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US20030232835A1 - Prophylactic or therapeutic agents for diseases associated with dysfunction of NOS - Google Patents

Prophylactic or therapeutic agents for diseases associated with dysfunction of NOS Download PDF

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US20030232835A1
US20030232835A1 US10/408,571 US40857103A US2003232835A1 US 20030232835 A1 US20030232835 A1 US 20030232835A1 US 40857103 A US40857103 A US 40857103A US 2003232835 A1 US2003232835 A1 US 2003232835A1
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Prior art keywords
nos
doca
group
dysfunction
hypertension
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Takafumi Ishihara
Yoshiharu Kanayama
Mikio Okamura
Junichi Yoshikawa
Haruo Shintaku
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Suntory Ltd
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Suntory Ltd
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Publication of US20030232835A1 publication Critical patent/US20030232835A1/en
Priority to US11/209,673 priority patent/US7820667B2/en
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    • C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2

Definitions

  • the present invention relates to a pharmaceutical composition for preventing and/or treating diseases associated with dysfunction of NOS, comprising as an effective ingredient, a compound of the formula (I):
  • R 1 and R 2 each represents a hydrogen atom or, taken together with each other, represent a single bond
  • R 3 represents —CH(OH)CH(OH)CH 3 , —CH(OCOCH 3 )CH(OCOCH 3 )CH 3 , —CH 3 , —CH 2 OH, or a phenyl group when R 1 and R 2 each represents a hydrogen atom, or —COCH(OH)CH 3 when R 1 and R 2 together represent a single bond, or a pharmaceutically acceptable salt thereof.
  • NO nitrogen monoxide
  • cardiovascular diseases such as hypertension, hyperlipemia, arteriosclerosis, ischemic heart disease, heart failure, thrombosis; respiratory diseases such as asthma, chronic obstructive pulmonary diseases, pulmonary hypertension, ARDS; gastrointestinal diseases such as hepatopathy, liver cirrhosis, gastrointestinal mucosa disorder, hypertrophic pyloric stenosis, pancreatitis; cerebrovascular diseases such as cerebral ischemia, infarction, cerebrovascular failure, senile dementia; renal or urologic diseases such as renal disorder, impotence; gynecological diseases such as toxemia; infectious diseases, immunological disorders, diabetes, burns; or diseases caused by drugs which decrease NO production.
  • the gene for NOS was cloned and structurally analyzed. As a result, the gene for NOS was found to contain a binding site for (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (hereinafter referred to as “BH4”) included in compounds of the formula (I) as active ingredients of the present invention, in addition to those for coenzymes such as calmodulin (CaM), flavin, NADPH. Moreover, BH4 has been suggested to actually be involved in control of the function of NOS.
  • (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin hereinafter referred to as “BH4”
  • the decrease of vasodilative reaction in hypertension may also be caused by the decreased activity of the endothelium-derived hyperdepolarization factor (EDHF) or an increase in the amounts of the endothelium-derived circulating factor (EDCF), both of which have been unknown about their entity.
  • EDHF endothelium-derived hyperdepolarization factor
  • EDCF endothelium-derived circulating factor
  • cardiovascular diseases are one of the main causes of death.
  • Various drugs such as antihypertensives, antihyperlipemic agents, diuretics, vasodilators, antiplatelets have been used in the treatment of diseases.
  • many of them are designed to improve parameters such as blood pressure or cholesterol level, but still unsatisfactory in the prevention of occurrence, retardation of deterioration or progress and long-term prognosis of these diseases.
  • Recently, on the above-mentioned diseases by investigating at a molecular level, a therapeutic strategy directed to blood vessels especially endothelial cells has been proposed and as one of the most promising therapies, treatment with an agent which regulates the production of the entity of EDRF, i.e.
  • Nitrate agents (nitroglycerin preparations, etc.) have been considered to be effective as exogenous NO donors for treating angina, heart failure or the like among the above diseases, but they show tolerance over long-term use. Namely, thiol groups (SH groups) become depleted during long-term use of nitrate agents, because SH groups are indispensable for NO production from these nitrate agents. Moreover, the balance of other endogenous substances may be disturbed during long-term use, because NO production requires metabolic enzymes and other NO-related materials such as nitrosothiol are produced during the reaction.
  • SH groups thiol groups
  • a new type of NO donors with the properties of ⁇ -blockers or K + channel openers have also been developed, but they are still within the range of the above-mentioned NO donors. Therefore, improvement of the functions of endothelial cells through regulating endogenous NO function is proposed to be one of the most ideal therapeutic ways for the prevention of occurrence, retardation of deterioration or progress and long-term prognosis of these diseases.
  • antihypertensive therapy is to prolong the life of patients in a satisfactory condition by preventing cardiovascular complications due to hypertension.
  • blood pressure must be controlled for a long period over life span by antihypertensives in addition to the general therapies such as salt reduction, amelioration of obesity kinesitherapy etc.:
  • anthihypertensives therapeutically used at present include thiazides, ⁇ -blockers, Ca-antagonists, angiotensin converting enzyme (ACE) inhibitors and ⁇ 1 -blockers. However, none of them satisfy all the following conditions desirable for antihypertensives:
  • Thiazide-based diuretics are favorably applied when salt limitation is difficult to obey or a tendency of fluid retention is observed, but are not be recommended to patients with abnormal glucose tolerance, hyperuricemia, renal dysfunction, hyperlipemia or hypokalemia.
  • ⁇ -blockers are favorably applied for young or tachycardiac patients, but are not recommended to patients with bronchial asthma, chronic obstructive pulmonary diseases, obstructive lesions in peripheral arteries or Raynaud's symptoms. They are also inappropriate for hypertension patients with diabetes because of the influence on insulin secretion.
  • Dihydropyridine derivatives among Ca antagonists have the following side effects, i.e. their vasodilating action may produce facial flush and headache, and their strong hypotensive action may cause hypotension, vertigo and tachycardia or palpitation due to reflex hypersympathicotonus.
  • ACE inhibitors have side effects such as orthostatic hypotension, dry cough, vascular edema, hyperkalemia etc.
  • side effects such as orthostatic hypotension, dry cough, vascular edema, hyperkalemia etc.
  • attention should be paid to the dosage and hyperkalemia because they are mainly excreted from kidney. Some of them have been reported to give harmful effects on fetus, and therefore contraindicated for pregnant women.
  • ⁇ 1 -blockers should be carefully applied so as not to cause side effects such as orthostatic hypotension.
  • antihypertensive therapy consists in preventing the progress of hypertension-induced organic disorders and lowering the incidence of heart failure, renal failure or cerebral apoplexy and the mortality therefrom.
  • Antihypertensive therapy can not prevent an increase in the number of patients with hypertension-induced renal failure, although it was reported that antihypertensive therapy improved the mortality of heart failure and cerebral apoplexy.
  • hypertension is produced by glomerular disorder.
  • the compounds of the formula (I) as effective ingredient(s) in the therapeutic agents of the present invention are known compounds for use in therapeutic agents against malignant hyperphenylalaninemia, depression, Parkinson's disease, etc.
  • KKAI Japanese Patent Public Disclosure
  • the object of the present invention is to provide a safe therapeutic agent for diseases associated with dysfunction of NOS which improves circulating and organic functions, retards the progress of complications and improves the quality of life of patients by preventing the decrease of endogenous NO production and regulating the functions of endothelial cells.
  • BH4 level might also be lowered in diseases associated with dysfunction of NOS.
  • BH4 was administered to DOCA-salt hypertension rats and DOCA-salt SHRs to test the hypothesis.
  • NOS expression level were found to be actually lowered in the DOCA-salt hypertension rats.
  • decrease of endogenous NO production was prevented and physiologically natural antihypertensive effects were obtained.
  • DOCA-salt SHRs also actually exhibited a decline of BH4 level as well as histopathological findings such as necrotizing glomerulitis and necrotizing angiitis
  • BH4 administration antihypertensive effects as well as remarkable improvement effects on said histopathological findings by regulating the functions of endothelial cells were obtained.
  • the present invention was accomplished on the basis of the finding that BH4 has an action to activate the decreased function of NOS. Accordingly, the present invention is directed to effective therapy with BH4 preparations for diseases associated with dysfunction of NOS.
  • FIG. 1 shows the time course of blood pressure change in a control group (-O-), DOCA group (- ⁇ -) and a group of DOCA-salt hypertension rats orally administered BH4 (DOCA+BH4 group, - ⁇ -).
  • FIG. 2 shows the time course of change of NO 2 /NO 3 content in urine in a control group (-O-), DOCA group (- ⁇ -) and a group of DOCA-salt hypertension rats orally administered BH4 (DOCA+BH4 group, - ⁇ -).
  • FIG. 3 shows the time course of change of BP content in urine in a control group (-O-), DOCA group (- ⁇ -) and a group of DOCA-salt hypertension rats orally administered BH4 (DOCA+BH4 group,
  • FIG. 4 shows the results of measurement of the expression of E-NOS mRNA in renal tissues.
  • FIG. 5 shows the time course of blood pressure change in a control group (- ⁇ -), DOCA group (- ⁇ -) and a group of DOCA-salt SHRs orally administered BH4 (DOCA+BH4 group, - ⁇ -).
  • FIG. 6 shows the time course of change of BP content in urine in a control group (- ⁇ -), DOCA group (- ⁇ -) and a group of DOCA-salt SHRs orally administered BH4 (DOCA+BH4 group, - ⁇ -).
  • FIG. 7 shows the incidences of histopathological findings in renal tissue samples on necrotizing glomerulitis and necrotizing angiitis in a control group, DOCA group and DOCA+BH4 group.
  • the present invention relates to a pharmaceutical composition for preventing and/or treating diseases associated with dysfunction of NOS, comprising as an effective ingredient, a compound of the formula (I):
  • R 1 and R 2 each represents a hydrogen atom or, taken together with each other, represent a single bond
  • R 3 represents —CH(OH)CH(OH)CH 3 , —CH(OCOCH 3 )CH(OCOCH 3 )CH 3 , —CH 3 , —CH 2 OH, or a phenyl group when R 1 and R 2 each represents a hydrogen atom, or —COCH(OH)CH 3 when R 1 and R 2 together represent a single bond, or a pharmaceutically acceptable salt thereof.
  • dysfunction of NOS means that the expression of NOS, which widely occurs in vascular endothelium, nervous systems, kidney, platelets, myocardium, smooth muscles or other organs, has been reduced for some reason or the activity of NOS is not exhibited by dysfunction of these cells even if it is expressed.
  • a typical example of dysfunction of NOS is a decrease in the endogenous NO level.
  • Diseases associated with dysfunction of NOS include those induced, deteriorated or hindered from cure by dysfunction of NOS, such as hypertension, hyperlipemia, arteriosclerosis, coronary vasospasm, ischemic heart disease, heart failure, thrombosis, pulmonary hypertension, cerebrovascular failure, cerebral vasospasm, glomerulonephritis, chronic renal failure, diabetes, postoperative restenosis, achalasia, portal hypertension, hepatic disorder, gastrointestinal mucosa disorder, hypertrophic pyloric stenosis, enteritis, impotence, chorioretinopathy, etc.
  • dysfunction of NOS such as hypertension, hyperlipemia, arteriosclerosis, coronary vasospasm, ischemic heart disease, heart failure, thrombosis, pulmonary hypertension, cerebrovascular failure, cerebral vasospasm, glomerulonephritis, chronic renal failure, diabetes, postoperative restenosis, achalasia, portal hypertension,
  • BH4 When administered to patients with these diseases, BH4 can prevent or treat these diseases by normalizing the functions of NOS through the stimulating effect on NOS production in vivo or through restoring the decreased function of endothelial cells.
  • the present invention is applied to treat or prevent diseases that can be treated by the stimulatory action of BH4 to activate the function of NOS.
  • Compounds of the formula (I) as effective ingredients of the present invention include the following ones and pharmaceutically acceptable salts thereof:
  • Compounds of the formula (I) used as effective ingredients in the present invention are known compounds.
  • KKAI Japanese Patent Public Disclosure
  • These compounds may be used as appropriate salts with pharmacologically non-toxic acids, including mineral acids such as hydrochloric acid, phosphoric acid, sulfuric acid, boric acid; and organic acids such as acetic acid, formic acid, maleic acid, fumaric acid, mesylic acid.
  • a pharmaceutical composition of the present invention is effective against the above mentioned diseases.
  • hypertension including not only essential hypertension but also malignant hypertension with a necrosis of arteriolar walls in the kidney and retina occurring in a short period, and renal hypertension accompanied by renal disorder.
  • hypertension such as essential hypertension, renal hypertension, renovascular hypertension, pregnancy-induced hypertension, senile hypertension and adrenal hypertension.
  • a pharmaceutical composition of the present invention is prepared by formulating a compound of the formula (I) with generally used carriers by conventional procedures into a dosage form suitable for oral, rectal or parenteral administration (including administration into vein and cerebrospinal fluid).
  • the carrier used for these pharmaceutical formulations generally include excipients, binders, disintegrators, etc. depending on the dosage form chosen.
  • excipients include starch, lactose, sucrose, glucose, mannitol and cellulose
  • binders include polyvinylpyrrolidone, starch, sucrose, hydroxypropyl cellulose, Arabic gum.
  • disintegrators include starch, agar, gelatin powder, cellulose, CMC, but any other conventional excipients, binders and disintegrators may also be used.
  • composition of the present invention may also contain antioxidants for stabilizing effective ingredients.
  • Antioxidants can be appropriately selected from those conventionally used for pharmaceutical preparations, such as ascorbic acid, N-acetylcysteine, L-cysteine, dl- ⁇ -tocopherol, natural tocopherol etc. They are used in an amount that stabilizes active ingredient (one or more) and generally, the ratio of an antioxidant between 0.2 and 2.0 parts by weight to 1 part of the active ingredient(s).
  • Formulations of the present invention suitable for oral administration may be provided in the form of tablets, sublingual tablets, capsules, powders, granules or fine granules, or suspensions in a non-aqueous liquid such as syrups, emulsions or draft (pro re nata preparation) that contain the prescribed amount of the active ingredient (one or more).
  • a non-aqueous liquid such as syrups, emulsions or draft (pro re nata preparation) that contain the prescribed amount of the active ingredient (one or more).
  • granules are prepared by homogeneously mixing active ingredient (one or more) with one or more auxiliary ingredients such as carriers and antioxidants as mentioned above, followed by granulation and sieving to uniform grain size.
  • Tablets can be prepared by compressing or molding active ingredient (one or more) optionally together with one or more auxiliary ingredients.
  • Capsules are prepared by filling powder or granules of active ingredient (one or more) optionally mixed homogeneously with auxiliary ingredient (one or more) into appropriate capsules using a capsule filling machine or the like.
  • Formulations for rectal administration can be provided as suppositories using conventional carriers such as cacao butter.
  • Parenteral formulations can be provided as dry solids of active ingredient (one or more) sealed in a nitrogen-filled sterilized containers. Such dry solid preparations can be administered to patients after dispersing or dissolving them into a determined amount of sterilized water just prior to administration.
  • antioxidants as mentioned above may preferably added to a mixture of effective ingredient and conventional carriers, and optionally one or more auxiliary ingredients selected from buffers, flavors, surfactants, viscosants, lubricants, etc. can also be added, if needed.
  • the dosage of active ingredients i.e. compounds of the formula (I) may vary with the administration route, the symptom to be treated and the patient condition, and the final determination of the dosage should be made by an attendant physician.
  • an appropriate dosage for treating hypertension ranges from 0.1 to 50 mg/kg (b.w.)/day, and representative optimal dosage is 0.5 to 10 mg/kg (b.w.)/day.
  • a desired dosage of said active ingredients may be administered once a day or in divided doses of two to four times a day at appropriate interval.
  • Active ingredients may be administered alone or in combination with pharmaceutical formulations containing other active ingredients suitable for the disease under treatment to facilitate control of the dosages for example.
  • formulations of the present invention may contain at least one auxiliary effective ingredient selected from the substrates or coenzyme or cofactor for NOS such as L-arginine flavins, for example, FAD, FMN, etc., or calcium. More excellent therapeutic effects can be expected when compounds of the formula (I) are mixed with these effective ingredients than when used alone.
  • the proportion of each of said auxiliary effective ingredients in formulations of the present invention is not specifically limited.
  • the weight ratio of at least one selected from L-arginine, flavins and calcium to 1 part of the compounds of the formula (I) may be within the range from 0.1 to 10, preferably 0.5 to 2.
  • an appropriate dosage of such mixed formulations for treating hypertension ranges from 0.1 to 50 mg/kg (b.w.)/day, preferably 0.5 to 10 mg/kg (b.w.)/day, in terms of the total amount of active ingredients.
  • a physician may appropriately choose formulations containing compounds of the formula (I) alone or in combination with other active ingredients, depending on the age, condition or other factors of the patient.
  • the most preferable active ingredients used in the present invention are (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) and salts thereof, but (6R,S)-5,6,7,8-tetrahydrobiopterin, 1′,2′-diacetyl-5,6,7,8-tetrahydrobiopterin, sepiapterin, 6-methyl-5,6,7,8-tetrahydropterin, 6-hydroxymethyl-5,6,7,8-tetrahydropterin or 6-phenyl-5,6,7,8-tetrahydropterin and salts thereof may also be used.
  • BH4 naturally occurring component is most preferable.
  • BH4 dihydrochloride has little toxicity to rats judging from the fact that an acute toxicity was more than 2 g/kg (b.w.).
  • An optically inactive analogue, (6R,S)-5,6,7,8-tetrahydrobiopterin is also only slightly toxic as reported in Japanese Patent Public Disclosure-No. 25323/84 for the treatment of Parkinson's disease, so that it can also be used for the therapy according to the present invention.
  • Other compounds of the formula (I) also show little or no acute toxicity.
  • This solution was added to 59 parts of an excipient (mannitol or lactose) and 15 parts of a disintegrant [corn starch or hydroxypropylcellulose (LH-22)], and the mixture was kneaded, granulated, dried, then sieved.
  • an excipient mannitol or lactose
  • a disintegrant corn starch or hydroxypropylcellulose (LH-22)
  • Example 2 The homogeneous solution of an active ingredient prepared in Example 1 was mixed with 58 parts of lactose and 15 parts of microcrystalline cellulose, then with 1 part of magnesium stearate and tableted.
  • Example 1 The dosage form prepared in Example 1 filled into capsules, wherein the formulation include 0.2% of magnesium stearate as a lubricant.
  • BH4 dihydrochloride 1.5 g Ascorbic acid 1.5 g L-cysteine hydrochloride 0.5 g Mannitol 6.5 g
  • This solution was added to a homogeneous mixture of 55 parts of mannitol, 1 part of polyvinylpyrrolidone, 14 parts of hydroxypropylcellulose and 5 parts of L-arginine or calcium, and the mixture was kneaded, granulated, dried, then sieved.
  • BH4 dihydrochloride 5 parts Ascorbic acid 5 parts L-cysteine hydrochloride 5 parts Mannitol 52 parts Polyvinylpyrrolidone (Kollidon 30) 1 part Hydroxypropylcellulose (LH-22) 12 parts L-arginine or calcium 10 parts
  • This solution was added to a homogeneous mixture of 10 parts of L-arginine or calcium, 50 parts of mannitol, 1 part of polyvinylpyrrolidone (Kollidon 30) and 9 parts of hydroxypropylcellulose (LH-22), and the mixture was kneaded, granulated, dried, then sieved.
  • DOCA deoxycorticosterone acetate
  • Urine was collected for 24 hours using a metabolic cage at the start of experiment and after 2, 4 and 5 weeks (at the termination of the observation period). At the termination of the observation period, blood sample was collected from abdominal aorta under anesthesia with Phenobarbital. The kidney was isolated after perfusing with physiological saline, and examined histologically and immunohistologically.
  • the measurement was carried out using Nitrate-Nitrite assay kit, (kit No. 780001, Cyman Chemical Company) according to the Griess method.
  • the values of NO 2 /NO 3 in urine means the activity of NOS, namely, higher the value, higher the activity.
  • BP Biopterin
  • BH4 a metabolite of BH4
  • RNA from renal tissues was performed by the guanidium/cesium chloride extraction method.
  • cDNA was synthesized from whole RNA by using MoMLV reverse transcriptase.
  • RNAasin RNAasin
  • MoMLV reverse transricptase RNAasin
  • PCR was performed using cDNA synthesized by the RT reaction as a template.
  • the RT reaction solution was added to a mixture of 5′- and 3′-primers for each of e-NOS to be detected and for malate dehyadrogenase (MDH) used as an internal standard, PCR buffer, 2.5 mM dNTP mixed solution and Taq DNA polymerase.
  • MDH malate dehyadrogenase
  • the reaction mixture was overlaid with mineral oil and centrifuged, after which the reaction was started in an automatic PCR apparatus.
  • PCR products were obtained by running 30 cycles wherein each cycle consists of 94° C. for 30 seconds, 50° C. for 30 seconds and 72° C. for 30 seconds.
  • the primers used for the detection of e-NOS and MDH were selected based on the report by Ujiie. K.
  • the base sequences of the primers used for the detection of e-NOS were TACGGAGCAGCAAATCCAC (SEQ ID NO: 1) for 5′ primer and CAGGCTGCAGTCCTTTGATC (SEQ ID NO: 2) for 3′ primer.
  • the base sequences of the primers used for the detection of MDH were CAAGAAGCATGGCGTATACAACCC (SEQ ID NO: 3) for 5′ primer and TTTCAGCTCAGGGATGGCCTCG (SEQ ID NO: 4) for 3′ primer.
  • PCR products were electrophoresed on 5% polyacrylamide gel and NOS mRNA expression was measured by Southern hybridization.
  • the PCR reaction solution was electrophoresed on 5% polyacrylamide and then, the gel was transferred to membrane filters. Hybridization was performed on the membrane filters using probes labeled with ⁇ 32 P-ATP at the 5′ prime for the detection of e-NOS and MDH (Ujiie, K. et al., 1994, supra.).
  • the base sequence of the probe was CTGGAACAATTTCCATCCG (SEQ ID NO: 5) for the detection of e-NOS and TTTGTCTTCTCCCTGGTGGA (SEQ ID NO: 6) for the detection of MDH.
  • autoradiography was run at ⁇ 70° C. for several hours and the exposed autoradiograms were analyzed by a densitometer. The results are shown in FIG. 4.
  • DOCA-salt-hypertension rats exhibited a rise in blood pressure, a decrease in NO 2 /NO 3 in urine and a decrease in NOS expression in renal tissues, indicating that dysfunction of vasoendothelial cells occurred in this model rats.
  • a decrease in BP in urine was also observed in this model rats.
  • oral administration of BH4 suppressed the rise in blood pressure and led to an increase of NO 2 /NO 3 in urine and an increase of NOS expression in renal tissues, indicating that BH4 is useful for the treatment of diseases caused by decreased endogenous NO production through activating the function of NOS (through regulation of NOS level/ NOS activity).
  • DOCA deoxycorticosterone acetate
  • Urine was collected for 24 hours using a metabolic cage at the start of experiment and after 2, 3, 4, 5 and 6 (at the termination of the observation period) weeks .
  • blood sample was collected from abdominal aorta under anesthesia with Phenobarbital.
  • the kidney was isolated after perfusing with physiological saline, and examined histologically.
  • BP Biopterin
  • BH4 a metabolite of BH4
  • DOCA-salt SHRs exhibited a rise in blood pressure and histopathological findings of necrotizing glomerulitis or necrotizing angiitis. A decrease in BP in urine was also observed in this model rats.
  • oral administration of BH4 suppressed the rise in blood pressure and remarkably improved histopathological findings, indicating that BH4 is useful for the treatment of diseases associated with dysfunction of endothelial cells through activating the function of NOS.
  • the present invention provides pharmaceutical composition agents that effectively prevent and/or ameliorate diseases associated with dysfunction of NOS.
  • active ingredients of therapeutic agents of the present invention have no adverse effects or the like over long-term use because they are substances that inherently exist in vivo.

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WO2006063215A3 (en) * 2004-12-08 2006-12-07 Biomarin Pharm Inc Methods and compositions for the treatment of pulmonary hypertension of the newborn
WO2008054693A3 (en) * 2006-10-30 2008-07-31 Univ Texas Uses of tetrahydrobiopterin and derivatives thereof
US7566714B2 (en) 2003-11-17 2009-07-28 Biomarin Pharmaceutical Inc. Methods and compositions for the treatment of metabolic disorders
US20110098306A1 (en) * 2006-10-30 2011-04-28 Pasricha Pankaj J Uses of tetrahydrobiopterin, sepiapterin and derivatives thereof
US8003126B2 (en) 2004-11-17 2011-08-23 Biomarin Pharmaceutical Inc. Stable tablet formulation
US9216178B2 (en) 2011-11-02 2015-12-22 Biomarin Pharmaceutical Inc. Dry blend formulation of tetrahydrobiopterin

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US8003126B2 (en) 2004-11-17 2011-08-23 Biomarin Pharmaceutical Inc. Stable tablet formulation
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US20090068264A1 (en) * 2005-01-14 2009-03-12 Chronorx Llc Clinical Applications of Tetrahydrobiopterin, Lipoic Acid and Their Salts and Methods of Preparing Tetrahydrobiopterin Bis-Lipoate
US20060194808A1 (en) * 2005-01-14 2006-08-31 Chronorx Llc, An Alaska Limited Liability Company Clinical applications of tetrahydrobiopterin, lipoic acid and their salts and methods of preparing tetrahydrobiopterin bis-lipoate
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