Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-06-29
2001-07-03
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S299000
Reexamination Certificate
active
06255338
ABSTRACT:
The present invention relates to the use of calcium intracellular store inactivators such as sesquiterpene lactones, particularly thapsigargin derivatives, and formulations thereof, as cell growth inhibitors, particularly lens cell growth inhibitors. In particular, the invention relates to intraocular lenses coated with such inhibitors.
It is a well-known technique, when a person is suffering from a cataract in the eye, surgically to remove the defective natural lens and implant an artificial lens (intraocular lens or IOL) into the lens capsular bag of the eye. Such artificial lenses are commonly comprised of a plastics material such as polymethyl methacrylate (PMMA) and other acrylic polymers, although silicone-based materials may also be used.
However, one of the well-recognised problems with this technique is that, after a relatively short period of time—a matter of months, perhaps and usually within two to three years—of effecting the lens-replacement operation, a so-called ‘after-cataract’ may form in the eye. After-cataract is also known as posterior capsular opacification. This after-cataract is caused by lens cells, still present on the anterior capsule of the bag, growing on to the lens posterior capsule (and the anterior surface of the IOL), producing lens proteins and wrinkling of the lens capsule, causing light entering the eye to be scattered.
Various attempts have been made to study the growth of such after-cataracts and of finding ways of preventing or treating such developments. For example, heparin-coated artificial lens has been reported (Cohen et al in JERMOV, Montpellier Meeting, Programme and Abstract Book (1994)) in which FGF (fibroblast growth factor) is attached to heparin and a growth inhibitor attached to the FGF. As the lens cells themselves contain FGF receptors, the heparin-FGF may bind to the lens cells, bringing with it the growth inhibitor which, it is hoped, in turn will kill the lens cells themselves. However, to test whether this system works, there has hitherto been possible only a crude in vitro test which is an attempt to simulate what happens to such an artificial lens in the patient's eye.
In the past, in vivo testing has been done in primates since lower animals do not provide as closely similar an environment to that in humans for the IOL. In lower animals, cells other than lens cells (as well as the lens cells themselves) tend to become involved in the formation of the after-cataract. However, testing on primates is expensive and may still not be fully representative of the human system. Hitherto, the only alternative to such in vivo testing has been in vitro testing by traditional culture methods in which isolated lens cells of the anterior capsule are monitored for growth under usual culture conditions. The present inventors have provided a method for culturing human body cells or tissue suitable for transplanting, which method comprises affixing at discrete points a plurality of such cells to a substrate which itself further comprises a suitable culture medium for the growth of such cells or tissue. For example, it is now possible to culture lens cells by affixing a capsular bag (containing an IOL) at discrete points thereof to a substrate such as a culture dish (for example a Petri dish) which substrate further comprises a suitable culture medium for growth of the lens cells and for representing the natural environment of the capsular bag in the eye.
It has now been found that compounds which inhibit release of the intracellular calcium store (either by “locking” the store in its full or empty states) inhibit or prevent the growth of lens epithelial cells. At least one such compound, a hydrophobic sesquiterpene lactone known generically as ‘thapsigargin’, is already known. Thapsigargin itself can be extracted from giant hogweed plants or Thapsiagarnica species. Another hydrophobic sesquiterpene lactone, also known (The Messenger 3(1) 1994), is 8-debutanoyl thapsigargin.
Thapsigargin has been described as a tumour-promoter (i.e. which promotes, not inhibits, cell growth) and has been said to affect the calcium ion concentration in intracellular stores so that it produces a histamine response on human skin (Thastrup et al in Proc. Natl. Acad. Sci. USA 87 2466-70 (1990) and Agents Actions 43 187-93 (1994)). Ghosh et al have reported on persistent intracellular calcium pool depletion by thapsigargin and its influence on cell growth (in Journal of Biol. Chem. 266 24690-7 (1991)), but no pharmaceutical composition, delivery device or use has been ascribed to the compound in the context of the eye or cell growth inhibition.
Furthermore, work previously carried out with thapsigargin was undertaken by adding it to a solution of bathing tissue-culture cells. Prior to work carried out by the present inventors, a method did not exist for determining whether or not thapsigargin could inhibit lens cell growth on native cells (i.e. on cells in vivo or ex vivo). Using the method mentioned above, and described in Example 1 hereof and further expounded by Liu et al in Investigative Ophthalmology & Visual Science, 37(5) 906-14 (1996), it was found that not only is thapsigargin effective in inhibiting or preventing the growth of intraocular lens epithelial cells but also that other inhibitors of intracellular calcium store release are effective in so doing.
The present invention now provides a compound suitable for use as a cell growth inhibitor, in particular an intraocular lens epithelial cell growth inhibitor, comprising a calcium intracellular store inactivator, such as either an inhibitor of calcium ATP-ase present in the endoplasmic or sarcoplasmic reticulum which is inert with respect to plasma membrane calcium ATP-ase or an inositol trisphosphate-(IP
3
)-release channel blocker.
Preferably, the compound is lipophilic or hydrophobic and exhibits antimigratory, antiproliferative or cytotoxic characteristics with respect to lens epithelial cells.
Examples of calcium ATP-ase inhibitors are thapsigargin or certain derivatives thereof and cyclopiazonic acid of formula
(N. W. Seidler et al J. Biol. Chem. 30 17816-23 (1989)); while examples of IP
3
-channel blockers include caffeine. The compound preferably comprises thapsigargin or a derivative thereof especially where the 7- and 11-hydroxy groups thereof remain functional. The invention therefore further provides a compound of formula (I):
or a salt, ester or prodrug thereof (hereinafter collectively referred to as ‘a compound of formula (I)’), other than thapsigargin or 8-debutanoylthapsigargin, as defined hereinabove. Preferably R
1
and R
2
are straight chain alkyl such as C
3
to C
10
alkyl. More preferably R
1
is at least heptyl (C
7
H
15
) and R
2
is at least propyl (C
3
H
7
).
The present invention therefore further provides a calcium intracellular store inactivator such as a compound of formula (I), including thapsigargin and 8-debutanoylthapsigargin per se, for use as a medicament in the treatment or prevention of cell growth and in particular intraocular lens epithelial cell growth.
However, even once the use of calcium intracellular store inactivators such as thapsigargin, cyclopiazonic acid and caffeine as lens cell growth inhibitors in vivo and ex vivo was invented by the present inventors, there remained the problem of how most appropriately to deliver them to an eye in need of such treatment.
Surprisingly, it has been found that such compounds can be-coated on an IOL which can then be used to deliver calcium intracellular store inactivator into the capsular bag of the eye. The IOL may be coated either ex vivo and then implanted into the eye for slow release of the compound or it may be coated in vivo during the final stages of cataract surgery by means of injecting the calcium intracellular store inactivator behind the IOL in situ. Therefore, an especially preferred aspect of the present invention is the use of the compound, such as a compound of formula (I), for coating an intraocular lens.
Furthermore, the present invention provides a method for preventing or inhibiting
Davies Peter
Duncan George
Liu Christopher
Wormstone Michael
Robinson Binta
Rotman Alan L.
Synnestvedt & Lechner LLP
The University of East Anglia
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