CA2096036C - Method for stimulating intracellular synthesis of glutathione using esters of l-2-oxothiazolidine-4-carboxylate - Google Patents
Method for stimulating intracellular synthesis of glutathione using esters of l-2-oxothiazolidine-4-carboxylateInfo
- Publication number
- CA2096036C CA2096036C CA002096036A CA2096036A CA2096036C CA 2096036 C CA2096036 C CA 2096036C CA 002096036 A CA002096036 A CA 002096036A CA 2096036 A CA2096036 A CA 2096036A CA 2096036 C CA2096036 C CA 2096036C
- Authority
- CA
- Canada
- Prior art keywords
- oxothiazolidine
- carboxylate
- ester
- glutathione
- cells
- Prior art date
- Legal status (The legal status 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 status listed.)
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
A method for stimulating the intracellular synthesis of glutathione comprising the step of administering to a mammal a therapeutically effective amount of an ester of 2-oxothiazolidine-4-carboxylate is provided.
Description
2C9603~, TITLE
"METHOD FOR STIMULATING INTRACELLULAR
SYN~n~SIS OF GLUTATHIONE USING ESTERS OF
S L-2-oxoTHIAzoLIDINE-4-~RRolryLATE~
BA~KuuNv OF THE lNv~n,lON
The present invention relates to methods for increasing cellular levels of glutathione and treatments utilizing same.
It is known that the intracellular levels of glutathione can be important with ~es~e~L to cell function. For example, reduced glutathione levels are found in many ~iseAce states, e.g., immune compl. ;sed patients.
Further, it is known that glutathione provides many benefits in protecting cells against damage. For eXample, glutathione protects cells against the effects of free rA~icAls and of oxygen inte -'iAtes. Free radicals are molecules with an unpaired electron creating an unstable and highly reactive molecule. Oxygen free radicals are highly reactive with biological macromolecules such as found in cell membranes and thereby can induce cell damage.
Indeed, a number of method of treatments have been devised using the ~timulation of intracellular glutathione levels to treat a number of ~i~ea~e states.
Such ~i~e--e states include: reperfusion in~ury ~see U.S. Patent No. 5,095,02~): hepatic ~i¢e~ adult respiratory distreQs sy..d~. -; immune disorders; and latent viral infections.
Unfortunately, according to the majority of literature in the art, intracellular glutathione levels cannot be increased by merely attempting to load the cell ;~C9603~;
with glutathione. See, U.S. Patent No. 4,784,685 "there are several reports on particular biological systems indicating that glutathione itself is not transported into cells" (column 2, lines 37-39).
Some methods are known to increase cellular levels of glutathione. Glutathione i8 -_ -sed of three amino acids: glutamic acid; cysteine; and glycine. Although a-~ inistration to animals of the amino acid precursors of glutathione may produce an increase in cellular glutathione, there is a limit to the effectiveness of this p~oced~
Concentrations of glutathione are dependent on the supply of cysteine. Cysteine can be derived from dietary protein and by trans-sulfuration from methionine in the liver. Cysteine administration is not an ideal method for increasing intracellular glutathione concel.t~ations.
Cysteine is rapidly metabolized and is very toxic (see U.S. Patent No. 4,434,158 "cysteine cannot be administered ifit~avenously due to its toxic effects on the system" (column 2, lines 6-8)).
A couple of ~ are known for increasing glutathione levels in the cells. For example, it is known to administer N-acetyl-L-cysteine, L-2-oxothja701idine-4-carboxylate, and glutathione esters.
Examples of patents relating to L-2-oxothiazolidine-4-carboxylate and glutathione esters are as follows:
4,335,210; 4,434,158; 4,438,124; 4,647,751; 4,665,082;
4,710,489: and 4,784,685.
L-2-oxothiazolidine-4-carboxylate is transported into most cells where it is converted by the action of 5-oxo-L-prolinase in the presence of adenosine triphosrhAte to produce S-carboxyl cysteine. S-carboxyl cysteine is then decarhoxylated to produce cysteine.
2C9603~, Cysteine is then rapidly used for glutathione synthesis.
There may be at least certain advantages achieved by L-2-oxothiazolidine-4-carboxylate over N-acetyl-L-cysteine and/or glutathione esters. These potential advantages the inventor believes include, inter ~ , the fact that L-2-oxothiazolidine-4-carboxylate is more rapid and has better bioavailability as a precursor of cysteine; in certain circumstances, it is preferable to supply adequate cysteine to restore or maintain cellular functions including glutathione synthesis.
However, there are some cells and body tissues wherein it is difficult to transport L-2-oxothiazolidine-4-carboxylate into the cells. Such cells may include at least select brain cells, spinal cord cells, peripheral cells in the nervous system, skin, and the cornea. Some such cells may lack a -~hAni~ for transporting L-2-oxothiazolidine-4-carboxylate into the cells. Even in cells having the ability to transport L-2-oxothiazolidine-4-carboxylate into the cells, the transport may be rate limiting as to the production of glutathione. Therefore, it may be desirable to bypass the transport. Still further, in some S~ LeS~ such as the cornea or skin, cornified protective surfaces may ~r~ent the transport of L-2-oxothiazolidine-4-carboxylate into the cells.
Although L-2-oxothiazolidine-4-carboxylateprovides a mechanism for increasing intracellular glutathione levels in most cells, there are some cells and tissues wherein this mechanism cannot be used or one may want to avoid the ~ '~ni~ .
SUMMA~Y OF THE lNv~n,lON
The present invention provides a method for stimulating the intracellular synthesis of glutathione 2~9~ 3~i comprising the step of ~ i~i~tering to a mammal a therapeutically effective amount of an ester of 2-oxothiazolidine-4-carboxylate. Preferably, the ester includes one to ten carbon atoms. In an embodiment, the ester is chosen from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tertiary butyl esters.
Additionally, pursuant to the present invention, a method is provided for stimulating the intracellular synthesis of glutathione in cells not readily penetratable by L-2-oxothiazolidine-4-carboxylate comprisinq the step of a~ ;nistering to a patient a therapeutically effective amount of an ester of 2-oxothiazolidine-4-carboxylate in an amount sufficient to stimulate the intracellular synthesis of cells that are not readily pen-~Latable by L-2-oxothiazolidine-4-carboxylate.
In an ~. D'; -~t, the ester is ~ ;n;stered to stimulate the intracellular synthesis of glutathione in cells chosen from the group consisting of the brain, skin, spinal cord, peripheral nervous system, skin, or cornea cells of a patient.
Still further, the present invention provides a topical c 3U ' for stimulating intracellular glutathione synthesis. The c _ ~ comprises an active ingredient consisting of an oil of 2-oxothiazolidine-4-carboxylate that is an oil at room temperature.
An advantage of the present invention is to provide a method for stimulating the intracellular synthesis of glutathione utilizing an ester of 2-oxothiazolidine-4-carboxylate.
A further advantage of the present invention is to provide a composition that can be used to stimulate the 2C~036 intracellular synthesis of glutathione in cells that are not readily penetratable by L-2-oxothiazolidine-4-carboxylate.
Additionally, an advantage of the present invention is to provide a composition that can be used to stimulate intracellular synthesis of glutathione in cells of t;esues that include cornified protective surfaces.
Furthermore, an advantage of the present invention is to provide a method for creating esters of 2-oxothiazolidine-4-carboxylate.
Further, an advantage of the composition of the present invention is that it can supply adequate cysteine to restore or maintain cellular functions including glutathione synthesis.
Still further, an advantage of the present invention is that it provides a composition that is an oil at room temperature and therefore can be used advantAgeo~ely in certain products, such as topical creams, ointments, and lotions.
Moreover, an advantage of the present invention is to provide a composition that can be used on tiesues that are sensitive to irritants.
Additional features and advantages of the present invention are described in, and will be apparent from, the detailed description of the presently preferred g DFT~TT.Kn D~-CcPTPTIoN
OF T~--K pkl~:xl!,n, I.Y ~k~ K~tltr:l~ DIME~ E
The ~e3en~ invention provides a method for increasing the intracellular synthesis of glutathione.
Pursuant to the method of the present invention, a therapeutically effective amount of an ester of 2-oxothiazolidine-4-carboxylate is administered to a 2~036 patient. It has been found that the ester can be utilized to increase the intracellular synthesis of qlutathione even in those cells that are not readily penetratable by L-2-oxothiazolidine-4-carboxylate.
In this regard, the inventor has found that the ester enh~nces lipophillicity of L-2-oxothiazolidine-4-carboxylate. Because the lipid solubility of L-2-oxothiazolidine-4-carboxylate is ~nh~nce~ in the ester, the ester will penetrate cells into which L-2-oxothiazolidine-4-carboxylate is not readilytransported.
Such cells include, the inventor believes, at least certain of the cells of the brain, spinal cord, and peripheral nervous system tissue, as well as skin and cornea. By utilizing the composition of the present invention, a method can be provided for stimulating the intracellular synthesis of glutathione in these cells.
Additionally, due to the lipophillicity of the ester, the ester can be used for topical applications through a body's r ,~iphiliC surfaces. Furthermore, the ester reduces the acidity of L-2-oxothiazolidine-4-carboxylate. Thus, in topical applications, the ester is specifically useful with Les~e~L to tissues that are at particular risk of irritability, for example, the ti~sueY and organs of the eye.
The ester is a saturated straight or branched, alkyl group of 1 to 10 carbon atoms. Preferably, the ester is chosen from a saturated straight alkyl group such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl and a saturated branched alkyl group such as isopropyl, isobutyl, sec-butyl, tert-butyl, or isopenyl.
Although methyl, ethyl, propyl, isopropyl, butyl, and isobutyl are especially useful for medical 2C9~
applications, at this time, ethyl is most preferred. The ethyl ester appears to be the most biologically compatible.
Generally, the ester is prepared by reacting L-2-oxothiazolidine-4-carboxylate with an alcohol (ROH
wherein R is an alkyl of 1 to 10 carbon atoms) in an acid catalyzed reaction, e.g., using hydrochloric, sulfuric, or phosphoric acid. The resulting c- aund can then be readily purified by crystallization. Preferably, ethanol is used to create the ethyl ester. ~owever, other alcohols can be used as set forth above including methanol, propanol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, and tertiary butyl alcohol. Of course, other methods can be used which lead to the pure ester.
The ester can be used to create compositions that can be a~ inistered enterally, parenterally, or topically.
An example of an enteral solution is as follows: 5 enteral administration L-2-oxothiazolidine-4-carboxylate can be solubilized in any of the common triglyceride oils ~ ly used in enteral nutrition products such as soybean oil, canola oil, corn oil, or palm oil. For example, the L-2-oxothiazolidine-4-carboxylate ethyl ester is solubilized at a concentration of approximately 1 to about 8% in corn oil. The oil cont~ining the active ~ ~~ ' is then processed with other nutritional ingredients to form an emulsion that is compatible with oral intake and rapid gastrointestinal absorption.
An example of a parenteral solution is as follows:
For parenteral administration, L-2-oxothiazolidine-4-carboxylate ethyl ester can be prepared in a lipid emulsion that is compatible with intravenous administration. The L-2-oxothiazolidine-4-carboxylate 2C9603~i ethyl ester is dissolved in a biologically compatible triglyceride such as soybean oil at a concentration of from approximately 1% (w/w) to about 10% (w/w). A
sterile lipid emulsion is prepared by using a biologically compatible surfactant such as egg phospholipids and an agent such as glycerol to maintain osmotic balance when infused intravenously. The triglyceride - ,_nent of the emulsion containing the active - ,.und can be prepared from approximately 10%
(w/w) to about 30% (w/w) of the emulsion to further vary the dosage of active agent.
For ophthalmic application of L-2-oxothiazolidine-4-carboxylate ethyl ester in a formulation designed for prolonged contact and slow release of the active agent, an ointment is prepared. The L-2-oxothiazolidine-4-carboxylate can be included in any non-irritant oil or lipid such as mineral oil or lanolin. In an ~ nt, in the ophthalmic ointment, L-2-oxothiazolidine-4-carboxylate ethyl ester is solubilized at a concentration of approximately 2% (w/w) to about 4% (w/w) in a mixture of white petrolatum and anhydrous lanolin. This mixture is optimized for ease of applications and slow release of the active agent for overnight use. An appropriate amount of an oil soluble anti-microbial agent such as chlorobutanol is added to preserve sterility of the ointment.
An example of a topical ointment is as follows:
For topical applications of L-2-oxothiazolidine-4-carboxylate ethyl ester an ointment designed for rapid release of the active agent is prepared. This topical ointment is prepared to contain approximately 2% (w/w) to about 6% (w/w) of L-2-oxothiazolidine-4-carboxylate ethyl ester in a gelled mineral oil base. To prepare an ointment with convenient properties for application and retention on the skin, approximately 2 to about S% (w/w) of low-density polyethylene is mixed with the oil containing the active agent and the mixture is heated and shock cooled to produce a colorless ointment with properties for convenient and effective applications on dermal surfaces with a broad range of surface and absorption characteristics.
By way of example, and not limitation, examples of the synthesis of the ester of the present invention will now be given:
~AMPLE 1 Ten (10) grams of finely divided L-2-oxothiazolidine-4-carboxylic acid (OTC) were s-~spended in 150 ml of absolute ethanol without external cooling.
A stream of dry hyd~ogen chloride gas was passed rapidly through this su~p~ncion until the OTC had gone into solution. The hot reaction mixture was then cooled in an ice bath while continl~ing the introduction of hyd.og~n chloride at a reduced rate to maintain saturation at 0-5~C. After one hour, the reaction vessel was removed from the ice bath and closed with a calcium chloride drying tube to protect the reaction from at ~ ?ric moisture.
After st~n~ing 3 to 4 hours at room temperature, a clear oil was formed in the reaction vessel. The reaction pLOdU~- was held overnight in the cold, then the supernatant was L~ -.ed and the product was washed twice with cold absolute ethanol and twice with ether.
The resultant product was dried i~ vacuo over sodium hydroxide pellets. The product remained a clear oil at 2C961D~;
room temperature. However, if held in the cold, a quasi-crystalline mass was formed.
The quasi-crystalline material formed a clear slightly colored oil when returned to room temperature after stAn~ing in the cold for several days. Elemental analysis of the oil was consistent with that of the ethyl ester of L-2-oxothiazolidine-4-carboxylic acid.
A mixture of 50 grams of L-2-oxothiazolidine-4-carboxylic acid (OTC) and 63 grams (39 ml) of twiceredistilled thionyl chloride was placed in a 1000 ml round bottom flask with 250 ml of n p~o~yl alcohol. The flask was fitted with a reflux condenser that was fitted with a calcium chloride guard tube. The flask was heated in a water bath for approximately one hour, until the evolution of HCl and sulfur dioxide ceased.
The reaction mixture was allowed to return to room temperature and 500 ml of ethyl ester was added. On stAn~;ng in the cold overnight, a clear colorless oil was formed. The supernatant was poured off and the oil was che~ twice with cold ethyl ether. The product was dried in vacuo over sodium chloride pellets.
After stAn~ing several days in the cold, a solid glass-like material formed which became a clear slightly colored oil at room temperature. Elemental analysis of the oil was consistent with that of the n-propyl ester of L-2-oxothiazolidine-4-carboxylic acid.
~A~pL~ 3 The esters of L-2-oxothiazolidine-4-carboxylate were also prepared by synthesis of esters of cysteine by refluxing the amino acid in HCl saturated solution of the parent alcohol such as methanol, ethanol, or n-propanol.
ZC9~;0;~i The ester hyd,ocl.loride of cysteine was then dissolved in an appropriate solvent and the L-2-oxothiazolidine-4-carboxylate ester was prepared as by the method of Kaneko et al, Bull, Chem. Soc. (Japan), Vol. 37, pp. 242-244 (1964) as modified by Shah et al, Cancer Research, Vol. 39, pp. 3942-3947 (1979).
By way of example, and not limitation, contemplative examples of methods of treatments pursuant to the present invention will now be given:
~XAMP~ lA
A patient presented to the hospital emergency clinic with bilateral pain, swelling, lacrimation, and itching of the eyes. Xeratitis of unknown etiology was diagnosed .
Since steroids are contraindicted in viral keratitis an ophthalmic ointment contain;ng 2% ~-2-oxothiazolidine-4-carboxylate ethyl ester was applied and a prescription was written with instructions to apply the ointment before retiring at night. An appointment was made with an ophthalmologist for 10 days later for a more complete diagnostic workup.
At the clinic visit, the patient reported that the pain, swelling, and itching was greatly Ai inich~
although excessive tearing still oc~u--ed. A ~iagnosi~
of herpes simplex keratitis was made and appropriate oral anti-viral therapy was initiated.
~A~PL~ 2A
Conjunctivitis in one eye developed in a group of children ages 4-6 who attended a day camp together.
Symptoms included foreign body sensation in the eye, lacrimation and swelling. On examination a focal erythema of the con~unctiva was noted.
2C96(:~3~i An ophthalmic solution of 2% L-2-oxothiazolidine-4-carboxylate ethyl ester was prescribed for application every four hours and an ophthalmic ointment con~Aining 2% L-2-oxothiazolidine-4-carboxylate ethyl ester was prescribed for application before retiring at night.
When e--- ine~ seven days later, the symptoms in all the children had diminished or disappeared and the ophthalmic ointment was continued until all symptoms had cleared.
An adenoviral infection was suspected but not confirmed.
~XANP~ 3A
At a preseAcon wrestling training camp in an ~n~euAlly hot August in addition to the usual abrasions and rashes experienced by wrestlers, an outbreak of cutAn~ouC herpes was noted. Eighteen of twenty-five athletes were noted to have erythematous vesicular lesions.
Because of concern for the consequences of steroid usage among athletes, the usual topical steroidal anti-inflammatory agents were not used. An ointment contAin;ng 5% L-2-oxothiazolidine-4-carboxylate ethyl ester was employed and a rapid clearing of the most serious lesions was noted. With increased vigilance for personal hygiene and mat cleaning, wrestling practice was continued with no further lesions noted. Anti-viral (acyclovir) was not required.
It should be understood that various chAr~as and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such chAnges and modifications can be made without departing from the spirit and scope of the ple8ent invention and without ~i ini~eh i ng its attendant advantages. It i5 therefore intended that such chAnges and modifications be covered by the Arps-de~ claims.
"METHOD FOR STIMULATING INTRACELLULAR
SYN~n~SIS OF GLUTATHIONE USING ESTERS OF
S L-2-oxoTHIAzoLIDINE-4-~RRolryLATE~
BA~KuuNv OF THE lNv~n,lON
The present invention relates to methods for increasing cellular levels of glutathione and treatments utilizing same.
It is known that the intracellular levels of glutathione can be important with ~es~e~L to cell function. For example, reduced glutathione levels are found in many ~iseAce states, e.g., immune compl. ;sed patients.
Further, it is known that glutathione provides many benefits in protecting cells against damage. For eXample, glutathione protects cells against the effects of free rA~icAls and of oxygen inte -'iAtes. Free radicals are molecules with an unpaired electron creating an unstable and highly reactive molecule. Oxygen free radicals are highly reactive with biological macromolecules such as found in cell membranes and thereby can induce cell damage.
Indeed, a number of method of treatments have been devised using the ~timulation of intracellular glutathione levels to treat a number of ~i~ea~e states.
Such ~i~e--e states include: reperfusion in~ury ~see U.S. Patent No. 5,095,02~): hepatic ~i¢e~ adult respiratory distreQs sy..d~. -; immune disorders; and latent viral infections.
Unfortunately, according to the majority of literature in the art, intracellular glutathione levels cannot be increased by merely attempting to load the cell ;~C9603~;
with glutathione. See, U.S. Patent No. 4,784,685 "there are several reports on particular biological systems indicating that glutathione itself is not transported into cells" (column 2, lines 37-39).
Some methods are known to increase cellular levels of glutathione. Glutathione i8 -_ -sed of three amino acids: glutamic acid; cysteine; and glycine. Although a-~ inistration to animals of the amino acid precursors of glutathione may produce an increase in cellular glutathione, there is a limit to the effectiveness of this p~oced~
Concentrations of glutathione are dependent on the supply of cysteine. Cysteine can be derived from dietary protein and by trans-sulfuration from methionine in the liver. Cysteine administration is not an ideal method for increasing intracellular glutathione concel.t~ations.
Cysteine is rapidly metabolized and is very toxic (see U.S. Patent No. 4,434,158 "cysteine cannot be administered ifit~avenously due to its toxic effects on the system" (column 2, lines 6-8)).
A couple of ~ are known for increasing glutathione levels in the cells. For example, it is known to administer N-acetyl-L-cysteine, L-2-oxothja701idine-4-carboxylate, and glutathione esters.
Examples of patents relating to L-2-oxothiazolidine-4-carboxylate and glutathione esters are as follows:
4,335,210; 4,434,158; 4,438,124; 4,647,751; 4,665,082;
4,710,489: and 4,784,685.
L-2-oxothiazolidine-4-carboxylate is transported into most cells where it is converted by the action of 5-oxo-L-prolinase in the presence of adenosine triphosrhAte to produce S-carboxyl cysteine. S-carboxyl cysteine is then decarhoxylated to produce cysteine.
2C9603~, Cysteine is then rapidly used for glutathione synthesis.
There may be at least certain advantages achieved by L-2-oxothiazolidine-4-carboxylate over N-acetyl-L-cysteine and/or glutathione esters. These potential advantages the inventor believes include, inter ~ , the fact that L-2-oxothiazolidine-4-carboxylate is more rapid and has better bioavailability as a precursor of cysteine; in certain circumstances, it is preferable to supply adequate cysteine to restore or maintain cellular functions including glutathione synthesis.
However, there are some cells and body tissues wherein it is difficult to transport L-2-oxothiazolidine-4-carboxylate into the cells. Such cells may include at least select brain cells, spinal cord cells, peripheral cells in the nervous system, skin, and the cornea. Some such cells may lack a -~hAni~ for transporting L-2-oxothiazolidine-4-carboxylate into the cells. Even in cells having the ability to transport L-2-oxothiazolidine-4-carboxylate into the cells, the transport may be rate limiting as to the production of glutathione. Therefore, it may be desirable to bypass the transport. Still further, in some S~ LeS~ such as the cornea or skin, cornified protective surfaces may ~r~ent the transport of L-2-oxothiazolidine-4-carboxylate into the cells.
Although L-2-oxothiazolidine-4-carboxylateprovides a mechanism for increasing intracellular glutathione levels in most cells, there are some cells and tissues wherein this mechanism cannot be used or one may want to avoid the ~ '~ni~ .
SUMMA~Y OF THE lNv~n,lON
The present invention provides a method for stimulating the intracellular synthesis of glutathione 2~9~ 3~i comprising the step of ~ i~i~tering to a mammal a therapeutically effective amount of an ester of 2-oxothiazolidine-4-carboxylate. Preferably, the ester includes one to ten carbon atoms. In an embodiment, the ester is chosen from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tertiary butyl esters.
Additionally, pursuant to the present invention, a method is provided for stimulating the intracellular synthesis of glutathione in cells not readily penetratable by L-2-oxothiazolidine-4-carboxylate comprisinq the step of a~ ;nistering to a patient a therapeutically effective amount of an ester of 2-oxothiazolidine-4-carboxylate in an amount sufficient to stimulate the intracellular synthesis of cells that are not readily pen-~Latable by L-2-oxothiazolidine-4-carboxylate.
In an ~. D'; -~t, the ester is ~ ;n;stered to stimulate the intracellular synthesis of glutathione in cells chosen from the group consisting of the brain, skin, spinal cord, peripheral nervous system, skin, or cornea cells of a patient.
Still further, the present invention provides a topical c 3U ' for stimulating intracellular glutathione synthesis. The c _ ~ comprises an active ingredient consisting of an oil of 2-oxothiazolidine-4-carboxylate that is an oil at room temperature.
An advantage of the present invention is to provide a method for stimulating the intracellular synthesis of glutathione utilizing an ester of 2-oxothiazolidine-4-carboxylate.
A further advantage of the present invention is to provide a composition that can be used to stimulate the 2C~036 intracellular synthesis of glutathione in cells that are not readily penetratable by L-2-oxothiazolidine-4-carboxylate.
Additionally, an advantage of the present invention is to provide a composition that can be used to stimulate intracellular synthesis of glutathione in cells of t;esues that include cornified protective surfaces.
Furthermore, an advantage of the present invention is to provide a method for creating esters of 2-oxothiazolidine-4-carboxylate.
Further, an advantage of the composition of the present invention is that it can supply adequate cysteine to restore or maintain cellular functions including glutathione synthesis.
Still further, an advantage of the present invention is that it provides a composition that is an oil at room temperature and therefore can be used advantAgeo~ely in certain products, such as topical creams, ointments, and lotions.
Moreover, an advantage of the present invention is to provide a composition that can be used on tiesues that are sensitive to irritants.
Additional features and advantages of the present invention are described in, and will be apparent from, the detailed description of the presently preferred g DFT~TT.Kn D~-CcPTPTIoN
OF T~--K pkl~:xl!,n, I.Y ~k~ K~tltr:l~ DIME~ E
The ~e3en~ invention provides a method for increasing the intracellular synthesis of glutathione.
Pursuant to the method of the present invention, a therapeutically effective amount of an ester of 2-oxothiazolidine-4-carboxylate is administered to a 2~036 patient. It has been found that the ester can be utilized to increase the intracellular synthesis of qlutathione even in those cells that are not readily penetratable by L-2-oxothiazolidine-4-carboxylate.
In this regard, the inventor has found that the ester enh~nces lipophillicity of L-2-oxothiazolidine-4-carboxylate. Because the lipid solubility of L-2-oxothiazolidine-4-carboxylate is ~nh~nce~ in the ester, the ester will penetrate cells into which L-2-oxothiazolidine-4-carboxylate is not readilytransported.
Such cells include, the inventor believes, at least certain of the cells of the brain, spinal cord, and peripheral nervous system tissue, as well as skin and cornea. By utilizing the composition of the present invention, a method can be provided for stimulating the intracellular synthesis of glutathione in these cells.
Additionally, due to the lipophillicity of the ester, the ester can be used for topical applications through a body's r ,~iphiliC surfaces. Furthermore, the ester reduces the acidity of L-2-oxothiazolidine-4-carboxylate. Thus, in topical applications, the ester is specifically useful with Les~e~L to tissues that are at particular risk of irritability, for example, the ti~sueY and organs of the eye.
The ester is a saturated straight or branched, alkyl group of 1 to 10 carbon atoms. Preferably, the ester is chosen from a saturated straight alkyl group such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl and a saturated branched alkyl group such as isopropyl, isobutyl, sec-butyl, tert-butyl, or isopenyl.
Although methyl, ethyl, propyl, isopropyl, butyl, and isobutyl are especially useful for medical 2C9~
applications, at this time, ethyl is most preferred. The ethyl ester appears to be the most biologically compatible.
Generally, the ester is prepared by reacting L-2-oxothiazolidine-4-carboxylate with an alcohol (ROH
wherein R is an alkyl of 1 to 10 carbon atoms) in an acid catalyzed reaction, e.g., using hydrochloric, sulfuric, or phosphoric acid. The resulting c- aund can then be readily purified by crystallization. Preferably, ethanol is used to create the ethyl ester. ~owever, other alcohols can be used as set forth above including methanol, propanol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, and tertiary butyl alcohol. Of course, other methods can be used which lead to the pure ester.
The ester can be used to create compositions that can be a~ inistered enterally, parenterally, or topically.
An example of an enteral solution is as follows: 5 enteral administration L-2-oxothiazolidine-4-carboxylate can be solubilized in any of the common triglyceride oils ~ ly used in enteral nutrition products such as soybean oil, canola oil, corn oil, or palm oil. For example, the L-2-oxothiazolidine-4-carboxylate ethyl ester is solubilized at a concentration of approximately 1 to about 8% in corn oil. The oil cont~ining the active ~ ~~ ' is then processed with other nutritional ingredients to form an emulsion that is compatible with oral intake and rapid gastrointestinal absorption.
An example of a parenteral solution is as follows:
For parenteral administration, L-2-oxothiazolidine-4-carboxylate ethyl ester can be prepared in a lipid emulsion that is compatible with intravenous administration. The L-2-oxothiazolidine-4-carboxylate 2C9603~i ethyl ester is dissolved in a biologically compatible triglyceride such as soybean oil at a concentration of from approximately 1% (w/w) to about 10% (w/w). A
sterile lipid emulsion is prepared by using a biologically compatible surfactant such as egg phospholipids and an agent such as glycerol to maintain osmotic balance when infused intravenously. The triglyceride - ,_nent of the emulsion containing the active - ,.und can be prepared from approximately 10%
(w/w) to about 30% (w/w) of the emulsion to further vary the dosage of active agent.
For ophthalmic application of L-2-oxothiazolidine-4-carboxylate ethyl ester in a formulation designed for prolonged contact and slow release of the active agent, an ointment is prepared. The L-2-oxothiazolidine-4-carboxylate can be included in any non-irritant oil or lipid such as mineral oil or lanolin. In an ~ nt, in the ophthalmic ointment, L-2-oxothiazolidine-4-carboxylate ethyl ester is solubilized at a concentration of approximately 2% (w/w) to about 4% (w/w) in a mixture of white petrolatum and anhydrous lanolin. This mixture is optimized for ease of applications and slow release of the active agent for overnight use. An appropriate amount of an oil soluble anti-microbial agent such as chlorobutanol is added to preserve sterility of the ointment.
An example of a topical ointment is as follows:
For topical applications of L-2-oxothiazolidine-4-carboxylate ethyl ester an ointment designed for rapid release of the active agent is prepared. This topical ointment is prepared to contain approximately 2% (w/w) to about 6% (w/w) of L-2-oxothiazolidine-4-carboxylate ethyl ester in a gelled mineral oil base. To prepare an ointment with convenient properties for application and retention on the skin, approximately 2 to about S% (w/w) of low-density polyethylene is mixed with the oil containing the active agent and the mixture is heated and shock cooled to produce a colorless ointment with properties for convenient and effective applications on dermal surfaces with a broad range of surface and absorption characteristics.
By way of example, and not limitation, examples of the synthesis of the ester of the present invention will now be given:
~AMPLE 1 Ten (10) grams of finely divided L-2-oxothiazolidine-4-carboxylic acid (OTC) were s-~spended in 150 ml of absolute ethanol without external cooling.
A stream of dry hyd~ogen chloride gas was passed rapidly through this su~p~ncion until the OTC had gone into solution. The hot reaction mixture was then cooled in an ice bath while continl~ing the introduction of hyd.og~n chloride at a reduced rate to maintain saturation at 0-5~C. After one hour, the reaction vessel was removed from the ice bath and closed with a calcium chloride drying tube to protect the reaction from at ~ ?ric moisture.
After st~n~ing 3 to 4 hours at room temperature, a clear oil was formed in the reaction vessel. The reaction pLOdU~- was held overnight in the cold, then the supernatant was L~ -.ed and the product was washed twice with cold absolute ethanol and twice with ether.
The resultant product was dried i~ vacuo over sodium hydroxide pellets. The product remained a clear oil at 2C961D~;
room temperature. However, if held in the cold, a quasi-crystalline mass was formed.
The quasi-crystalline material formed a clear slightly colored oil when returned to room temperature after stAn~ing in the cold for several days. Elemental analysis of the oil was consistent with that of the ethyl ester of L-2-oxothiazolidine-4-carboxylic acid.
A mixture of 50 grams of L-2-oxothiazolidine-4-carboxylic acid (OTC) and 63 grams (39 ml) of twiceredistilled thionyl chloride was placed in a 1000 ml round bottom flask with 250 ml of n p~o~yl alcohol. The flask was fitted with a reflux condenser that was fitted with a calcium chloride guard tube. The flask was heated in a water bath for approximately one hour, until the evolution of HCl and sulfur dioxide ceased.
The reaction mixture was allowed to return to room temperature and 500 ml of ethyl ester was added. On stAn~;ng in the cold overnight, a clear colorless oil was formed. The supernatant was poured off and the oil was che~ twice with cold ethyl ether. The product was dried in vacuo over sodium chloride pellets.
After stAn~ing several days in the cold, a solid glass-like material formed which became a clear slightly colored oil at room temperature. Elemental analysis of the oil was consistent with that of the n-propyl ester of L-2-oxothiazolidine-4-carboxylic acid.
~A~pL~ 3 The esters of L-2-oxothiazolidine-4-carboxylate were also prepared by synthesis of esters of cysteine by refluxing the amino acid in HCl saturated solution of the parent alcohol such as methanol, ethanol, or n-propanol.
ZC9~;0;~i The ester hyd,ocl.loride of cysteine was then dissolved in an appropriate solvent and the L-2-oxothiazolidine-4-carboxylate ester was prepared as by the method of Kaneko et al, Bull, Chem. Soc. (Japan), Vol. 37, pp. 242-244 (1964) as modified by Shah et al, Cancer Research, Vol. 39, pp. 3942-3947 (1979).
By way of example, and not limitation, contemplative examples of methods of treatments pursuant to the present invention will now be given:
~XAMP~ lA
A patient presented to the hospital emergency clinic with bilateral pain, swelling, lacrimation, and itching of the eyes. Xeratitis of unknown etiology was diagnosed .
Since steroids are contraindicted in viral keratitis an ophthalmic ointment contain;ng 2% ~-2-oxothiazolidine-4-carboxylate ethyl ester was applied and a prescription was written with instructions to apply the ointment before retiring at night. An appointment was made with an ophthalmologist for 10 days later for a more complete diagnostic workup.
At the clinic visit, the patient reported that the pain, swelling, and itching was greatly Ai inich~
although excessive tearing still oc~u--ed. A ~iagnosi~
of herpes simplex keratitis was made and appropriate oral anti-viral therapy was initiated.
~A~PL~ 2A
Conjunctivitis in one eye developed in a group of children ages 4-6 who attended a day camp together.
Symptoms included foreign body sensation in the eye, lacrimation and swelling. On examination a focal erythema of the con~unctiva was noted.
2C96(:~3~i An ophthalmic solution of 2% L-2-oxothiazolidine-4-carboxylate ethyl ester was prescribed for application every four hours and an ophthalmic ointment con~Aining 2% L-2-oxothiazolidine-4-carboxylate ethyl ester was prescribed for application before retiring at night.
When e--- ine~ seven days later, the symptoms in all the children had diminished or disappeared and the ophthalmic ointment was continued until all symptoms had cleared.
An adenoviral infection was suspected but not confirmed.
~XANP~ 3A
At a preseAcon wrestling training camp in an ~n~euAlly hot August in addition to the usual abrasions and rashes experienced by wrestlers, an outbreak of cutAn~ouC herpes was noted. Eighteen of twenty-five athletes were noted to have erythematous vesicular lesions.
Because of concern for the consequences of steroid usage among athletes, the usual topical steroidal anti-inflammatory agents were not used. An ointment contAin;ng 5% L-2-oxothiazolidine-4-carboxylate ethyl ester was employed and a rapid clearing of the most serious lesions was noted. With increased vigilance for personal hygiene and mat cleaning, wrestling practice was continued with no further lesions noted. Anti-viral (acyclovir) was not required.
It should be understood that various chAr~as and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such chAnges and modifications can be made without departing from the spirit and scope of the ple8ent invention and without ~i ini~eh i ng its attendant advantages. It i5 therefore intended that such chAnges and modifications be covered by the Arps-de~ claims.
Claims (20)
1. The use of an administrable therapeutically effective amount of an ester of 2-oxothiazolidine-4-carboxylate for stimulating the intracellular synthesis of glutathione.
2. The use of Claim 1 wherein the ester is chosen from the group consisting of alkyls including 1 to 10 carbon atoms.
3. The use of Claim 1 wherein said use is parenteral.
4. The use of Claim 1 wherein said use is enteral.
5. The use of Claim 1 wherein said use is topical.
6. The use of Claim 1 wherein the ester is ethyl.
7. The use of an administrable therapeutically effective amount of an ester of 2-oxothiazolidine-4-carboxylate for stimulating the intracellular synthesis of glutathione in cells not readily penetratable by L-2-oxothiazolidine-4-carboxylate, said amount being sufficient to stimulate the intracellular synthesis of glutathione in cells that are not readily penetrated by 2-oxothiazolidine-4-carboxylate.
8. The use of Claim 7 wherein the ester of 2-oxothiazolidine-4-carboxylate is used to stimulate the intracellular synthesis of glutathione in the brain cells of the patient.
9. The use of Claim 7 wherein the ester of 2-oxothiazolidine-4-carboxylate is used to stimulate the intracellular synthesis of glutathione in at least select cells of the skin of the patient.
10. The use of Claim 7 wherein the ester of 2-oxothiazolidine-4-carboxylate is used to stimulate the intracellular synthesis of glutathione in cells located in the spinal cord of the patient.
11. The use of Claim 7 wherein the ester of 2-oxothiazolidine-4-carboxylate is used to stimulate the intracellular synthesis of glutathione in cells of the peripheral nervous system of the patient.
12. The use of Claim 7 wherein the ester of 2-oxothiazolidine-4-carboxylate is used to stimulate the intracellular synthesis of glutathione in cells of the cornea of the patient.
13. The use of Claim 7 wherein the ester is chosen from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tertiary butyl esters.
14. The use of Claim 7 wherein said use is enteral.
15. The use of Claim 7 wherein said use is parenteral.
16. The use of Claim 7 wherein said use is topical.
17. A topical ointment capable of stimulating the intracellular synthesis of glutathione in at least cells to which the ointment is applied comprising:
a therapeutically effective amount of an ester of 2-oxothiazolidine-4-carboxylate that is an oil at room temperature; and a mineral oil base.
a therapeutically effective amount of an ester of 2-oxothiazolidine-4-carboxylate that is an oil at room temperature; and a mineral oil base.
18. The topical ointment of Claim 17 wherein the ester is ethyl.
19. An ophthalmic ointment capable of stimulating the intracellular synthesis of glutathione in the cells of a patient's eye comprising:
a therapeutically effective amount of an ester of 2-oxothiazolidine-4-carboxylate that is an oil at room temperature; and a base chosen from the group consisting of non-irritant oils and lipids.
a therapeutically effective amount of an ester of 2-oxothiazolidine-4-carboxylate that is an oil at room temperature; and a base chosen from the group consisting of non-irritant oils and lipids.
20. The ophthalmic ointment of Claim 19 wherein the base includes mineral oil.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/932,761 | 1992-08-20 | ||
| US07/932,761 US5208249A (en) | 1992-08-20 | 1992-08-20 | Method for stimulating intracellular synthesis of glutathione using esters of L-2-oxothiazolidine-4-carboxylate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2096036A1 CA2096036A1 (en) | 1994-02-21 |
| CA2096036C true CA2096036C (en) | 1999-04-27 |
Family
ID=25462874
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002096036A Expired - Fee Related CA2096036C (en) | 1992-08-20 | 1993-05-12 | Method for stimulating intracellular synthesis of glutathione using esters of l-2-oxothiazolidine-4-carboxylate |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US5208249A (en) |
| EP (1) | EP0583863B1 (en) |
| JP (1) | JPH06183973A (en) |
| AU (1) | AU666931B2 (en) |
| CA (1) | CA2096036C (en) |
| DE (1) | DE69306063T2 (en) |
| ES (1) | ES2094479T3 (en) |
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| ES2092539T3 (en) * | 1991-01-10 | 1996-12-01 | Transcend Therapeutics Inc | USE OF THIAZOLIDINE-4-CARBOXYLATE DERIVATIVES FOR THE TREATMENT OF PULMONARY DISEASES. |
| US5747459A (en) * | 1991-02-04 | 1998-05-05 | Nestec, Ltd. | Method for insuring adequate intracellular glutathione in tissue |
| US5430045A (en) * | 1992-04-23 | 1995-07-04 | Free Radical Sciences, Inc. | Method of reducing or preventing bone marrow hypoplasia |
| EP0656201A1 (en) * | 1993-11-09 | 1995-06-07 | Transcend Therapeutics, Inc. | Use of stimulators of glutathione synthesis as hait growth promotors |
| US5447712A (en) * | 1993-12-09 | 1995-09-05 | Free Radical Sciences | Method of reducing cyclophosphamide induced hemorrhagic cystitis |
| US5596011A (en) * | 1995-04-06 | 1997-01-21 | Repine; Karen M. | Method for the treatment of macular degeneration |
| FR2742750B1 (en) * | 1995-12-22 | 1998-01-30 | Oreal | NOVEL DERIVATIVES OF L-2-OXOTHIAZOLIDINE 4-CARBOXYLIC ACID AND THEIR USE FOR SKIN CARE |
| FR2742658B1 (en) * | 1995-12-22 | 1998-01-30 | Oreal | USE OF PROCYSTEIN AS A DEPIGMENTING AGENT |
| FR2751331A1 (en) * | 1996-07-18 | 1998-01-23 | Oreal | NOVEL KOJIC ACID DERIVATIVE AND ITS USE AS DEPIGMENTING AGENT |
| US5780489A (en) * | 1996-08-21 | 1998-07-14 | Brooks; Benjamin Rix | Method for treating amyotrophic lateral sclerosis |
| ATE444760T1 (en) * | 1997-01-13 | 2009-10-15 | Univ Emory | GLUTATHIONE FOR THE TREATMENT OF INFLUENCE INFECTIONS |
| RU2144374C1 (en) * | 1998-11-23 | 2000-01-20 | Закрытое акционерное общество "ВАМ" | Method of preparing of oxidized glutathione-cis- diaminodichloroplatinum complex and pharmaceutical compositions based on this complex for controlling metabolism, proliferation, and differentiation, and mechanisms of apoptosis of normal and transformated cells |
| US20070142267A1 (en) * | 1998-11-23 | 2007-06-21 | Novelos Therapeutics, Inc. | Methods for production of the oxidized glutathione composite with CIS-diamminedichloroplatinum and pharmaceutical compositions based thereof regulating metabolism, proliferation, differentiation and apoptotic mechanisms for normal and transformed cells |
| EP1119352A4 (en) * | 1999-08-09 | 2004-05-26 | Webb Waring Inst For Biomedica | A method for the treatment of ocular oxidative stress |
| AU6676100A (en) * | 1999-08-17 | 2001-03-13 | University Of Saskatchewan Technologies Inc. | Improved treatment for acute physical insult to the central nervous system |
| FR2816838B1 (en) * | 2000-11-17 | 2004-12-03 | Oreal | USE OF DERIVATIVES OF 2-OXOTHIAZOLIDINE-4-CARBOXYLIC ACID AS PRODESQUAMANTS |
| US20020137779A1 (en) * | 2001-02-14 | 2002-09-26 | Advanced Biochemicals Inc. | Use of L-2-oxothiazolidine-4-carboxylic acid for the treatment of type 2 diabetes |
| CA2668311C (en) * | 2002-04-19 | 2011-08-02 | Arizona Board Of Regents, Acting On Behalf Of The University Of Arizona | Enhancing photodamage caused by ultraviolet light using a 3-hydroxypyridine analog |
| FR2854160B1 (en) * | 2003-04-25 | 2005-06-17 | Oreal | NOVEL HETEROCYCLIC DERIVATIVES OF 2-OXOTHIAZOLIDINE4-CARBOXYLIC ACID, USE AS ACTIVE PHOTOPROTECTION AGENT |
| US7022317B2 (en) | 2003-04-25 | 2006-04-04 | L'oreal | Heterocyclic derivatives of 2-oxothiazolidine-4-carboxylic acid, and use as active photoprotective agents |
| FR2877004B1 (en) * | 2004-10-21 | 2007-03-09 | Oreal | ESTERS AND SILANIC AMIDES OF 2-OXOTHIAZOLIDINE-4-CARBOXYLIC ACID AND THEIR COSMETIC USES. |
| CN100434062C (en) * | 2006-08-28 | 2008-11-19 | 卢小明 | Application of L-2-oxathiaazalane-4-carboxylic acid and ester derivative thereof in cosmeceutical product |
| US20110064828A1 (en) * | 2009-09-11 | 2011-03-17 | Novelos Therapeutics, Incorporated | Treatment of metastatic tumors and other conditions |
| US11279674B2 (en) | 2011-01-03 | 2022-03-22 | The William M. Yarbrough Foundation | Isothiocyanate functional surfactant and associated method of use |
| US9962361B2 (en) | 2011-01-03 | 2018-05-08 | The William M. Yarbrough Foundation | Isothiocyanate functional surfactants, formulations incorporating the same, and associated methods of use |
| US10273205B2 (en) | 2011-01-03 | 2019-04-30 | The William M. Yarbrough Foundation | Isothiocyanate functional surfactants, formulations incorporating isothiocyanate functional surfactants and associated methods for treating biofilms |
| US8933119B2 (en) | 2011-01-03 | 2015-01-13 | The William M. Yarbrough Foundation | Method for treating phytophotodermatitis |
| US11407713B2 (en) | 2011-01-03 | 2022-08-09 | The William M. Yarbrough Foundation | Isothiocyanate functional surfactants, formulations incorporating the same, and associated methods of use |
| US10640464B2 (en) | 2011-01-03 | 2020-05-05 | The William M. Yarbrough Foundation | Use of isothiocyanate functional surfactants as Nrf2 inducers to treat epidermolysis bullosa simplex and related diseases |
| US10647668B2 (en) | 2011-01-03 | 2020-05-12 | The William M. Yarbrough Foundation | Isothiocyanate functional surfactant and associated method of use |
| US10308599B2 (en) | 2011-01-03 | 2019-06-04 | The William M. Yarbrough Foundation | Isothiocyanate functional surfactants, formulations incorporating the same, and associated methods of use |
| US8865765B2 (en) | 2011-01-12 | 2014-10-21 | The William M. Yarbrough Foundation | Method for treating eczema |
| US9532969B2 (en) | 2011-02-08 | 2017-01-03 | The William M. Yarbrough Foundation | Method for treating psoriasis |
| US10080734B2 (en) | 2012-07-26 | 2018-09-25 | The William M. Yarbrough Foundation | Method for treating autism and other neurodevelopmental disorders |
| US10335387B2 (en) | 2012-07-26 | 2019-07-02 | The William M. Yarbrough Foundation | Method for treating infectious diseases with isothiocyanate functional compounds |
| US10441561B2 (en) | 2012-07-26 | 2019-10-15 | The William M. Yanbrough Foundation | Method for treating benign prostatic hyperplasia (BPH), prostatitis, and prostate cancer |
| US10434081B2 (en) | 2012-07-26 | 2019-10-08 | The William M. Yarbrough Foundation | Inhibitors of macrophage migration inhibitory factor |
| US9839621B2 (en) | 2012-07-26 | 2017-12-12 | The William M. Yarbrough Foundation | Method for treating bladder cancer |
| US10434082B2 (en) | 2012-07-26 | 2019-10-08 | The William M. Yarbrough Foundation | Isothiocyanate functional compounds augmented with secondary antineoplastic medicaments and associated methods for treating neoplasms |
| US9949943B2 (en) | 2012-07-26 | 2018-04-24 | The William M. Yarbrough Foundation | Method for treating neurodegenerative diseases |
| WO2014018874A1 (en) | 2012-07-26 | 2014-01-30 | The William M. Yarbrough Foundation | Method for treating skin cancer |
| ES2838693T3 (en) * | 2015-07-30 | 2021-07-02 | Merck Patent Gmbh | Method to increase the level of glutathione in cells |
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|---|---|---|---|---|
| US4434158A (en) * | 1981-02-11 | 1984-02-28 | Cornell Research Foundation | Cysteine delivery system |
| US4335210A (en) * | 1981-02-11 | 1982-06-15 | Cornell Research Foundation | Method of producing L-cysteine |
| US4647571A (en) * | 1981-02-11 | 1987-03-03 | Cornell Research Foundation | Cysteine delivery composition |
| US4665082A (en) * | 1981-02-11 | 1987-05-12 | Cornell Research Foundation | Cysteine delivery system |
| US4438124A (en) * | 1981-02-11 | 1984-03-20 | Cornell Research Foundation, Inc. | Cysteine delivery system |
| US4710489A (en) * | 1985-04-22 | 1987-12-01 | Cornell Research Foundation, Inc. | Glutathione delivery system |
| ES2068253T3 (en) * | 1988-12-09 | 1995-04-16 | Allergan Inc | USE OF THIAZOLIDIN-4-CARBOXYLLIC ACIDS SUBSTITUTED IN POSITION 2 FOR TREATMENT OF CATARACTS. |
| US5095027A (en) * | 1991-02-28 | 1992-03-10 | Clintec Nutrition Co. | Method for treating reperfusion injury employing L-2-oxothiazolidine-4-carboxylic acid |
| AU661379B2 (en) * | 1992-04-23 | 1995-07-20 | Transcend Therapeutics, Inc | Method of reducing or preventing toxicity associated with antiretroviral therapy |
| US5306724A (en) * | 1992-08-17 | 1994-04-26 | Clintec Nutrition Company | Method for preventing and treating atherosclerosis |
| AU5040493A (en) * | 1992-11-30 | 1994-06-09 | Transcend Therapeutics, Inc | Method for treating systemic inflammatory response syndrome |
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- 1993-04-23 EP EP93303213A patent/EP0583863B1/en not_active Revoked
- 1993-05-12 CA CA002096036A patent/CA2096036C/en not_active Expired - Fee Related
- 1993-08-20 JP JP5205958A patent/JPH06183973A/en active Pending
Also Published As
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|---|---|
| EP0583863B1 (en) | 1996-11-20 |
| DE69306063T2 (en) | 1997-05-22 |
| EP0583863A1 (en) | 1994-02-23 |
| US5208249A (en) | 1993-05-04 |
| CA2096036A1 (en) | 1994-02-21 |
| AU666931B2 (en) | 1996-02-29 |
| ES2094479T3 (en) | 1997-01-16 |
| JPH06183973A (en) | 1994-07-05 |
| AU3718193A (en) | 1994-02-24 |
| DE69306063D1 (en) | 1997-01-02 |
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