AU5495599A - Creation of Inventions and Patents with Artificial Intelligence

AU5495599A – Pharmaceutical control of inflammation
– Google Patents

AU5495599A – Pharmaceutical control of inflammation
– Google Patents
Pharmaceutical control of inflammation

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AU5495599A

AU5495599A
AU54955/99A
AU5495599A
AU5495599A
AU 5495599 A
AU5495599 A
AU 5495599A
AU 54955/99 A
AU54955/99 A
AU 54955/99A
AU 5495599 A
AU5495599 A
AU 5495599A
AU 5495599 A
AU5495599 A
AU 5495599A
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Prior art keywords
heme
oxygenase
activity
compound
inflammation
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1994-09-22
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AU54955/99A
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AU723677B2
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Adrian Richard Moore
Dean Willis
Derek Albert Willoughby
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Harvey William Research Ltd

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Harvey William Research Ltd
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1994-09-22
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1999-10-15
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2000-01-06

1999-10-15
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1999-10-15
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2000-01-06
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2000-08-31
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2000-08-31
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2015-09-22
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AUSTRALIA
Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Applicant(s): WILLIAM HARVEY RESEARCH LIMITED Invention Title: Pharmaceutical Control of Inflammation a a a The following statement is a full description of this invention, including the best method of performing it known to me/us: Pharmaceutical Control of Inflammation This invention relates to the control of the inflammatory response, to pharmaceuticals that inhibit or decrease inflammation, to pharmaceuticals that promote, induce or increase inflammation and to treatment of disease states by inhibiting or promoting inflammation. In particular, this invention relates to control of the activity or the amount or both the activity and the amount of heme-oxygenase in the body.
This invention finds in addition to other applications, particular application in the treatment of diseases manifested in or exacerbated by an inflammatory response (such as in the treatment of chronic inflammatory diseases, for example, rheumatoid arthritis), in humans suffering hypersensitivity reactions such as in asthma, in humans suffering conditions in which ROS (Reactive Oxygen Species) have a pathogenic role such as reperfusion injury and atherosclerosis and, in humans having immunosuppressed states resulting from drug treatments or from pathologies such as AIDS.
o Chronic inflammatory diseases place a heavy social and economic burden on the resources of many nations, but the number of safe and effective treatments is limited. To date, the major research effort has concentrated on those mediators t.o 0 responsible for the initiation and maintenance of the pathological process. In contrast little attention has been focused on endogenous factors responsible for too.
the resolution of the inflammation.
The main anti-inflammatory pharmaceutical agents are the glucocorticoids and the non-steroidal anti-inflammatory drugs (NSAIDs). Both suffer from well catalogued disadvantages, indeed nearly one quarter of adverse drug reactions reported in the UK are due to NSAIDs. Side-effects of NSAIDs commonly affect the gastrointestinal tract, and also the liver, kidney, spleen, blood and bone marrow. NSAIDs are not effective in treatment of some chronic inflammatory -2disorders.
Glucocorticoids are powerful anti-inflammatory agents, suppressing both acute and chronic phases of inflammation. They carry the hazard, however, that they also suppress the immune response and can decrease many aspects of essential cell repair processes. Generally, they must be given by injection and are not effective on oral administration.
There thus exists an on-going need for further anti-inflammatory drugs, which can be givern orally and which are effective against chronic inflammation.
Conversely, a number of diseases are known in which there is a significant suppression of the inflammatory response. One example is acquired immune deficiency syndrome (AIDS) in which infection by HIV leads typically to such immuno-suppression that an infected person dies from a separate, opportunistic, infection, often a bacterial or viral infection rarely fatal in a healthy person.
Stimulation or induction of inflammation in this case could assist in preventing death from non-HIV infections. However, no suitable pharmaceutical is known for this pro-inflammatory purpose.
Heme (ferri-protoporphyrin-IX) plays a vital role in cellular metabolism, functioning as the prosthetic group of hemeproteins (eg. hemoglobin and cytochromes). It’s catabolism is a two-step process. The first, and rate limiting reaction, is the production of biliverdin and carbon monoxide by the microsomal enzyme heme-oxygenase. The second step is the production of bilirubin from biliverdin by the cytosolic enzyme, biliverdin reductase.
o°° Heme-oxygenase is found in liver, kidney, spleen and skin, and has also been localised to specific cell types, notably fibroblasts and macrophages. The enzyme exists in at least two isoforms, one constitutive and the other inducible.
Heme, heavy metal ions (eg. tin, gold, platinum and mercury) and transition metal ions (eg. iron, cobalt, chromium and nickel) can all induce heme- -3oxygenase. In addition, heme-oxygenase is induced as part of a generalised stress response to stimuli such as thermal shock (hence the alternative name heat-shock protein 32; hsp32), oxidative stress and cytokines such as interleukin-1 tumour necrosis factor and IL-6. The stress response is seen as beneficial in that it results in protection of vulnerable cell enzymes from inactivation.
Animal biles have been used in traditional Chinese medicine for centuries in the treatment of bronchitis, asthma and other hypersensitivity reactions. More recently, it has been shown that biliverdin and bilirubin scavenge reactive oxygen species (ROS) which can have a range of proinflammatory effects including inactivation of protease inhibitors, depolymerisation of hyaluronic acid to angiogenic fragments and alteration of proteins to give rise to endogenous antigens.
Abraham et al., Int. J. Biochem. 20(6): 543-558 (1988) provides a general review of heme-oxygenase and its role in mammalian physiology including regulation of its activity by endogenous and exogenous factors. The interaction of this enzyme with NADPH-cytochome P450 reductase is discussed, as is the role of heavy metal ions in inducing heme-oxygenase activity. Metal Porphyrins are taught as inhibitors. At p. 548 of the reference, the author states: “In general, heme-oxygenase activity increases when cells are under stress or in a disease state. In fact, the enzyme may be regarded as a red light signalling the occurrence of abnormality.”
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Sacerdoti et al., Science 243: 388-390 (1-20-89) asserts that hypertension was linked to kidney cytochrome P450 levels, and that enzyme could be depleted by inducing heme-oxygenase production. This was done by treatment with Co2.
McCarty (Chemical Abstract, 100: 1864024 (19841 purports to teach the effect of selenium in reducing leukotrienes which are alleged to be prominent mediators of hyper-sensitivity and inflammation. McCarty, in fact, teaches the -4administration of a dietary adjuvant per os.
U.S. Patent No. 5102670 relates to the reduction of ocular swelling by administering a heme-oxygenase inducer to the swollen eye of an individual to increase production of heme-oxygenase to reduce the amount of 12(R) hydroxyeicostetraenoic acid (12(R)-HETE) present in the eye as well as 12(R) Dihydroxyeicosatrienoic acid (12(R)-DIHETE) also present in the eye. The scheme presented in the patent for reducing corneoconjunctival swelling is thus dependent on the reduction of the arachidonic acid metabolites 12(R)HETE and 12(R)DIHETE-found mainly in the eye. In particular, it is explained that the therapeutic effect is primarily on maintaining the blood aqueous barrier, a barrier not seen other than in the eye. Thus, the teachings in the patent relate solely to the eye and have very little other applicability.
During about the same time period Messrs. George S. Drummond and Hallah Kappas of The Rockefeller University, Drummond, N.Y. were involved together and with others in research relating to heme-oxygenase. The result of the research appears embodied, at least in part, in U.S. Patents No.’s 4657902; 4699903; 4684637; 5010073 and 5223494.
U.S. Patent No. 4657902 purports to teach the use of the novel compound tin mesoporphyrin and compositions containing it to inhibit heme metabolism in S mammals, to control the rate of tryptophan metabolism in mammals, and to increase the rate at which heme is excreted by mammals.
9 The patent disclosure provides as follows at Column 1, lines 22-36: “In mammals and other vertebrates heme is oxidatively degraded by heme-oxygenase to form the open chain tetrapyrrole biliverdin. In mammals biliverdin is reduced to bilirubin by biliverdin reductase. In liver bilirubin is converted to the mono- and diglucuronide conjugates by the hepatic glucuronyl transferase system prior to its excretion.
Bilirubin is a toxic compound, but normally this toxicity is not manifest since bilirubin is rapidly bound to plasma proteins, transported to liver, conjugated and excreted. However, in the newborn, high undesirable concentrations of bilirubin exist in serum and may produce neurotoxicity. The intractable neurological syndrome known as “kernicterus” is the most severe manifestation of bilirubin toxicity.” The inventors, therefore, provide at column 3, lines 43-48: “It has now been discovered that the compound Sn(tin)mesoporphyrin (SnMP) can be employed in the treatment of mammals including humans in need of such treatment to decrease the rate of heme metabolism, to increase the rate at which heme is excreted and to control the rate of tryptophan metabolism in the liver.” U.S. Patent No. 4699903 purports to teach a method of increasing the rate at which heme is excreted by a mammal in need of increased disposal of heme by administering tin diiododeuteroporphyrin.
U.S. Patent No. 4684637 discloses methods for decreasing the rate of metabolism for decreasing the rate of metabolism of heme in mammals by administration of tin or chromium protoporphrins IX.
U.S. Patent No. 5010073 purports to relate to liposomal metalloporphyrin preparations for targeting the spleen for inhibition of heme-oxygenase activity in the spleen.
a a U.S. Patent No. 5223494 purports to teach a method for inhibiting hemeoxygenase activity in the intestine by administering mesoporphyrin for reducing the absorption of iron from foodstuffs by,animals in need of such prevention.
-6- This latter group of patents relates to inhibiting heme-oxygenase in selected body tissues by targeting those body tissues (for example, the spleen or intestine) for specified purposes.
Heat shock proteins (HSPs) or stress proteins are a group of proteins that are among the most highly conserved and abundant proteins in the biosphere.
Although many of the isoforms of the proteins are expressed under normal physiological conditions and serve vital roles in the cell, they are greatly upregulated by factors which threaten the integrity of the cell. These factors include heat and cold shock, oxygen radicals, heavy metals, hypoxia, infection, ethanol, ionophores and thiol reactive agents. This increase in the cell’s concentration of HSPs leads to the cell being transiently resistant to an otherwise lethal insult, and unresponsive to some biological mediators.
The role of HSPs in pathological conditions has attracted much attention.
Immune responses to HSPs can be highly cross-reactive and even auto-reactive due to their extensive inter-species amino acid homology. Immune responses to HSPs have already been implicated in adjuvant arthritis in the rat, pristane arthritis in the mouse, diabetes mellitus in the non-obese diabetic mouse, i” rheumatoid arthritis, systemic lupus erythematosus, atherosclerosis and in tumour surveillance. Therefore, it appears that HSPs may have a paradoxical effect in pathological conditions, having a cyto-protective effect on cells and tissue in stressful environments, but eliciting a detrimental immune response in some autoimmune diseases.
Nitric oxide formed from L-arginine and molecular oxygen by isoforms of the enzyme nitric oxide synthase (NOS EC 1.14.13.39), is involved in a variety of physiological and pathophysiological processes. The reactivity of this molecule and its capacity to complex with metalloproteins, underlies many of its biological actions. For example, activation by NO of heme-containing soluble guanylate cyclase (EC 4.6.1.2) in vascular smooth muscle results in vasoregulation, whilst in host defence, inhibition of iron-sulphur enzymes causes -7metabolic dysfunction in invading pathogens.
Inflammation involves the sequential release of various mediators including vasoactive mediators, chemoattractants, cytokines, prostaglandins, free radicals and proteases. In rheumatoid arthritis, a chronic inflammatory disease, HSPs are upregulated in the synovial lining of patients. However, their role in inflammation has yet to be completely elucidated.
Objects of this invention are to provide improved (or at least alternative) means for control of inflammation, in particular treatment of chronic inflammation or stimulation of an inflammatory response, such as in treatment of an immunosuppressed condition.
We have now discovered that by controlling the amount or the activity or both the amount and the activity of heme-oxygenase in the body, either a generalized anti-inflammatory effect or response is obtained wherein hemeoxygenase is induced, or a general inflammatory response is obtained wherein heme-oxygenase is suppressed (or inhibited).
According to one aspect of our invention, inflammation is treated by administration of a compound that induces heme-oxygenase or stimulates or increases the activity of heme-oxygenase. The treatment can be systemic or targeted, for example targeted to an inducible heme-oxygenase found in monocytes and macrophages in the human body. This treatment induces hemeoxygenase production and/or stimulates its activity; specific medical applications include the treatment of chronic inflammatory diseases for example, rheumatoid arthritis, the treatment of hypersensitivity reactions such as in asthma, and, the treatment of injury, atherosclerosis and infarction.
In an embodiment of the invention, a pharmaceutical composition comprises a compound that induces, stimulates or increases the activity of heme-oxygenase, in combination with a pharmaceutically acceptable carrier. The composition is in 8the form of a solution for injection, an orally acceptable composition or a topical composition.
A suitable solution for injection includes a sterile, saline-containing solution, preferably containing saline at approximately physiological concentration.
For oral administration, the composition can be in a solid form-such as a tablet, a pill or a powder for suspension in water or for dissolution in water. The preparation of such a solid composition will be known to a person of skill in this art. It is an option to supplement the oral composition with a taste enhancing agent, to make the composition more palatable, or at least less unpleasant by mouth. Suitable taste enhancers includes sweeteners, flavourings and agents that mask or reduce any unpleasant or undesirable taste in the active component of the pharmaceutical.
In the case of a topical composition, the carrier is preferably a non-aqueous carrier adapted to retain the composition in place following application. Suitable carriers include a cream, a gel, a wax, an oil and an emulsion.
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o The invention thus provides a further anti-inflammatory pharmaceutical. It can be given orally, according to the particular compound chosen, and initial tests have demonstrated useful anti-inflammatory activity. The products of heme- 0 I oxygenase are believed to have multiple effects in the progression of inflammation, whereas the products of the enzyme targeted by most NSAIDs, cycloxygenase, have fewer effects, so the compositions of the invention present
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a pharmaceutical activity potentially more powerful than that seen in NSAIDs.
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Another embodiment of the invention is an anti-inflammatory composition comprising a heme-oxygenase inducer or stimulator and a pharmaceutically acceptable carrier.
A further embodiment of the invention is the use of a compound that induces, -9stimulates or increases the activity of heme-oxygenase in the manufacture of a medicament for the treatment of inflammation.
Agents suitable for inducing heme-oxygenase include prostaglandins of the A series; analogues, derivatives, complexes and conjugates of prostaglandins of the A series that are agonists of prostaglandin A receptors; agonists of prostaglandin A receptors; vitamin B, 2 hemin; and fragments, sub-units, conjugates, analogues, derivatives and complexes thereof that retain hemeoxygenase inhibiting activity. Suitable dosage amounts are from 0.1 to pmoles/kg ofbody weight of for example, a human. For example, where hemin (FePP) is used, suitable dosage amounts would be from about 0.06mg hemin to about 24 mg hemin per kilogram of body weight.
Alternative agents for induction or activation of heme-oxygenase are agents that inhibit or decrease nitric oxide synthesis. We have discovered a substantially reciprocal relationship between nitric oxide (NO) levels and heme-oxygenase activity wherein decreasing NO levels results in an increase in HO activity, and is anti-inflammatory. Thus, another embodiment of the first aspect of the invention is a pharmaceutical composition comprising, as an active ingredient, a substance that decreases NO levels, such as an inhibitor of nitric oxide synthetase (NOS).
According to a still further embodiment of the invention, a method of inducing (increasing) the level of heme-oxygenase in the body of a patient is provided, said method comprising administration of an effective dosage amount of hemeoxygenase inducer to reduce the inflammatory response in the patient.
In specific embodiments of the invention, inflammation is treated by inducing or stimulating a heme-oxygenase in mononuclear cells, such as in particular an inducible heme-oxygenase found in monocytes and macrophages. This is advantageous when treating chronic inflammation, typically medicated by and characterised by a large population of these cells at an inflammation site.
1[l ThLNM;fF1Yii[ITflhi~h According to another embodiment of the invention, a method of controlling the inflammatory response in the human body is provided, said method comprising reducing the inflammatory response by administration of an effective dosage amount of heme-oxygenase inducer.
Preferably, the inducer is administered in a suitable pharmaceutically acceptable vehicle in any suitable manner (for example, sterile water, saline (sterile)). A buffered, isotonic aqueous solution having a pH of between about pH7 and pH8 is suitable. Lyophilised preparations are also be suitable. The lyophilised preparations may be reconstituted with sterile water.
In preferred embodiments of the invention, specifically chronic inflammation is treated. Diseases comprising chronic inflammation that can be treated according to the first aspects of the invention include chronic inflammatory joint disease eg rheumatoid arthritis, chronic inflammatory bowel disease eg Crohn’s disease, respiratory inflammatory disease eg asthma, chronic inflammation of the brain eg multiple sclerosis, and inflammation of soft tissues eg tendonitis.
0% According to another embodiment of the invention, a method of reducing the inflammatory response in the human body generally (treating inflammation) is provided, the method comprising monitoring the presence (expression) of HSP32 isoform of heme-oxygenase and, if decreased below normal level, administering an effective dosage amount of heme-oxygenase inducer to increase expression of the heme-oxygenase enzyme to thereby reduce the inflammatory response (inflammation). The inducer is preferably targeted at monocytes and macrophages.
Dosage amount(s) can be given over a period of time. However, the effects of compounds used to date appear to peak 24 hours after administration of each dosage amount and regress at 48 hours after administration.
-11 The formulation can be in a unit dosage form (for one dosage) or may be packaged as a multiple formulation composition from which suitable dosage amounts can be extracted and used. For example, a solution in a vial may provide the multiple formulation composition from which the dosage amounts can be taken and administered. Compositions and uses of the first aspect of the invention are optionally supplemented by one or both of a NSAID, and a NOS (nitric oxide synthetase) inhibitor.
According to a second aspect of the invention, there is provided stimulation of an inflammatory response by inhibition or suppression of heme-oxygenase. In an embodiment of the second aspect, a pharmaceutical composition for stimulating or enhancing inflammation comprises a heme-oxygenase inhibitor and a pharmaceutically acceptable carrier.
The expressions “stimulate inflammation” and “enhance inflammation” are intended to indicate that at least one characteristic feature of inflammation is stimulated or enhanced; likewise the expressions “suppress inflammation”, S,*o “decrease inflammation” and variants of all these expressions.
In treatment of immunosuppression using a composition according to the second aspect of the invention, for example treatment of AIDS, a heme-oxygenase inhibitor is administered to stimulate activity of monocytes and/or macrophages.
These two cell types are crucial to fighting bacterial and viral infections, so increasing their activity offers a novel therapy, e.g. for AIDS suffers.
SAgents suitable for inhibiting heme-oxygenase (for example, inducible hemeoxygenase in monocytes and macrophages) are typically analogues of FePP (nb.
which induces heme-oxygenase) in which the Fe ion is replaced by another metal ion, or the PP is replaced. Examples are: SnPP SnMP SnDPP CrPP CrMP CrDPP ZnPP ZnMP ZnDPP MnPP MnMP MnDPP where: -12- Sn tin, Cr-chromium, Zn zinc, Mn manganese, PP protoporphyrin, MP=mesoporphyrin and DPP=diiododeuteroporphyrin Suitable dosage amounts of these agents would range from 0.1 to 50 /moles/kg of body weight of for example, a human. For example, where tin protoporphyrin (SnPP) is used, suitable dosage amounts of SnPP would be from 0.07mg/kg to 46mg/kg of body weight of a human.
Antagonists of prostaglandin A receptors are further agents suitable for decreasing hene-oxygenase activity.
Alternative agents for reducing HO activity are agents that increase NO levels.
Thus, another embodiment of the second aspect of the invention is a pharmaceutical composition comprising, as an active ingredient, a substance that increases the level of NO in a patient. The substance is, optionally, a substrate for nitric oxide synthetase (NOS) or a stimulator of this enzyme. A known substrate for NOS is L-arginine and a known NO donor is sodium nitroprusside.
According to another embodiment of the invention, a method of reducing the level of heme-oxygenase in the body is provided, said method comprising administration of an effective dosage amount of heme-oxygenase inhibitor to decrease the inflammatory response, for example, targeting an inducible hemeoxygenase found in monocytes and macrophages.
According to a further embodiment of the invention, a method of controlling the inflammatory response in the human body is provided, said method comprising activating the inflammatory response by administration of an effective dosage amount of heme-oxygenase inhibitor, for example, one that targets an inducible heme-oxygenase found in monocytes and macrophages.
The inhibitor can be administered in any suitable pharmaceutically acceptable -13 vehicle in any suitable manner (for example, sterile water, saline (sterile)). A buffered isotonic aqueous solution having a pH of between about pH7 and pH8 is suitable. Lyophilised preparations may also be suitable. The lyophilised preparations may be reconstituted with sterile water and administered.
According to another embodiment of the invention, a method of increasing an inflammatory response is provided (such as for a person suffering from AIDS), the method comprising monitoring the presence (expression) of HSP32 isoform of heme-oxygenase and, if increased above normal level, administering an effective dosage amount of heme-oxygenase inhibitor, thereby to increase the inflammatory response.
Dosage amount(s) can be given over a period of time. However, the effects of compounds used to date appear to peak 24 hours after administration of each dosage amount and regress at 48 hours after administration.
So**OO A still further embodiment of the invention is the use of a heme-oxygenase inhibitor in the manufacture of a medicament for treating immunosuppression.
Another is the use of a heme-oxygenase inhibitor in the manufacture of a medicament for increasing the activity of monocytes and macrophages.
Immunosuppression can also be caused as a side effect of other therapies, for example post transplant immunosuppression due to drugs designed to suppress rejection of a transplanted organ. Rejection is largely mediated by a T cell response in these circumstances, so immunosuppression is to remove damaging T cell activity. However, a parallel loss of monocyte and macrophage activity (usually due to decreased numbers) is also seen. Thus, another use of the second aspect of the invention is the selective stimulation of monocytes and macrophages. By “selective” it is intended to indicate that activity and/or number of these cells is increased in higher proportion to any increase in activity and/or number of T cells.
1 -14- The invention will now be illustrated in specific embodiments with reference to the figures in which:- Figure 1 illustrates the development of an acute inflammation at 2, 6 and 24 hours after injection of carrageenin into the rat pleural cavity (open boxes Cell exudate, closed boxes Total cells, n= 6 each time point); Figure 2 illustrates the measurement of HO activity as nmol bilirubin protein against time in hours during acute inflammation 6 each time point); Figure 3 is a photograph showing HSP detection by Western blot analysis, with a peak at 24 hours; Figure 4 shows the development of acute inflammation in hours after injection of carrageenin into the rat pleural cavity (E Exudate volume, Total inflammatory cells, n Figure 5 shows heme-oxygenase (HO) activity of inflammatory cells against time (hours) during carrageenin pleurisy, the activity is expressed as pmoles bilirubin/mg protein/hour, n=9 (results are expressed as the mean s.e.mean.
Peripheral blood mononuclear cells (PBMNs), E Time course of inflammatory cells); Figures 6 and 7 show Western blot analysis for heme-oxygenase isoforms: Fig. 6) Analysis of inflammatory cell pellet for HO-1. Lanes, inflammatory cells taken at 2, 6, 12, 24 and 48 hours, spleen homogenate PBL Fig. 7) Analysis of inflammatory cell pellet for HO-2. Lanes, inflammatory cells taken at 2, 6, 12, 24 and 48 hours, brain homogenate PBL (BL); Figures 8-10 show immunolocalization of inflammatory cell smears for hemeoxygenase 1 confirming increased positive staining for heme-oxygenase-1 protein in mononuclear cells: Fig. 8) Normal rabbit serum (control), Fig. 9) 6 ~r 1 hour inflammatory cell smear, Fig. 10) 48 hour inflammatory cell smear; Figures 11-16 show the effect of heme-oxygenase (HO) modulators on inflammation and HO activity: Effect of tin protoporphyrin dichloride (SnPP) on acute inflammation at 24 hours (Fig. 11 exudate volume, Fig. 12 cell number), Effect of ferriprotoporhyrin IX dichloride (FePP) on acute inflammation at 24 hours (Fig. 13 exudate volume, Fig. 14. cell number), Effect of SnPP (Fig. 15) and FePP (Fig. 16) administration on HO activity in 24 hour inflammatory cells, inflammatory cells were collected after treatment with the above porphyrtns and HO activity measured as for Figure 5, n=6. P<0.05, P<0.01 and P<0.001; Figures 17 and 18 shows the effect of NG-nitro-L-arginine methyl ester (L- NAME) on rat brain and spleen heme-oxygenase activity, Fig. 17 brain homogenates, Fig. 18 spleen homogenates 0.5, 1, 5 or 10mM of L- NAME was incubated with reaction mixture. Results are expressed as percentage activity of control (con) group which received no compound, n =8, P<0.001); Figures 19 and 20 show the effect of L-arginine on rat brain and spleen hemeoxygenase activity, Fig. 19 brain homogenates, Fig. 20 spleen homogenates. 0.1, 0.5, 1, 5 or 10mM of L-arginine was incubated with reaction mixture. Results are expressed as percentage activity of control (con) group which received no compound, n=8, P<0.05, P<0.001); Figures 21 and 22 show the effect of D-arginine on rat brain and spleen hemeoxygenase activity, Fig. 21 brain homogenates, Fig. 22 spleen homogenates. 0.1, 0.5, 1, 5 or 10mM of D-arginine was incubated with reaction mixture, S results are expressed as a percentage of control (con) group which received no compound, n= and Figures 23 and 24 show the effect of sodium nitroprusside on rat brain and 16 spleen heme-oxygenase activity, Fig.23 brain homogenates, Fig. 24 spleen homogenates. 0.001, 0.01, 0.1, 1 or OmM sodium nitroprusside was incubated with reaction mixture, results are expressed as a percentage of control (Con) group which received no compound, n=8, P99 0 0 MNs <1 N. D. D. 12 hours PMNs>99 0 0 MNs 1 N. D. N. D.
24 hours PMNs 62 0 0 MNs 38 36 41 48 hours PMNs 30 0 0 MNs 70 89 46 1Immunocyto chemical analysis of inflammatory cell smears.
.Relative percentage of polymorphonuclear cells (PMNs) and mononuclear cell (MNs) in inflammatory cell smear. Percentage of PMNs and MNs present, which are positive for heme-oxygenase isoforms. N.D. insufficient cells present for analysis.
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a a 28 Table 3 brain n=8 spleen Heme-oxygenase activity pmol 40±4 85-5 bilirubin/mg nitric oxide synthase activity pmol 358 +78 2.38 1 citrulline/mg Heme-oxygenase and nitric oxide synthase activity in rat brain and spleen homogenates. Mean s.e.mean.
Thus, control of inflammation according to the invention is achieved, in embodiments of the invention, by control of HO, or control of levels of nitric oxide, alone or in combination with control of HO.
As many changes can be made to the embodiment of the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.
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Claims (33)

1. Use of a compound that alters activity, or amount, of heme-oxygenase in a mammal, in the manufacture of a medicament for control of inflammation; provided that the compound is not Vitamin B 12

2. Use according to Claim 1 of a compound that increases heme-oxygenase activity in the manufacture of a compound for the treatment of inflammation.

3. Use according to Claim 2 of a compound that induces heme-oxygenase.

4. A pharmaceutical composition for the treatment of inflammation, said composition comprising a compound that increases heme-oxygenase activity provided that the compound is not Vitamin B 12 wherein said composition is in the form of a tablet, a pill, a powder for suspension in aqueous solution, a powder for dissolution in aqueous solution, a topical preparation further comprising an oil, a wax, a gel, a cream or an emulsion, or is a sterile aqueous solution for injection. A pharmaceutical composition according to Claim 4 comprising a compound that increases heme-oxygenase activity selected from a prostaglandin of the A series; an agonist of a prostaglandin A receptor; hemin; and a fragment, sub-uni, conjugate, analogue, derivative or complex of hemin retaining heme-oxygenase inducing activity.

6. A pharmaceutical composition according to Claim 4 o 30 or 5 further comprising a taste enhancing agent and being for oral administration.

7. Use of a compound that increases heme-oxygenase eeeeo J:\Speci\200 299\250 299\29797.dc 15/10/99 activity in the manufacture of a medicament for treatment of chronic inflammation.

8. Use of a compound that increases heme-oxygenase activity in the manufacture of a medicament for treatment of a disease selected from rheumatoid arthritis, a chronic inflammatory bowel disease, multiple sclerosis, asthma, airways inflammatory disease, tendonitis and chronic inflammation in the brain.

9. use according to Claim 1 of a compound that decreases heme-oxygenase activity in the manufacture of a medicament for stimulating an inflammatory response. Use according to Claim 9 of a heme-oxygenase inhibitor.

11. Use according to Claim 10 wherein the heme- oxygenase inhibitor is an analogue of FePP.

12. Use according to Claim 11 wherein the analogue is selected from SnPP, SnMP, SnDPP, CrPP, CrMP, CrDPP, ZnPP, ZnMP, ZnDPP, MnPP, MnMP, MnDPP, wherein PP equals protoporphyrin, MP equals mesoporphyrin and DPP equals diiododeuteroporphyrin.

13. Use according to any of Claims 9-12 in the manufacture of a medicament for treatment of Simmunosuppression.

14. Use according to Claim 13 in the manufacture of a medicament for treatment of AIDS.

15. Use according to any of Claims 9-14 in the manufacture of a medicament for stimulation of mononuclear cells. A method of controlling inflammation in a patient 30 comprising administration of a pharmaceutical composition that alters the activity of heme-oxygenase, provided that the composition does not contain Vitamin B 12

17. A method according to Claim 16 for reducing J:\Spec200 299\250 299\29797.dc 15/10/99 I inflammation comprising administration of a compound that increases heme-oxygenase activity or increases heme- oxygenase levels.

18. A method according to Claim 17 comprising administration of a heme-oxygenase inducer.

19. A method according to Claim 16 or 17 comprising administration of a prostaglandin A receptor agonist. A method according to Claim 16 for stimulation of an inflammatory response comprising administration of a compound that decreases heme-oxygenase activity.

21. A method according to Claim 20 comprising administration of a heme-oxygenase inhibitor.

22. A method according to Claim 21 comprising administration of an analogue of FePP, wherein the analogue inhibits heme-oxygenase.

23. A method according to any of Claims 20-22 for the treatment of immunosuppression, such as seen in AIDS.

24. Use of a compound that alters activity, or amount, of heme-oxygenase in a mammal for control of inflammation, provided that the compound is not Vitamin S. B12.

25. Use according to claim 24 of a compound that increases heme-oxygenase activity for the treatment of inflammation. 25 26. Use of according to claim 25 of a compound that induces heme-oxygenase.

27. Use of a compound that increases heme-oxygenase activity for treatment of chronic inflammation.

28. Use of a compound that increases heme-oxygenase 30 activity for treatment of a disease selected from rheumatoid arthritis, a chronic inflammatory bowel disease, ooo JASpcc2(X) 29\250 299\29797 dc 15/09/99 32 multiple sclerosis, asthma, airways inflammatory disease, tendonitis and chronic inflammation in the brain.

29. Use according to claim 24 of a compound that decreases heme-oxygenase activity in the manufacture of a medicament for stimulating an inflammatory response. Use according to claim 29 of a heme oxygenase inhibitor.

31. Use according to claim 30 wherein the heme- oxygenase inhibitor is an analogue of FePP.

32. Use according to claim 31 wherein the analogue is selected from SnPP, SnMP, SnDPP, CrPP, CrDPP, ZnPP, ZnMP, ZnDPP, MnPP, MnMP, MnDPP, wherein PP equals protoporphyrin, MP equals mesoporphyrin and DPP equals diiododeuteroporphyrin.

33. Use according to any of claims 29 to 32 for treatment of immunosuppression.

34. Use according to claim 33 for treatment of AIDS. Use according to any of claims 29 to 34 for stimulation of mononuclear cells.

36. A pharmaceutical composition when used for the treatment of inflammation, said composition comprising a compound that increases heme-oxygenase activity, provided :that the compound is not Vitamin B 12

37. Use of a compound according to any one of claims 25 1, 7 or 8, the use being substantially as described herein with reference to the Examples.

38. A method of controlling inflammation according to a. a claim 16, the method being substantially as described herein with reference to the Examples. 30 39. Use of a compound according to any one of claims 24, 27 or 28, the use being substantially as described herein with reference to the Examples.

40. A composition according to claim 4, the composition being substantially as described herein with reference to the Examples. J:\Speci\2(X) 299\250 299\29797.doc 15/09/99 ~I j

41. A composition according to claim 36, the composition being substantially as described herein with reference to the Examples. Dated this 15 October 1999 WILLIAM HARVEY RESEARCH LIMITED By their Patent Attorneys GRIFFITH HACK

AU54955/99A
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Method for stimulating production of heme oxygenase using vitamin b12.

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