brain swelling (cerebral edema).
- MSO metal-oxide-semiconductor
- glutamine does not accumulate during hyperammonemia.
- glutamine cannot serve as * an intracellular organic osmolyte, thereby preventing cerebral edema.
- MSO is its known property as a convulsant. In sufficient quantities, this compound has been proven to cause convulsions in human beings, as well as other animals.
- LSMSO may be administered in limited amounts while still retaining the ability to prevent and reduce brain swelling.
- the result of these limited doses are reduced swelling and the lack of the convulsant side effect.
- the presently claimed dosage of the active LS isomer of MSO yields the requisite inhibition of glutamine synthetase and does not produce adverse neurologic signs, such as seizures.
- the novel dosage amounts of L-Methionine S-sulfoximine that produces this effect is the subject of this application.
- the present invention contemplates a method of treating primates, especially humans, suffering from progressive hyperammonemic encephalopathy.
- the claimed method comprises the administration of L-methionine S-sulfoximine (hereinafter "LSMSO”) in dosages of 10 mg/kg or less which is sufficient to alleviate and reduce the swelling of the brain without the convulsant side-effects produced by MSO.
- LSMSO L-methionine S-sulfoximine
- the claimed invention comprises treating subjects in the various stages of progressive hyperammonemic encephalopathy with low doses of LSMSO of no more than 10 mg/kg, preferably no more than 8 mg/kg, more preferably no more than 5 mg/kg, and most preferably no more than 2.5 mg/kg.
- LSMSO can be administered to subjects, for example, patients with symptomatic chronic low grade hyperammonemia, subjects with increasing plasma ammonium levels, and also subjects with high risk of developing hyperammonemia. It is believed that this treatment prevents any further brain glutamine accumulation and, therefore, prevents any further increase in cerebral edema.
- LSMSO may also be administered in the amounts specified herein to patients suffering from other diseases in which the inhibition of glutamine synthetase would be beneficial.
- the present invention is not intended for use in patients with far-advanced, nonresectable cancers.
- the claimed invention also results in reduced brain swelling, minimizes or prevents seizures, the inhibition of glutamine synthetase, and the minimization or prevention of neurologic symptoms.
- the LSMSO may be administered to the subject orally, intravenously, or subcutaneously.
- the IV preparation can be administered as a sterile buffered saline solution, while the oral preparation will be prepared with the standard pharmaceutically acceptable excipients through standard pharmaceutical manufacturing techniques.
- inert, pharmaceutically acceptable carriers are used.
- the pharmaceutical carrier can be either solid or liquid.
- Solid form preparations include, for example, powders, tablets, dispersible granules, capsules, and cachets.
- a solid carrier can be one or more substances which can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
- the carrier is generally a finely divided solid which is in a mixture with the finely divided active component.
- the active compound is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
- Powders and tablets preferably contain between about 5% to about 70% by weight of the active ingredient.
- Suitable carriers include, for example, magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter and the like.
- compositions can include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier, which is thus in association with it.
- a carrier which is thus in association with it.
- cachets are also included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
- Liquid pharmaceutical compositions include, for example, solutions suitable for oral or parenteral administration, or suspensions, and emulsions suitable for oral administration.
- Sterile water solutions of the active component or sterile solutions of the active component in solvents comprising water, ethanol, or propylene glycol are examples of liquid compositions suitable for parenteral administration.
- Sterile solutions can be prepared by dissolving the active component in the desired solvent system, and then passing the resulting solution through a membrane filter to sterilize it or, alternatively, by dissolving the sterile compound in a previously sterilized solvent under sterile conditions.
- Aqueous solutions for oral administration can be prepared by dissolving the active compound in water or other appropriate solvents and adding suitable flavorants, coloring agents, stabilizers, and thickening agents as desired.
- Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
- the pharmaceutical composition is in unit dosage form.
- the composition is divided into unit doses containing appropriate quantities of the active LSMSO.
- the unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, for example, packeted tablets, capsules, and powders in vials or ampules.
- the unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
- the compounds of the present invention are generally in a pharmaceutical composition so as to be administered to a subject at dosage levels of no more than 10.0 mg/kg per day, and preferably no more than 8.0 mg/kg per day, and more preferably no more than 5.0 mg/kg per day, and most preferably at no more than 2.5 mg/kg per day for a normal human adult of approximately 70 kg of body weight. For such a normal human adult, these amounts correspond to a dose of 700 mg, 560 mg, 350 mg, and 175 mg, respectively.
- the specific dosages employed, however, can be varied depending upon the requirements of the patient, and the severity of the condition being treated. The determination of optimum dosages for a particular situation is within the skill of the art.
- Figure 1 presents a species difference in the inhibitory effect of LSMSO on primates as compared to rats and a comparison of the effect of low dose intravenous L-methionine S-sulfoximine (LSMSO) on the inhibition of glutamine synthetase was studied in rat brain and Rhesus monkey brain and compared to the Hawkins (1991 ) data.
- the Hawkins data is represented with closed circles whereas the comparison tested rats are represented with "+" and open circle symbols.
- the monkey results are shown with triangles. N represents the number of animals studied.
- LSMSO low dose intravenous L-methionine S-sulfoximine
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Abstract
Description
Claims
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CA002474813A CA2474813A1 (en) | 2002-01-31 | 2003-01-29 | A novel dosage form of l-methionine s-sulfoximine |
AU2003205362A AU2003205362A2 (en) | 2002-01-31 | 2003-01-29 | A novel dosage form of L-Methionine S-Sulfoximine |
EP03704050A EP1480632A4 (en) | 2002-01-31 | 2003-01-29 | A novel dosage form of l-methionine s-sulfoximine |
JP2003563547A JP2005516976A (en) | 2002-01-31 | 2003-01-29 | Novel dosage form of L-methionine S-sulfoximine |
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US10/060,099 | 2002-01-31 | ||
US10/060,099 US6875792B2 (en) | 2002-01-31 | 2002-01-31 | Dosage form of L-Methionine S-Sulfoximine |
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WO2003063857A1 true WO2003063857A1 (en) | 2003-08-07 |
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PCT/US2003/002513 WO2003063857A1 (en) | 2002-01-31 | 2003-01-29 | A novel dosage form of l-methionine s-sulfoximine |
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US (1) | US6875792B2 (en) |
EP (1) | EP1480632A4 (en) |
JP (1) | JP2005516976A (en) |
AU (1) | AU2003205362A2 (en) |
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Cited By (1)
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WO2016201307A1 (en) * | 2015-06-12 | 2016-12-15 | The United State of America, as represented by the Secretary, Dept. of Health and Human Services | Glutamine antagonists for use in treating cerebral edema and cerebral malaria |
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GB2442881B (en) * | 2005-03-25 | 2010-08-04 | Uab Research Foundation | Methods for altering gene expression and methods of treatment utilizing same |
EP1752143A1 (en) * | 2005-08-08 | 2007-02-14 | NewThera | Novel uses for drugs targeting glutamine synthetase |
US8530515B2 (en) | 2010-08-09 | 2013-09-10 | William Brusilow | Use of methionine sulfoximine to treat acute liver failure and other diseases caused by an inflammatory cytokine response |
EP4295904A3 (en) | 2017-05-24 | 2024-02-28 | Thoeris GmbH | Use of glutamine synthetase for treating hyperammonemia |
-
2002
- 2002-01-31 US US10/060,099 patent/US6875792B2/en not_active Expired - Lifetime
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2003
- 2003-01-29 WO PCT/US2003/002513 patent/WO2003063857A1/en not_active Application Discontinuation
- 2003-01-29 AU AU2003205362A patent/AU2003205362A2/en not_active Abandoned
- 2003-01-29 EP EP03704050A patent/EP1480632A4/en not_active Withdrawn
- 2003-01-29 JP JP2003563547A patent/JP2005516976A/en active Pending
- 2003-01-29 CA CA002474813A patent/CA2474813A1/en not_active Abandoned
Non-Patent Citations (3)
Title |
---|
HARTH ET AL.: "An inhibitior of exported mycobaterium tuberculosis glutamine synthase selectively blocks the growth of pathogenic mycobacteria in axenic culture and in human monocytes: extracellular proteins as potential novel drug targets", JOURNAL OF EXP. MED., vol. 189, no. 9, 3 May 1999 (1999-05-03), pages 1425 - 1435, XP002961536 * |
See also references of EP1480632A4 * |
TAKAHASHI ET AL.: "Restoration of cerebrovascular CO2 responsivity by glutamine synthesis inhibition in hyperammonemic rats", CIRCULATION RESEARCH, vol. 71, no. 5, November 1992 (1992-11-01), pages 1220 - 1230, XP002961537 * |
Cited By (1)
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WO2016201307A1 (en) * | 2015-06-12 | 2016-12-15 | The United State of America, as represented by the Secretary, Dept. of Health and Human Services | Glutamine antagonists for use in treating cerebral edema and cerebral malaria |
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AU2003205362A2 (en) | 2003-09-02 |
US20030144357A1 (en) | 2003-07-31 |
US6875792B2 (en) | 2005-04-05 |
EP1480632A4 (en) | 2005-11-09 |
JP2005516976A (en) | 2005-06-09 |
CA2474813A1 (en) | 2003-08-07 |
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