Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-11-15
2003-08-26
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S232800, C514S912000
Reexamination Certificate
active
06610686
ABSTRACT:
The present invention concerns the use of pirenoxine for the protection of the corneal tissues in photokeratectomy interventions. More particularly, the invention concerns the use of pirenoxine and salts thereof as agents able to inhibit within the cornea the oxidative phenomena determined by reactive oxygen species (or ROS, reactive oxygen species) which are produced in the tissues following the laser irradiation.
As known, the ophthalmic surgery, and particularly the refractive one, which aims to modify the eye refractive power in order to correct not negligible visual defects makes use of various, less or more consolidated or in evolution techniques, some examples of which are radial keratectomy, epikeratofachia and keratomileusis. In addition to these, also in the ophthalmology field the use of laser, particularly solid state laser, (like neodymium:yttrium-aluminiumrnarnet laser, known as Nd:YAG), and, above all, excimer laser, is remarkably increased.
Excimer laser is a pulse laser which, due to the decay of excited noble gas dimers (excimers obtained from gas mixtures of halogen and noble gases), are able to emit large amounts of energy in form of radiation within the range of far ultraviolet (UV-C), in the form of pulse trains having predetermined duration, frequency and fluence. Any photon emitted during the irradiation has enough energy to break the intramolecular bonds of the exposed material, in such a way that the irradiated molecules are “broken” in small volatile fragments which are expulsed at supersonic speed embodying a process known as “photodecomposition”.
In the applications using the excimer laser in corneal surgery interventions usually an argon-fluorine laser, emitting radiation with a wavelength of 193 nm, which is suitable to carry out highly precise interventions with an optimal control on the penetration depth and a minimal thermal or mechanical damage effect on adjacent to exposed tissues, is usually employed. Contrary to other lasers used in clinical field, the excimer laser does not emit energy concentrated in a focal point but it has a radius with a large cross section which, going through suitable slits, is directed to strike large surface cornea zones with an accurate control of the shape and sizes of the exposed zones. The emitted energy is almost totally adsorbed by a surface layer within a thickness of few microns and results, by means of evaporation, in ablation at every pulse of cornea layers little more thicker than molecular, with a reproducibility not attainable by other techniques.
The excimer laser is widely used for corneal refractive re-modelling in techniques known as photorefractive keratectomy or PRK and LASIK (laser intrastromal keratomileusis), for the correction of various ametropias among which the most diffused is myopia. As known, the latter is a defect determined by a cornea curvature higher than required by the length of ocular bulb, so that light rays from outside are refracted in a such way that, before to reach the retina, they converge in a focal point. In this circumstance the use of excimer laser provides that layers of corneal tissue, the thickness of which is increasing toward the centre, be ablated reducing therefore the curvature of the cornea. When the technique is used for the correction of hypermetropia, wherein, on the contrary, the modification to be obtained is an increase of the cornea curvature, the amount of ablated tissue within the periphery of the exposed zone is more important than in the centre. Finally for the correction of the astigmatism which, as known, is an ametropia caused by curvature difference in various meridians of the ocular surface, the depth of the ablation can be asymmetric, depending on the meridian to be “flatted”.
More recently the use of the excimer laser has been suggested for the therapeutic removal of surface corneal tissues, for the treatment of various corneal irregularities and opacities: like of dystrophic, degenerative, cicatricial or infective type. Such an operation, called phototherapeutic keratectomy or PTK, has been used, for example, for the treatment of recurrent corneal erosions, post-operation kerattis, corneal dystrophies as Reis-Buckler dystrophies, corneal opacities or cicatrices caused by Herpes simplex, surface irregularities following surgical interventions, for example as outcomes from keratoplasty or refractive corneal interventions. Contrary to refractive photokeratectomy PTK aims to eliminate irregularities on the corneal surface in order to flat the profile thereof and therefore involves the ablation of tissue layers with different thickness in the various zones of treated corneal surface.
Although the above described photokeratectomy interventions appear to be an alternative less traumatic than surgical ophthalmic techniques, the restorative process after the photoablation is not without drawbacks which are less or more transitory and boring or dis-enabling for the patient, among which, for example, there are corneal cicatricial problems, generation of under-epithelial opacities called “haze”, which determine a reduction of visual efficiency resulting from “light scattering” phenomenon (light diffusion) and, in some circumstances, a reduction of refractive values as result of operation. It appears to be not debatable by those skilled in the field that at least partially such effects result from the formation of free radicals and, generally, reactive oxygen species, which was detected as side effect of UV irradiation and temperature increase occurring in the involved tissues.
As known the term “reactive oxygen species (or substances)”, or ROS, presently collectively means the free radicals and not radical chemical species which currently take part into oxidative biological processes and whose excess with respect to the natural equilibrium conditions is considered to be the base of an ever increasing number of degenerative and pathological phenomena. Specifically the term ROS comprises superoxide anionic radical O
2
., hydroxyl radical OH
−
, singlet oxygen
1
O
2
and the hydrogen peroxide, H
2
O
2
, as well as alkoxide RO. and peroxide ROO. radicals which are generated from organic molecules during the oxidative processes. The activity of these species exerts, within the organism, on various cellular components, among which there are a large number of structural proteins and enzymes, DNA, RNA and, above all, the membrane lipids.
In fact the lipid peroxidation is the most known mechanism by which ROS exert their degenerative activity on the cellular structures damaging polyunsaturated fatty acids (PUFA) contained in the cytoplasmic membranes, often as phospholipid esters. In the initial step of this process the action of a free radical abstracts an hydrogen atom H. from the lipid chain, forming a free radical R* which undergoes a molecular rearrangement of the double bonds resulting in a conjugated diene radical. The latter rapidly reacts with molecular oxygen forming thus a lipid peroxide radical ROO., which, being a so strong oxidant to attack another PUFA, starts the propagation step of the reaction. In such a way a lipid hydroperoxide radical, ROOH; and, correspondingly, another lipid peroxide radical ROO., are formed. Therefore the above described main branch of the reaction occurs by means of radical chain attacks to the membrane lipids which are thus transformed step by step in the corresponding hydroperoxides till to the chain termination by means of a free radical.
Various agents naturally occurring in the cellular tissues can perform the above described action, practically functioning as scavengers or antoxidants. Among these the most known are C (ascorbic acid) and E (alpha tocopherol) vitamins, antioxidant enzymes as superoxide dismutase (SOD), catalase, gluthatione peroxidase and various low molecular weight compounds, among which gluthatione (GSH), tyrosine, uric acid. The natural protection from oxidative stresses performed by these substances, however, can not be enough strong to antagonize the degradation effect of ROS, in whic
Enrico Boldrini
Mario Ciuffi
Ausimont S.p.A.
Bryan Cave LLP
Fay Zohreh
LandOfFree
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