WO1991016053A1 - The use of synthetic metalloporphyrins in the treatment of hypertension and other vascular disorders - Google Patents
The use of synthetic metalloporphyrins in the treatment of hypertension and other vascular disorders Download PDFInfo
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- WO1991016053A1 WO1991016053A1 PCT/US1991/002657 US9102657W WO9116053A1 WO 1991016053 A1 WO1991016053 A1 WO 1991016053A1 US 9102657 W US9102657 W US 9102657W WO 9116053 A1 WO9116053 A1 WO 9116053A1
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- vascular resistance
- hypertension
- treatment
- metalloporphyrin
- heme
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- 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
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
Definitions
- the present invention relates to a method of using metalloporphyrins in the treatment of hypertension and other high vascular resistance disorders including primary or secondary vasospasm, angina pectoris, cerebral ischemia, preeclampsia of pregnancy and bronchial asthma.
- vasodilators such as acetylcholine, nitrovasodilators, prostaglandin and other arachidonic acid metabolites as noted by Pinto et al, "Arachidonic Acid-Induced Endothelial-Dependent Relaxations of Canine Coronary Arteries: Contribution of a Cytochrome P- 450-Dependent Pathway", J. Pharmacol. Exp. Thera .
- Heme Arginate Lowers Blood Pressure in Spontaneous Hypertensive Rats Clin. Res., 37, 553A (1989) also noted that other heme oxygenase inducers such as heme arginate have been demonstrated to cause reduction of renal P-450 and a decrease in blood pressure in young SHR.
- the blood pressure lowering effect of heme arginate could be attributed to the heme component.
- the heme effect may be due to an induction of heme oxygenase, since it is blocked by an inhibitor of heme oxygenase.
- Kordac et al "Changes of Myocardial Functions in Acute Hepatic Porphyrias. Role of Heme Arginate Administration", Ann. Med. , 21, 273-276 (1989) disclosed the use of heme arginate in the treatment of acute hepatic porphyria. Heme arginate was administered to those patients because it was speculated that acute hypoxia occurs in a porphyrin crisis due to lack of heme. The arginate was used as a way to solubilize the heme for administration to the patient.
- He e is a red pigment comprised of four subunits called pyrroles; these subunits are chemically joined to form a single large tetrapyrrole (porphyrin) ring structure.
- a metal atom is chelated at the center of this porphyrin: in higher organisms this metal is iron and the porphyrin ring structure is called protoporhyrin IX.
- protoporhyrin IX In physiological systems heme is bound to certain proteins; these hemeproteins bind oxygen at the site of the metal atom or they function as components of membrane bound electron transport systems. Cellular respiration, energy generation and chemical oxidations are dependent on these hemeproteins.
- heme is oxidatively degraded by heme oxygenase to form the open chain tetrapyrrole biliverdin.
- heme oxygenase In mammals and other vertebrates heme is oxidatively degraded by heme oxygenase to form the open chain tetrapyrrole biliverdin.
- mammals biliverdin In mammals biliverdin is reducted to bilirubin by biliverdin reductase.
- liver bilirubin is normally converted to the mono- and di-glucuronide conjugates by the hepatic glucuronyl transferase system prior to its excretion.
- CoPP cobalt protoporhyrin
- mesoporphyrin CoMP are useful in the treatment of high vascular resistance disorders including hypertension, primary or secondary vasospasm, angina pectoris, cerebral ischemia and preeclampsia of pregnancy in a mammalian organism, such as a human.
- the present invention provides a method for treating hypertension in a mammalian organism by administering to a mammalian organism in need of such treatment a sufficient amount of a selected metalloporphyrin to treat hypertension.
- the invention provides a method for treating vasospasm in a mammalian organism in need of such treatment a sufficient amount of a selected metalloporphyrin to treat vasospasm.
- the present invention provides a method for treating angina pectoris in a mammalian organism by administering to a mammalian organism in need of such treatment a sufficient amount of a selected metalloporphyrin to treat angina pectoris.
- the present invention provides a method for treating cerebral ischemia in a mammalian organism by administering to a mammalian organism in need of such treatment a sufficient amount of a selected metalloporphyrin to treat cerebral ischemia.
- the present invention provides a method for treating preeclampsia in an mammalian organism by administering to a mammalian organism in need of such treatment a sufficient amount of a selected metalloporphyrin to treat preeclampsia.
- a further embodiment of the present invention involves a method for treating bronchial asthma in a mammalian organism by administering to a mammalian organism in need of such treatment a sufficient amount of a selected metalloporphyrin to treat bronchial asthma.
- a particular advantage of the synthetic metalloporphyrins for such use is that on metabolic degradation in the mammalian body, they do not form iron or bilirubin as does heme. Both of these compounds are recognized as toxic if they are allowed to accumulate in the body. Additionally, the physiological effects of the products employed in the invention are long lasting, and they are effective even at low dosages.
- the compounds are generally non-toxic, a particularly important characteristic with therapeutic agents intended for long term treatment, as in usually the case with the treatment vascular resistance disorders.
- Hypertension is characterized by persistently high arterial blood pressure. Various criteria for its threshold have been suggested ranging from 140 mm Hg systolic and 90 mm Hg diastolic. Hypertension may have no known cause (essential or idiopathic hypertension) or be associated with other primary diseases (secondary hypertension) .
- Vasospasm refers to a spasm of the blood vessels, resulting in a decrease in their caliber.
- Primary vasospasm can be described as a cold sensitivity of the Raynaud's type without an underlying disease.
- Secondary vasospasm generally refers to cold sensitivity of the Raynaud's type secondary to an associated disease such as lupus, scleroderma, certain medication, chronic arterial disease, dysprotenemias and the like.
- Angina pectoris is a paroxysmal thoracic pain oftentimes accompanied by a feeling of suffocation and impending death, due, most often, to anoxia of the myocardium and precipitated by effort or excitement.
- Cerebral ischemia is a deficiency of blood in the brain, due to functional constriction or actual obstruction of a blood vessel.
- Preeclampsia is a toxemia of late pregnancy characterized by hypertension, edema and proteinuria.
- Bronchial asthma is a reversible obstructive lung disorder characterized by increased responsiveness of the airways. Bronchial asthma attacks are characterized by narrowing of large and small airways due to spasm of bronchial smooth muscle, edema and inflammation of the bronchial mucosa and production o.f tenacious mucus. The role of inflammation in the perpetuation of the abnormal airway responses (late-phase reaction) is only now being appreciated.
- Airways obstruction causes hypoventilation in some lung areas, and continued blood flow to these area leads to a ventilation/perfusion imbalance resulting in hypoxema.
- Arterial hypoxemia is almost always present in attacks severe enough to require medical attention. Hyperventilation occurs early in the attack. As the attack progresses, the patient's capacity to compensate by hyperventilation of unobstructed areas of the lung is further impaired by more extensive airways narrowing and muscular fatigue. Arterial hypoxema worsens and can lead to respiratory acidosis.
- an effective dosage of metalloporphyrin to reduce vascular resistance would be in the range of about 0.05 to about 1 umol/kg body weight, although appreciable variation is possible without loss of the advantages of the invention.
- Pediatric dosages would typically contain proportionally less of the active ingredient.
- the selected metalloporphyrin will be administered parenterally, preferably intramuscularly.
- compositions of this invention will be prepared by the usual procedures employed for such purposes.
- the usual pharmaceutical carriers for parenteral administration may be used such as aqueous media made isotonic by the addition of sodium chloride, glucose or other standard solutes.
- the compositions will be buffered, for example with a phosphate buffer to a pH of about 7 to 8, preferably 7.4 to 7.5.
- the concentration of metalloporphyrin in the composition will be from 100 to 2500 umol/liter so that they can be formed into dosage unit forms adequate to provide the above described dosages. Accordingly, the dosage units will normally contain from 0.1 to 2.5 umol/liter of solution.
- sterile vehicles for example sesame or cottonseed oil may also be employed.
- Results are mean + SE, significance from control, p ⁇ 0.001, CoPP induced renal HO by 7 fold and subsequently reduced P450 content by 50%.
- AA ⁇ / ⁇ -1 hydroxylase was the most affected P450 isozyme following CoPP administration, i.e., a reduction of 65% in its activity vs. 20-40% reduction in other P450 isozymes.
- the marked and prolonged (4 days) reduction of blood pressure by one single dose of CoPP is evident from the table.
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Abstract
A method for treating a high vascular resistance disorder in a mammal by administering to a mammalian organism in need of such treatment a sufficient amount of a synthetic metalloporphyrin with heme oxygenase inducing activity to treat a high vascular resistance disorder.
Description
THE USE OF SYNTHETIC METALLOPORPHYRINS IN THE TREATMENT OF HYPERTENSION AND OTHER VASCULAR DISORDERS
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to a method of using metalloporphyrins in the treatment of hypertension and other high vascular resistance disorders including primary or secondary vasospasm, angina pectoris, cerebral ischemia, preeclampsia of pregnancy and bronchial asthma.
Description of the Prior Art
The disposition of hypertensive patients to develop vascular disease which leads to increased mortality from stroke and myocardial infarction is a major problem in the western world. The development of hypertension can relate to abnormalities in the production or activities of vasoactive substances. Alteration in the responsiveness to both vasoconstrictors and vasodilators has been well documented in spontaneous hypertensive rats, (SHR) , the most frequently used animal model for the study of human essential hypertension. Thus, an increase in the constractile response of vascular smooth muscle of spontaneous hypertensive rats to vasoconstrictors such as norepinephrine as noted by Lais et al, "Mechanism of Vascular Hyperresponsiveness in the Spontaneously Hypertensive Rat", Cir. Res. , 36/37: Suppl. 1, 1-216 to 1-22 (1975), and a decrease in the relaxant response to vasodilators such as acetylcholine, nitrovasodilators, prostaglandin and
other arachidonic acid metabolites as noted by Pinto et al, "Arachidonic Acid-Induced Endothelial-Dependent Relaxations of Canine Coronary Arteries: Contribution of a Cytochrome P- 450-Dependent Pathway", J. Pharmacol. Exp. Thera . , 240, 856-863 (1987) and Luscher et al, "Endothelium-Dependent Responses in Carotid and Renal Arteries of Normotensive and Hypertensive Rats", Hypertension, 11, 573-578 (1988), may contribute overall to the development of high blood pressure.
It has also been demonstrated that cytochrome P-450-arachidonate metabolism is increased rn the kidney of young SHR and a selective reduction in the formation of these metabolites via induction of heme degradation with SnCl2 caused a marked decrease in blood pressure as noted by Sacerdoti et al, "Treatment with Tin Prevents the Development of Hypertension in Spontaneously Hypertensive Rats", Science, 243, 388-390 (1989). Martasek et al,
"Heme Arginate Lowers Blood Pressure in Spontaneous Hypertensive Rats", Clin. Res., 37, 553A (1989) also noted that other heme oxygenase inducers such as heme arginate have been demonstrated to cause reduction of renal P-450 and a decrease in blood pressure in young SHR. The blood pressure lowering effect of heme arginate could be attributed to the heme component. The heme effect may be due to an induction of heme oxygenase, since it is blocked by an inhibitor of heme oxygenase.
An increase in hepatic and renal cytochrome P-450 content and its related drug metabolizing enzyme systems has been demonstrated in SHR as noted by Merrick et al, "Alterations in Hepatic Microsomal Drug Metabolism and Cytochrome P450 Proteins in Spontaneously Hypertensive Rats", Pharmacol. , 30, 129-135 (1985) and Sacerdoti et al, "Renal Cytochrome P450-Dependent Metabolism of Arachidonic Acid in Spontaneously Hypertensive Rats", Biochem. Pharmacol., 37, 521-527 (1988). More recently Sacerdoti et al demonstrated that abnormalities of renal function in young SHR may be a functional expression of an alteration in renal cytochrome P-450-dependent metabolism of arachidonic acid. Cytochrome P-450 levels are regulated by the availability of cellular heme which in turn is controlled by the levels of heme oxygenase which is the controlling enzyme in the metabolism of heme to bilirubin. Induction of heme oxygenase by heavy metals such as SnCl results in a depletion of renal cytochrome P-450 as described by Kappas et al, "Control of Heme Metabolism with Synthetic Metalloporphyrins", J. Clin. Invest. , 77, 335-339 (1986) and Simionatto et al, "Studies on the Mechanism of Sn-Protoporphyrin Suppression and Hyperbilirubinemia: Inhibition of Heme Oxidation and Bilirubin Production", J. Clin. Invest. , 75, 513-521 (1985).
Furthermore, it has recently been demonstrated by Escalante et al, "19(S)Hydroxyeicosatetraenoic Acid is a Potent Stimulator of Renal Na -K - ATPase", Biochem. Biophys. Res. Commun. , 152, 1269-1273 (1988) and Escalante et al, "Vasoactivity
of 20-Hydroxyeicosatetraenoic Acid is Dependent on Metabolism by Cyclooxygenase", J. Pharmacol. Exp. Therap. , 248, 229-232 (1989) that arachidonic acid metabolites of cytochrome P-450 ω/ω -1 hydroxylases, 19(S)-HETE (hydroxyeicosatetragenoic acid) and 20-HETE is a potent renal Na -K -ATPase stimulator and 20-HETE is a vasoconstrictor.
An acute attack of acute intermitten porphyria, a disease caused by inborn errors of porphyrin metabolism, is a life threatening condition, often characterized by agonizing abdominal pain, paresis and frequently accompanied by hypertension. The exact pathogenesis of hypertension in an acute porphyric attack is not well understood. Currently, hemin in the form of heme arginate is used in Europe in the treatment of acute attacks of acute intermittent porphyria so as to normalize the levels of "free" heme and thereby decrease the induced levels of delta-aminolevulinic acid synthetase, an enzyme under negative feedback control by unbound or "free" heme. Kordac et al, "Changes of Myocardial Functions in Acute Hepatic Porphyrias. Role of Heme Arginate Administration", Ann. Med. , 21, 273-276 (1989) disclosed the use of heme arginate in the treatment of acute hepatic porphyria. Heme arginate was administered to those patients because it was speculated that acute hypoxia occurs in a porphyrin crisis due to lack of heme. The arginate was used as a way to solubilize the heme for administration to the patient.
He e is a red pigment comprised of four subunits called pyrroles; these subunits are chemically joined to form a single large tetrapyrrole (porphyrin) ring structure. A metal atom is chelated at the center of this porphyrin: in higher organisms this metal is iron and the porphyrin ring structure is called protoporhyrin IX. In physiological systems heme is bound to certain proteins; these hemeproteins bind oxygen at the site of the metal atom or they function as components of membrane bound electron transport systems. Cellular respiration, energy generation and chemical oxidations are dependent on these hemeproteins.
In mammals and other vertebrates heme is oxidatively degraded by heme oxygenase to form the open chain tetrapyrrole biliverdin. In mammals biliverdin is reducted to bilirubin by biliverdin reductase. In liver bilirubin is normally converted to the mono- and di-glucuronide conjugates by the hepatic glucuronyl transferase system prior to its excretion.
A large number of synthetic metalloporphyrins are known in which the chelated ion is replaced with another metal such as copper, cobalt, tin, chromium, zinc or cadmium. Some have been identified as heme oxygenase inducers, others have the opposite effect. The activity of a specific synthetic metalloporphyrins in unpredictable.
SUMMARY OF THE INVENTION
Surprisingly, the present inventors now find that synthetic metalloporphyrins such as cobalt protoporhyrin (CoPP) and mesoporphyrin CoMP are useful in the treatment of high vascular resistance disorders including hypertension, primary or secondary vasospasm, angina pectoris, cerebral ischemia and preeclampsia of pregnancy in a mammalian organism, such as a human.
In one aspect, the present invention provides a method for treating hypertension in a mammalian organism by administering to a mammalian organism in need of such treatment a sufficient amount of a selected metalloporphyrin to treat hypertension.
In another aspect, the invention provides a method for treating vasospasm in a mammalian organism in need of such treatment a sufficient amount of a selected metalloporphyrin to treat vasospasm.
In a further aspect, the present invention provides a method for treating angina pectoris in a mammalian organism by administering to a mammalian organism in need of such treatment a sufficient amount of a selected metalloporphyrin to treat angina pectoris.
In yet another aspect, the present invention provides a method for treating cerebral ischemia in a mammalian organism by administering to a
mammalian organism in need of such treatment a sufficient amount of a selected metalloporphyrin to treat cerebral ischemia.
In an additional aspect, the present invention provides a method for treating preeclampsia in an mammalian organism by administering to a mammalian organism in need of such treatment a sufficient amount of a selected metalloporphyrin to treat preeclampsia.
A further embodiment of the present invention involves a method for treating bronchial asthma in a mammalian organism by administering to a mammalian organism in need of such treatment a sufficient amount of a selected metalloporphyrin to treat bronchial asthma.
Other objects and advantages of the present invention will be apparent from the following description.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
It has now been discovered that certain synthetic metalloporphyrins which are heme oxygenase inducers are therapeutically useful for treating high vascular resistance disorders in mammals in need of such treatment.
A particular advantage of the synthetic metalloporphyrins for such use is that on metabolic degradation in the mammalian body, they do not form iron or bilirubin as does heme. Both of these
compounds are recognized as toxic if they are allowed to accumulate in the body. Additionally, the physiological effects of the products employed in the invention are long lasting, and they are effective even at low dosages. The compounds are generally non-toxic, a particularly important characteristic with therapeutic agents intended for long term treatment, as in usually the case with the treatment vascular resistance disorders.
For convenience, this invention will be described principally by reference to the presently preferred compounds CoPP and CoMP. However, other heme oxygenase inducers such as the corresponding diiodoporphyrin and analogs of the three compounds mentioned in which the cobalt is replaced with other metals such as chromium or copper are also useful.
Hypertension is characterized by persistently high arterial blood pressure. Various criteria for its threshold have been suggested ranging from 140 mm Hg systolic and 90 mm Hg diastolic. Hypertension may have no known cause (essential or idiopathic hypertension) or be associated with other primary diseases (secondary hypertension) .
Vasospasm refers to a spasm of the blood vessels, resulting in a decrease in their caliber. Primary vasospasm can be described as a cold sensitivity of the Raynaud's type without an underlying disease. Secondary vasospasm generally refers to cold sensitivity of the Raynaud's type
secondary to an associated disease such as lupus, scleroderma, certain medication, chronic arterial disease, dysprotenemias and the like.
Angina pectoris is a paroxysmal thoracic pain oftentimes accompanied by a feeling of suffocation and impending death, due, most often, to anoxia of the myocardium and precipitated by effort or excitement.
Cerebral ischemia is a deficiency of blood in the brain, due to functional constriction or actual obstruction of a blood vessel.
Preeclampsia is a toxemia of late pregnancy characterized by hypertension, edema and proteinuria.
Bronchial asthma is a reversible obstructive lung disorder characterized by increased responsiveness of the airways. Bronchial asthma attacks are characterized by narrowing of large and small airways due to spasm of bronchial smooth muscle, edema and inflammation of the bronchial mucosa and production o.f tenacious mucus. The role of inflammation in the perpetuation of the abnormal airway responses (late-phase reaction) is only now being appreciated. Airways obstruction causes hypoventilation in some lung areas, and continued blood flow to these area leads to a ventilation/perfusion imbalance resulting in hypoxema. Arterial hypoxemia is almost always present in attacks severe enough to require medical attention. Hyperventilation occurs early in the
attack. As the attack progresses, the patient's capacity to compensate by hyperventilation of unobstructed areas of the lung is further impaired by more extensive airways narrowing and muscular fatigue. Arterial hypoxema worsens and can lead to respiratory acidosis.
The precise amount of synthetic metalloporphyrin suitable for use in the practice of the present invention will vary depending on the selected compound and the condition for which the drug is administered, the age, weight, and general physical condition of the mammal and other factors readily evaluated by the skilled physician or veterinarian.
Typically, an effective dosage of metalloporphyrin to reduce vascular resistance would be in the range of about 0.05 to about 1 umol/kg body weight, although appreciable variation is possible without loss of the advantages of the invention. Pediatric dosages would typically contain proportionally less of the active ingredient.
The selected metalloporphyrin will be administered parenterally, preferably intramuscularly.
Therapeutic compositions of this invention will be prepared by the usual procedures employed for such purposes. The usual pharmaceutical carriers for parenteral administration may be used such as aqueous media made isotonic by the addition
of sodium chloride, glucose or other standard solutes. Typically the compositions will be buffered, for example with a phosphate buffer to a pH of about 7 to 8, preferably 7.4 to 7.5. The concentration of metalloporphyrin in the composition will be from 100 to 2500 umol/liter so that they can be formed into dosage unit forms adequate to provide the above described dosages. Accordingly, the dosage units will normally contain from 0.1 to 2.5 umol/liter of solution.
Other sterile vehicles, for example sesame or cottonseed oil may also be employed.
In one study, the effect of a single dose (35 mg/kg bw) of CoPP on renal HO, P450 content, P450- Aa metabolism and blood pressure in 7-week-old SHR was studied. Results are summarized in the following table:
Changes in blood pressure (mmHg)
P450 (pmol/mg)
P450-Aa ω/ω -1 hydroxylase (nmol/mg/30 min) HO (nmol/mg/hr)
Results are mean + SE, significance from control, p<0.001,
CoPP induced renal HO by 7 fold and subsequently reduced P450 content by 50%. AA ω/ω -1 hydroxylase was the most affected P450 isozyme following CoPP administration, i.e., a reduction of 65% in its activity vs. 20-40% reduction in other P450 isozymes. The marked and prolonged (4 days) reduction of blood pressure by one single dose of CoPP is evident from the table.
Similar results are achieved with CoMP and other synthetic metalloporphyrins of the invention.
Claims
1. A method for treating a high vascular resistance disorder in a mammal, said method comprising parenterally administering to a mammalian organism in need of such treatment a sufficient amount of a synthetic metalloporphyrin heme oxygenase inducer to treat a high vascular resistance disorder.
2. The method as claimed in Claim 1, wherein the high vascular resistance disorder is hypertension.
3. The method as claimed in Claim 1, wherein the high vascular resistance disorder is primary or secondary vasospasm.
4. The method as claimed in Claim 1, wherein the high vascular resistance disorder is angina pectoris.
5. The method as claimed in Claim 1, wherein the high vascular resistance disorder is cerebral ischemia.
6. The method as claimed in Claim 1, wherein the high vascular resistance disorder is preeclampsia.
7. The method as claimed in Claim 1, wherein metalloporphyrin is administered at a dosage of from about 0.05 to 1 umo/kg body weight per day.
8. The method as claimed in Claim 7, wherein metalloporphyrin is administered at a dosage of from about 0.05 to 1 umol/kg body weight per day.
9. The method as claimed in Claims 1, 2, 3, 5, 6, and 7 wherein the metalloporphyrin is cobalt protoporphyrin or cobalt mesoporphyrin.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US51375190A | 1990-04-24 | 1990-04-24 | |
| US513,751 | 1990-04-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1991016053A1 true WO1991016053A1 (en) | 1991-10-31 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1991/002657 WO1991016053A1 (en) | 1990-04-24 | 1991-04-18 | The use of synthetic metalloporphyrins in the treatment of hypertension and other vascular disorders |
Country Status (2)
| Country | Link |
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| AU (1) | AU7755591A (en) |
| WO (1) | WO1991016053A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5948771A (en) * | 1996-01-31 | 1999-09-07 | The Trustees Of Columbia University In The City Of New York | Method for treating heart failure using tetrapyrroles and metallotetrapyrroles |
| WO2001068099A1 (en) * | 2000-03-10 | 2001-09-20 | The Rockefeller University | Modulation of cardiovascular injury |
| WO2002078623A2 (en) * | 2001-03-30 | 2002-10-10 | Hofmann Robert F | Uses of targeted oxidative therapeutic formulation in arteriosclerosis |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4684637A (en) * | 1981-07-15 | 1987-08-04 | The Rockefeller University | Method of decreasing rate of heme metabolism |
| US4948792A (en) * | 1986-02-21 | 1990-08-14 | The Rockefeller University | Methods for suppressing the endocrine system |
| US4997828A (en) * | 1989-02-14 | 1991-03-05 | The Rockefeller University | Method of weight control by low level administration of cobalt protoporphyrin or cobalt mesoporphyrin |
-
1991
- 1991-04-18 WO PCT/US1991/002657 patent/WO1991016053A1/en unknown
- 1991-04-18 AU AU77555/91A patent/AU7755591A/en not_active Abandoned
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4684637A (en) * | 1981-07-15 | 1987-08-04 | The Rockefeller University | Method of decreasing rate of heme metabolism |
| US4948792A (en) * | 1986-02-21 | 1990-08-14 | The Rockefeller University | Methods for suppressing the endocrine system |
| US4997828A (en) * | 1989-02-14 | 1991-03-05 | The Rockefeller University | Method of weight control by low level administration of cobalt protoporphyrin or cobalt mesoporphyrin |
Non-Patent Citations (6)
| Title |
|---|
| BIOCHEM BIOPHYS RES COMM 157(2): published 15 December 1988, see pages 480-487. * |
| BIOCHIM ET BIOPHYS ACTA 1073: published 1991, see pages 221-224. * |
| CLIN EXP PHARM PHYS 2(5): published 1975, see pages 365-371. * |
| EUR J BIOCHEM 192(3): published February 1990, pages 577-582. * |
| J. PHARMACOBIO-DYN 12(1): published 1989, see pages 50-59. * |
| ZH ESKP KLIN MED 26(6): published 1986, see pages 515-520. * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5948771A (en) * | 1996-01-31 | 1999-09-07 | The Trustees Of Columbia University In The City Of New York | Method for treating heart failure using tetrapyrroles and metallotetrapyrroles |
| WO2001068099A1 (en) * | 2000-03-10 | 2001-09-20 | The Rockefeller University | Modulation of cardiovascular injury |
| WO2002078623A2 (en) * | 2001-03-30 | 2002-10-10 | Hofmann Robert F | Uses of targeted oxidative therapeutic formulation in arteriosclerosis |
| WO2002078623A3 (en) * | 2001-03-30 | 2004-03-04 | Hofmann Robert F | Uses of targeted oxidative therapeutic formulation in arteriosclerosis |
Also Published As
| Publication number | Publication date |
|---|---|
| AU7755591A (en) | 1991-11-11 |
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