Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1999-06-11
2001-03-13
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S182000
Reexamination Certificate
active
06200966
ABSTRACT:
This invention relates to a method of treating chronic and acute inflammation of the airways, including asthmatic conditions. The invention also relates to steroid or steroid analogues used in the treatment, and to pharmaceutical compositions comprising these compounds as the active agent. In a preferred embodiment, the active component inhibits inflammation and smooth muscle cell proliferation in the airway wall. It may also have at least one other activity selected from anti-angiogenesis, anti-oxidation and the ability to disrupt microtubule formation.
BACKGROUND OF THE INVENTION
Two distinct classes of agents are currently used in the treatment of asthma. Symptomatic relief is provided by using bronchodilators which include the &bgr;
2
-adrenoceptor agonists such as salbutamol and salmeterol. Other agents with bronchodilatory properties include the muscarinic-receptor antagonist, ipratroipium bromide, and phosphodiesterase inhibitors such as theophylline.
The second class of agents is prophylactic, and includes glucocorticoids such as beclomethasone dipropionate. Disodium cromoglycate and nedocromil sodium are also used, even though these are less effective than the glucocorticoids.
However, none of these agents completely reverses airway hyperresponsiveness or prevents catastrophic life-threatening and fatal episodes of asthma in all patients. The fact that these conditions prevail and sometimes are the cause of death highlights the fact that the benefits from these agents are sub-optimal.
Asthma is now regarded as a disease of chronic airways inflammation characterised by eosinophilic bronchitis [Frigas et al., 1991]. In common with other chronic inflammatory diseases, the inflammation in asthma initiates tissue remodelling, which has been documented in the airways in post mortem studies [Dunnill et al., 1969] and by bronchial biopsy from living donors [Brewster et al., 1990; Bai & Pare, 1995]. The remodelling involves: epithelial sloughing; marked infiltration of eosinophilis into the mucosa; activation of mast cells and lymphocytes; enlargement of mucous glands; deposition of wound-type collagen immediately below the true basement membrane of the epithelium and throughout the mucosa; and an increase in the number of myofibroblasts. In addition, there is an increase in the volume and number of blood vessels in asthmatic airways, indicating that an angiogenesis accompanies the remodelling process [Kuwano et al., 1993]. The overall volume of the airway wall is increased [James et al., 1989] in association with an increase in the volume of airway smooth muscle [Kuwano et al., 1993] which results from both hypertrophic and hyperplastic responses [Ebina et al., 1993].
Airway hyperresponsiveness (AHR) is the excessive bronchoconstrictor response of asthmatic subjects to a diverse array of stimuli. The concept that the airway wall thickening is central to the development of AHR has gained acceptance during the last 10 years. The thickening of the airways has been shown by mathematical modelling studies to amplify the consequences of smooth muscle shortening—a given amount of smooth muscle shortening is calculated to cause a much greater increase in airways resistance in asthmatics compared with healthy subjects (e.g. 40 % shortening gives a 15-fold increase in healthy subjects, but a 290-fold increase in asthmatics) [James et al., 1989]. The airway wall area is increased by 50-250%, with larger increments being observed in the larger airways [James et al., 1989]. The muscle increases in volume by 2-3 fold, and the extent of the increase is related to the severity of asthma [Kuwano et al., 1993]. The nature of the change has not been extensively investigated, but it comprises both hyperplasia and hypertrophy [Ebina et al., 1993]. After prolonged allergen avoidance by allergic asthmatics, decreases in airways responsiveness to the levels observed in healthy subjects have been demonstrated, and are accompanied by a resolution of the symptoms [Platts-Mills et al., 1987]. Studies such as this are consistent with the notion that the structural changes in the asthmatic airway are also reversible.
These long-term changes in the asthmatic airway offer new targets for therapeutic intervention [Stewart et al., 1993]. Consequently there has been considerable interest in identifying the mechanisms for this airway wall remodelling response and the influence of existing anti-asthma drugs on these processes. A large number of factors have been established as mitogens for cultured airway smooth muscle from various species, including humans [see Stewart et al., 1995a for a review]. As expected, the stimuli belonging to the growth factor families, including basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF
BB
) and epidermal growth factor (EGF) are the most effective proliferative agents [Hirst et al., 1992; Stewart et al., 1995a]. Thrombin is also an effective growth factor [Tomlinson et al., 1994], whereas bronchoconstrictors such as endothelin-1 and the thromboxane A
4
mimetic, U46619, are only weakly active, and some other constrictors such as histamine and neurokinins are completely inactive [Stewart et al., 1995a].
In human cultured airway smooth muscle, continuous exposure to &bgr;-adrenoceptor agonists reduces the proliferative responses to a wide range of mitogens, including thrombin, EGF and the thromboxane A, analogue, U46619 [Tomlinson et al., 1994; 1995]. Furthermore, dexamethasone and other anti-inflammatory steroids also have an anti-proliferative effect on cultured airway smooth muscle [Stewart et al., 1995b], but the magnitude of the inhibition depends on the mitogen that stimulates proliferation in the first instance. It is also important to note that long-term treatment with inhaled anti-inflammatory steroids produces only a modest reduction in AHR [Sotomayor et al., 1984; Lungren et al., 1988], whereas &bgr;
1
-agonists are reported to have either no effect or to increase AHR [Wahedna et al., 1993]. Thus, the two most commonly used and most effective drug classes for the treatment of asthma have sub-optimal effects on AHR, and are therefore unlikely to be effective in regulating the structural changes associated with airway remodelling that contribute to the progression and development of the condition.
We have been investigating potential ways of arresting or modulating the remodelling process and have surprisingly identified a steroid and analogues thereof whcih are suitable for this purpose.
SUMMARY OF THE INVENTION
2-methoxyestradiol is a natural metabolite of 17&bgr;-estradiol, the physiological estrogen in humans.
It is produced in a two-step process, involving hydroxylation of oestrogen to produce a catecholoestrogen followed by methoxylation to produce the corresponding methoxyestrogen by an inducible cytochrome p450 pathway [Spink et al., 1994]. Hitherto considered to be biologically inactive [Rosner et al., 1991], in cell culture studies it has been established that 2-methoxyestroadiol inhibits proliferation of certain transformed cell lines [Lottering et al., 1992] and of actively proliferating or non-quiescent endothelial cells and fibroblasts [Fotsis et al., 1994]. Fotsis et al also showed that administration of 2-methoxyestradiol inhibited the growth of tumurs by suppressing tumour-induced angiogenesis, rather than by direct inhibition of tumour cell proliferation. It was proposed that the compound reduced basal membrane breakdown, thus preventing cell migration into the extracellular matrix and rendering it a potential anti-angiogenic agent for the treatment of solid tumours or angiogenic diseases. Inhibition of tumour neovascularization was also demonstrated in Klauber et al, 1997.
The anti-proliferative effects of 2-methoxyestradiol on cultured smooth muscle cells from rabbit aorta &lsqb
Amrad Operations Pty. Ltd.
Merchant & Gould P.C.
Spivack Phyllis G.
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