IE83778B1 - Method and products for treating the eye - Google Patents
Method and products for treating the eyeInfo
- Publication number
- IE83778B1 IE83778B1 IE1992/0817A IE920817A IE83778B1 IE 83778 B1 IE83778 B1 IE 83778B1 IE 1992/0817 A IE1992/0817 A IE 1992/0817A IE 920817 A IE920817 A IE 920817A IE 83778 B1 IE83778 B1 IE 83778B1
- Authority
- IE
- Ireland
- Prior art keywords
- molecule
- masking agent
- acid
- composition
- eye
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- Y10S514/913—
Description
Title
Method and Products for Treating the Eye
Glaucoma is any condition of the eye characterized by elevated intraocular
pressure. It may be chronic or acute, and may be due to disease, injury, or the result of
conventional operative techniques. Glaucoma can cause loss of sight, loss of light
perception and/’or intense pain.
There are various treatments for glaucoma, although none are entirely satisfactory
for all indications. A relatively recent advance in the treatment of glaucoma is disclosed
in U.S. Patent 4,757,089 to Dr. David L. Epstein. This patent discloses a method for
treating glaucoma by increasing aqueous humor outflow in the eye of a patient, thereby
reducing intraocular pressure. Increasing outflow is accomplished by treating the eye
with a molecule that contains a group capable of reacting with the sulfhydryl groups in
the trabecular meshwork of the eye, and in particular treating the eye with ethacrynic
acid and analogs thereof.
The present invention involves substantial improvements to the subject matter of
the foregoing patent.
Accordingly, in a first aspect of the invention, there is provided the use of a
masking agent (a) in the manufacture of a medicament, for use in the treatment or
prevention of glaucoma with a molecule (b) having one or more groups capable of
reacting with sulfliydryl groups in the trabecular meshwork of the eye, to increase
aqueous humor outflow, said masking agent (a) being capable of reversibly binding to
the sulfhydryl reactive group(s) in the molecule (b) and thereby preventing said
molecule from causing a medically unacceptable side effect.
In a second aspect of the invention, there is provided a composition for use in the
treatment or prevention of glaucoma comprising a molecule having one or more groups
capable of reacting with sulfhydryl groups in the trabecular meshwork of the eye to
increase aqueous humor outflow, characterised by further comprising a masking agent
capable of reversibly binding to the sulfhydryl reactive group(s) in the molecule in a
sufficient amount to thereby prevent said molecule from causing a medically
unacceptable side effect.
In a third aspect of the invention, there is provided a device for delivering a
composition according to the second aspect of the invention comprising a container
constructed and arranged to deliver an ophthalmic preparation topically to the eye and
an opthalmic preparation contained in the container, wherein the opthalmic preparation
includes the composition or precursors thereof in an amount sufficient for delivering a
therapeutically effective dose.
Preferred embodiments of the invention in any of its various aspects are as
described below or as defined in the sub claims.
Thus, the invention relates to compositions for the safe and effective treatment
of the eye with molecules that contain one or more groups capable of reacting with
sulfhydryl groups in the trabecular meshwork of the eye. In conjunction with
delivering the sulfhydryl—reactive molecule to the eye, a masking agent is administered
in sufficient amount to prevent medically unacceptable side effects, which otherwise
could occur without administering the masking agent. The masking agent forms with
the sulfhydryl-reactive molecule an adduct, thereby protecting the sulfhydryl groups of
the cornea from harmful Chemical interaction with the molecule.
The products of the invention and their use for manufacturing medicaments are
particularly useful in treating or preventing glaucoma.
One embodiment of the invention features topical application of the foregoing
adduct, and preferred adducts are those of ethacrynic acid or analogs thereof.
Application of an excess of masking agent can improve the results. The topical
treatment may include administration of a delivery enhancing agent as well. The
adducts, masking agents and delivery enhancing agents may be provided in
pharmaceutically acceptable ophthalmic preparations and may be contained in
containers constructed and arranged to deliver topically to the eye the ophthalmic
preparations.
The invention provides compositions for effective, non—surgical treatment of
glaucoma in a manner to increase fluid outflow while preventing medically
unacceptable side effects. Other features and advantages of the invention will be
apparent from the following description of the preferred embodiments thereof, and from
the claims.
As described above, the invention relates to compositions for the treatment of
glaucoma with sulfhydryl-reactive molecules used in conjunction with masking agents.
It has been discovered that when therapeutically active molecules bearing sulfhydryl
reactive groups are applied to the eye, medically unacceptable side effects may follow.
One such side effect is corneal edema. Corneal edema is a condition evidenced by
abnormal accumulation of fluid within the intercellular spaces of the comea. Clinical
symptoms of corneal edema include corneal haziness and increased corneal thickness,
apparent upon ophthalmoscopic examination. A major cause of corneal edema is
impaired function of the corneal endothelium, the cell layer covering the inner surface
of the cornea, in response to certain chemicals or conditions. The corneal endothelium is
known to possess sulfhydryl groups.
According to one aspect of the invention, medically unacceptable side effects, in
particular corneal edema, can be avoided by creating conditions which reduce or prevent
the interaction between the sulfhydryl reactive groups of the therapeutic molecules and
the sulfhydryl groups in the corneal cells. This may be accomplished by delivering the
molecules in conjunction with masking agents. These masking agents are
biocompatible, and bind reversibly to the sulfhydryl reactive groups on the
therapeutically active molecules. The compound formed by the binding of the
therapeutically active molecule and the masking agent is called an adduct. When
topically applied to the surface of the eye, such an adduct crosses the cornea without
causing corneal edema. Surprisingly, the topical application of the adduct still results in
an increase in aqueous humor outflow. Thus, the use of the masking agent, by
decreasing medically undesirable side effects and increasing the margin of safety,
allows the use of therapeutic compounds at dosages which would otherwise be clinically
unacceptable.
Although not wishing to be bound by any theory of the invention, it is believed
that the adducts pass through the cornea and then enter the aqueous humor where they
dissociate to release the therapeutically active molecules. The sulfhydryl-reactive
groups on these molecules then may react with the sulfhydryl groups in the trabecular
meshwork, as described in U.S. Patent 4,757,089 (Epstein, issued July 12, 1988)
causing an increase in the outflow of aqueous humor from the eye, which is beneficial
in the medical management of glaucoma.
The preferred molecules useful in the methods of the invention have a number of
properties, now discussed in greater detail.
Sulfhydryl Reactivity
The molecules contain chemical groups which are capable of reacting with the
sulfhydryl groups of the trabecular meshwork to increase aqueous humor outflow. The
molecules react with the sulfhydryl groups in a manner which does not cause an
unacceptable amount of swelling of the cells of the trabecular meshwork, particularly
the inner wall endothelial cells of Schlemm's canal, because swelling can decrease
outflow. "Unacceptable amount of swelling", as used herein, means an amount of
swelling which counteracts the outflow increasing effects of the compounds, resulting in
no net outflow increase.
Whether swelling is caused by a pa11icular compound can be determined by
testing the compound in the system described in Epstein et al. (1982) Invest.
Ophthalmal. Vis. Sci. 22, 6, 752-756, and examining the trabecular meshwork cells
morphologically.
Suitable sulfhydryl reactive groups include C=C, C=O, sulfliydryl, alkyl (e.g.,
methyl or ethyl) and aryl (e.g., phenyl) substituted with a good leaving group, e.g.,
halogen, tosyl, or mesyl. Preferably, in the case of substituted alkyl groups, substitution
is primary, rather than secondary or tertiary, for greater reactivity.
In the preferred embodiment, the therapeutically active molecule is ethacrynic
acid. The structural formula of ethacrynic acid is:
Other embodiments of suitable therapeutically active molecules include analogs of
ethacrynic acid. An analog is a molecule which is structurally similar to the parent
molecule, and is capable of achieving the same or substantially the same function or
activity in terms of increasing aqueous humor outflow. Specific embodiments of
suitable molecules of the invention include analogs of ethacrynic acid and their ester or
amide derivatives, and pharrnaceutically acceptable salts thereof, being of the general
formula
wherein each X1 and X2, independently, is a halogen, H, or CH3, or X1 and X;
together form a substituted or unsubstituted aromatic ring; X3 is an organic group,
preferably, a sulfhydryl reactive organic group as defined above; X4 is OH or an organic
group; and where, preferably, each X1 and X3, independently, is H, Cl, CH3, or X1 and
X3 together form a phenyl ring; X3 is one of chloropropanoyl, tosyl or rnesyl; and X4 is
one of hydroxy, amino or alkoxy. Specifically, preferred embodiments of analogs of
ethacrynic acid include the following molecules:
Medically unacceptable side effects, which may result from interaction of the
molecules described above with corneal sulfhydryl groups, are prevented by masking
the sulfhydryl reactive groups of the therapeutically active molecules with a masking
agent in a reversible chemical reaction. A masking agent is an agent which is capable of
preventing the sulfhydryl reactive group of the therapeutically active molecule from
participating in chemical reactions with the sulfhydryl groups on and within the cornea.
The kinetics of the binding reaction between the active molecule and masking agent are
such that while comeal toxicity is prevented by formation of the adduct, the adduct
dissociates, allowing outflow—increasing interaction between the unbound active
molecule and the sulfhydryl groups of the trabecular meshwork.
The masking agent reacts with the sulfhydryl reactive group of the active
molecule by the conjugate addition reaction known as the Michael reaction. An example
of chemical systems that undergo the Michael reaction is alpha, beta—unsaturated
carbonyl compounds of general formula I. Nucleophiles (:Nu) readily add to I to yield
the Michael addition product 11. One chemical property of the Michael reaction is its
reversability under which the addition product may disassociate to yield the two
reactants. In the presence of another nucleophile (:B) an exchange reaction may occur to
yield a different Michael addition product (111). This subsequent Michael reaction may
proceed either in a stepwise manner (path a) or by way of a concerted mechanism (path
To illustrate the Michael reaction_ more specifically, a reaction is shown below,
with ethacrynic acid (IV) depicted as the therapeutically active molecule, and RSH as
the masking agent. The compound V is an adduct of ethacrynic acid. The reaction is
reversible, with the dissociation of the adduct occurring by a retro michael reaction.
O/\(,ooH
‘ct Y
The masking agent is administered in conjunction with the therapeutically active
molecule. By "in conjunction with" it is meant that the masking agent is administered
coupled to the therapeutically active molecule as an adduct, uncoupled but substantially
simultaneously with the active molecule, or in addition to a formed adduct. By
substantially simultaneously, it is meant that the molecule and the masking agent are
administered close enough in time to beneficially protect sulfhydryl groups within the
cornea from reacting with the sulfhydryl reactive groups of the active molecule. The
masking agent may be administered in equimolar amount with the active molecule or
adduct, or may be administered either in molar excess or deficit to the therapeutically
active molecule. The ideal relative amounts will depend upon the particular active
molecule and masking agent selected, the kinetics of their binding, the manner of their
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administration and the particular condition they are being administered to treat. These
factors are of the type which those of ordinary skill in the art are capable of evaluating.
The masking agent must be biocompatible, meaning that it causes no medically
unacceptable side effects when administered to the eye either separately or as a
component of an adduct or therapeutic mixture. The masking agent may be any
compound which is biocompatible, undergoes a Michael reaction with the sulfhydryl
reactive group of the therapeutically active molecules characterized above, and which
has acceptable reaction kinetics for the therapeutic efficacy in treatment of glaucoma
while preventing corneal edema. While many others will be apparent to those skilled in
the art, the following are examples of masking agents:
TABLE 1‘
SH—-C1l2—-CH-(NH2)'O0OH cysteine
SH~CH2~CHé‘C0OH
thiosalicylic acid
3-mescaptopropionic acid
sH—c;H2~cHi-1~m—.c~ CH3 N ~ acetyl xnercaptoethylamine
l
tbi ophenol
- mercaptophenol
SH 1- /w\ 2. 5 ~ dicblorobenzenc-thiol
$}{Q%| 3. 4 — dichlozobenzenethiol
M (1
SH-CH3 methanethiol
SH-O—C}-[3 methansulfinic acid
SH-C—(CH3)3 tertiary butylthiol
SH-(CH2 )3—- C1 3-chloropropanethiol
SH-CH2—CH = CH2 allylthiol
benzylthiol
SH@l
SH‘CH2— CH.S—CH2—OH 1~hydroxymet:hylethanedithio1
rnercaptoacetic acid
SH-Cfli-COOH
SH— CH2. CH-(NH-CO‘C}1'3)' COOH Ivacetylcysteine
“~<3i;~Gi2-CH—(NIi2)—coou
(+ H3—~N—CH-CH2-CH2-‘C>O‘N'H-CH-G)NHCH2—OOOH) glutathione
COOH cuzsy
thioacetic‘acid
dihydrogen sulfide
SH
2
NH‘(CH3)2 dimethylamine
/ N
l5 It pyridine
\\
N\\ pyrazole
N«/
Pd imidazole
\//j
R)
K/|
I /05 theo n lline
N N P Y
N
cu;
The preferred masking agents are cysteine, cysteamine, N—acety1cysteine, N-
acetylcysteamine, glutathione, or thiosalicylic acid. The most preferred is cysteine as the
adduct-forming masking agent and N—acetylcysteine applied separately in molar excess.
The compositions of the invention are useful whenever medically unacceptable
side effects may occur as a result of delivering a therapeutically effective amount of a
compound with sulfhydryl reactive groups to the trabecular network.
This includes the use of compositions in the treatment of existing chronic and
acute conditions, as well as prophylactic treatment to prevent such conditions. The
adducts or masking agents of the invention may be administered topically to the eye, by
iritracameral injection, when reforming the anterior chamber after surgery, or
systemically. The preferred manner of administration is topical.
When administered topically, the compounds of the invention are delivered in a
medically acceptable ophthalmic preparation. Such preparations may routinely contain
pharmaceutically acceptable concentrations of salts, buffering agents, preservatives,
thickening agents, chelating agents, wetting agents, and delivery enhancing agents. A
delivery enhancing agent is a substance that facilitates the delivery of the therapeutic
compound of the invention into the aqueous humor, including substances which
increase comeal permeability, such as surfactants, wetting agents, liposomes, DMSO,
and agents which mildly disrupt the corneal surface. A wetting agent is a substance
wliieli evenly coats the outer corneal surface. A preferred wetting agent is benzalkonium
chloride. Other examples of wetting agents include sorbitan esters and polyoxyethylene
ethers.
The adducts and masking agents of the invention are administered in
therapeutically effective amounts. A therapeutically effective amount is one which
causes a medically useful increase in outflow of aqueous humor from the eye.
The adducts and masking agents of the invention are administered in nontoxic
amounts with acceptable margins of safety. As used herein, "margin of safety" refers to
the ratio of the dosage of the outflow increasing molecules which causes medically
unacceptable side effects, and the dosage which causes substantial (i.e., medically
useful) increase in aqueous humor outflow in treating or preventing glaucoma (e .g., in a
typical patient with open angle glaucoma). The margin of safety of the molecules must
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be at least 2.0, and more preferably at least 4.0. It is also important that the molecules
not produce, at effective dosages, long—tenn deleterious changes in the eye.
The compounds of the invention are for treatment of glaucomatous conditions in
eyes of mammalian subjects (e .g., humans, dogs and cats).
The adducts and masking agents of the invention may be supplied in different
containers and forms. In one embodiment, the adducts and/or masking agent will be
supplied in the form of a solution in a bottle constructed and arranged to facilitate
administration of the solution as eyedrops. Such a bottle may have a dropper tip as the
upper part, with a detachable cap which seals the dropper tip when the cap is replaced
on the bottle. An alternative bottle may have a separable dropper instrument which is
attached to the bottle cap, and which is contained inside the bottle when the cap is
replaced.
The adducts and molar excess of masking agent, if present, may be supplied in a
single container or in separate containers. In one embodiment, the therapeutically active
molecules and masking agent are supplied in separate containers, adducts being formed
only after administration.
In another embodiment, the adducts and/or masking agents of the invention are
supplied as a lyophilized powder within the lower chamber of a two chamber vial. The
upper chamber contains sterile diluent or sterile and pyrogen-free diluent. Access to the
chambers is provided by frangible membranes. In use, the membranes are pierced by the
needle of a syringe, and the diluent flows into the lower chamber, dissolving the
lyophilized powder. In another embodiment, the upper and lower chambers are
constructed and arranged within a syringe, wherein the action of advancing the plunger
of the syringe causes the contents of the two chambers to mix. In these embodiments,
the diluent may contain sterile water, organic and inorganic electrolytes, and buffering
agents. Examples of inorganic electrolytes include, but are not limited to, the chlorides
of sodium, potassium, calcium and magnesium. Suitable buffering agents may include
the sodium or potassium salts of boric acid, citric acid, phosphoric acid, acetic acid and
the like. The lyophilized powder of the invention may contain, in addition to the active
ingredient, other pharrnaceutically acceptable inert ingredients such as bulking agents,
electrolytes, and buffering agents.
Suitable bulking agents include mannitol and dextran. Acceptable electrolytes
include the chlorides of sodium, potassium, magnesium and calcium. Buffering agents
may be taken from the group of mono- or di—sodium or potassium salts of boric acid,
citric acid, phosphoric acid, or acetic acid.
Thus, the components in the lyophilized powder and the vehicle for reconstitution
may be adjusted such that the final formulation for injection is compatible with
osmolarity and pH of the aqueous humor. Acceptable osmolarity may be in the range of
to 350 mOsm/kg, while pH of the formulation may vary from 6.2 - 7.8.
The compounds of the invention and appropriate solutions for their use may be
supplied in suitable containers in the form of kits. These kits may include instructions
for use, useful additional implements, and may be supplied in a sterile condition in
impervious protective covering.
Examples
In Vitro Use of An Adduct of the Invention
Enucleated calf eyes were obtained from a local abattoir and were transferred on
cold nonnal saline. Upon receipt, the eyes were placed in a beaker filled with normal
saline into a water bath set at 25°C. Calf eye corneas were trephined and Grant corneal
fittings were attached to allow fluid flow to enter the eye Because the eye is a closed
system, the facility of outflow was measured in microliters of fluid to enter the eye per
mm Hg per minute. Two pairs of calf eyes were perfused during each experiment with a
mock aqueous fluid: Dulbecco's phosphate buffered saline containing calcium chloride
and 5.5 mM glucose.
The calf eyes were perfused at 15 mm Hg for 1 hour and then a baseline facility
measurement was obtained. The anterior chamber fluid was then exchanged with a drug
Ix)
U:
solution for the experimental eye and a sham for the control eye. The calf eyes were
perfused with the drug or sham solution from an attached reservoir for an additional five
hours, during which facility measurements were taken hourly. Drug effects can be
found by comparing the amount of fluid which entered the experimental calf eyes
compared to that of the control eyes from the baseline measurement to the end of the
experiment.
The following summary chart contains results from many experiments.
Mean "/9 Facility Change
Experimental Control H H
,, “/8 ‘>5 "/9
OOt3n1M 103 mi 74 *— "£387 *
ECA alone
0 2"/O2
J SIHM 104 38 66
l:(;/3/cysteine
! 0.06/0.06mM 100 42 58
ECA/Cysteine
0703/0 Oamlvl 84 47 37
bi:/Vbysteine
0 01/0 O1mM ( F
tcflvcysteine l y H i
1 l l
0 ‘3’0e3J'“M l we 3 01 5.86: 1 1. 94 ‘ 50 44
':CA/Cysteine C 215 318 [ 1
l
V02p5//ofi25mM 5E 2 35 4.22 1.87 70 10 50
tfimktoysteine C 2.38 3.06 O 68
o 25/O.25mM BE 2 29 3 83 1 54 72 30 l 42
EC;/Vtjlutathione C; 2 32 1 54 0 68
0.25/U.2bmM IE 2 46 3.87 1.41 57 20 37
ECAI Thiosalicyclic C 9 2? 264 0,42
Acid
0.25/O.25rnM SF 2.47 4 73 2.26 96 51 45
ECA/Neacetyle C 2.29 3.45 1 16
cysteine
O ?5/ 7
O 25mM BC 205 3.22 1.17 55 35 19
ECA’N*aC0ty| C 2.03 2.76 0.73
cysteine
The number of calf eyes in each experiment is listed under N. The mean outflow
facilities are the average microliters of Dulbecco ‘s PBS + glucose that entered the calf
eyes per mmHg per minute. The chart contains only the baseline and 5 hour
measurements. The mean percent facility change calculates the change in fluid flow
from the baseline measurement to the end of the experiment; comparing these values
would be the best way to evaluate the drug effect.
In Vivo Use of An Adduct of the Invention
A mixture of ‘ethacrynie acid (sodium salt) and L-cysteine applied topically to
cynomolgus monkeys was associated with a lowering of intraoccular pressure.
Each monkey was randomly assigned one experimental and one control eye. Slit
lamp examination was done to ensure nonnal, healthy eyes prior to the experiment. The
monkeys were anesthetized with 10 mg/kg ketamine hydrochloride administered
intramnscularly. Supplemental anesthesia was administered as needed with additional
mg/kg/15 minutes. Baseline intraocular pressure (baseline A) was measured in each
eye with a Digilab Pneumotonometer following topical anesthesia with one drop of
0 .5 97¢ proparacaine hydrochloride. A solution of 75 mM N—aeetylcysteine (N—AC) was
made in sterile water and the pH was adjusted to 7. One drop of 0.5% proparacaine HCl
was given to each eye for anesthesia, followed by one drop of 75 mM N—AC to the
experimental eye. N0 sham drop was given to the control eye. A total of 15 minutes
elapsed from the time the drug was mixed to the time the drug was administered.
After a half hour, one drop of topical 0.5% proparacaine HCl was given to each
eye prior to a second baseline pressure measurement (baseline B). A mixture of 130 mM
ethacrynic acid (ECA) and 130 mM cysteine in 1/2000 benzalkoniurn were combined at
the time the drugs were administered. One drop of 0.5% proparcaine HCl was given to
rd
Kit
each eye for anesthesia followed by one drop of ECA/cysteine in the experimental eye
and one drop of l :20()() benzalkonium chloride to the control eye. After 2 minutes, a
second drop of ECA/cysteine was given to the experimental eye and a second drop of
l:2t)OO benzalkonium chloride to the control eye.
The monkeys were carefully examined with a slit lamp at 24 and 48 hours and
additional pressures were taken with topical 0.5% proparacaine HCl. Results are
summarized in the following monkey topical summary chart. The average baseline
pressure was 25 mm Hg in the experimental eye and 25.5 mm Hg in the control eye. At
24 hours post experiment, the average pressure was 17 mm Hg in the experimental eye
and 20.5 mmHg in the control eye. Therefore, the average lowering of pressure in the
experimental eye was 8 mmHg at 24 hours associated with minimal, if any, corneal
toxicity.
MONKEH TOPICAL SUMMARY
Pretreat 75 mH N—acety1cysteine (pH 7. 1 drop).W3it 30
min.
mm ECA/130 mn cysteine in 1/2000 benzalkonium
chloride (pa 7. 2 drops)
row 51 MKY 51 MKY 51
C E C E E C
baseline A 31 so 27 27 22 23
baseline B 28 30 28 27 21 22
24 hour 29 16 27 20 17 19
48 hour 20 20
MKY 51 MKY 51 MK‘! 2467"
E C C E 1-: C
baseline A 28 23 21 21 22 23
baseline B 29 34 19 17 23 20
24 hour 20 23 s 18 11 21
48 hour 6 21
Aye E STD AVG C STD
baseline A 25.0 3.5 25.5 3-5
baseline B 24.5 4.8 25-2 5 3
24 hour 17.0 1.5 21.5 8.2
48 hour 13.0 7.0 20.5 0 5
SLIT LAMP EXAM @ 24 HOURS:
/6 Monkeys normal
‘ 1/6 Monkeys diffuse stromal edema
r.)
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Similar experiments were performed on rabbits, except that the quantity of drops
varied. Rabbits were randomly assigned one experimental and one control eye and
received a single drop of topical 0.5% proparacaine HCl in each eye prior to baseline
pressure (baseline A) measurements. A solution of 100 mM N-acetylcysteine was made
in sterile water and the pH was adjusted to 7. A total of 15 minutes elapsed from the
time the drug was mixed to the time the drops were administered. Another drop of
topical 0.5% proparacaine HCl was given to each eye, followed by 2 drops of 100 mM
N-acetylcysteine, separated by 2 minutes, to the experimental eye; no sham drops were
given.
After a half hour, one drop of 0.5% topical proparacaine HCl was given to each
eye and a second baseline pressure (baseline B) was measured. A mixture of 130 mM
ECA and 130 mM cysteine was made in 12000 benzalkonium chloride and the pH was
adjusted to pH 7. A total of 15 minutes elapsed between the time the drugs were
combined to the time they were administered. A total of 8 drops of the ECA/cysteine
mixture were given to the experimental eye, each drop separated by 2 minutes. At the
same time, a total of 8 drops of 112000 benzalkonium Chloride were given to the control
eye, each drop separated by 2 minutes.
The eyes were examined for corneal edema at 24 hours and pressures were taken
with 0.5% topical proparacaine HCl for anesthesia. The results are summarized in the
following chart.
,_.
L/I
RABBIT TOPICAL EXPERIMENT
mm N—acety1cysteine
fiu],dd‘~ . . ' ' .
.1 1t10nal rabblt expenment was performed xdentlcal to the precedmg one
exc 1 th' t 4 d - . . _
“P d rops of pretreatment w1th 100 mM N-acetylcysteme were glven pr10r to 8
d f th 13 - -
TOPS 0 6 0 mM ECA and 130 mM cyste1ne m1xture. Results were as follows:
RABBIT TOPICAL EXPERIMENT
_ .___..__ _-_-——-—A4»—~——
Pretreat (4 drops) 1oo—mM NAC
Topical (8 drops) 130 mm ECA/130 um qrsteine (PH 7: PH 73
n1 #2 “3
E c E C C E
baseline A 22 21 21 19 23 23
baseline B 17 20 20 20 23 25
24 hr 20 21 22 21 22 23
a4 #5 “5
c E E C E C
baseline A 21 21 22 22 22 2°
baseline B 22 22 24 24 23 22
24 hr 26 25 24 24 22 26
a7 R8 R9
C E C E C E
baseline A 24 28 27 28 29 31
baseline 8 26 29 28 30 30 28
24 hr 18 24 15 9 23 14
«10 all H12
C E C E C E
baseline A '31 32 22 24 25 gs
baseline B “ 35 35 36 32 33 13
24 hr 18 is 22 21 ~’ 24 “
AVG E STD AVG C STD
baseline A 25.2 398 23.8 g-E
baseline B 26.5 5~3 25-5 '2
24 m 19 4 4.9 21~7 fiwf; ________ __
w r« - " t al .
hOTLr B/12 fobDltS no m ted conjunctiva
trace corneal edema.
/12 rabbits _
1+ corneal coema, re
/12 rabbits _
1/12 rabbits 2+ corneal enema
d conjunctiva
An additional rabbit experiment was performed, similar to the other experiments
but without any pretreatment step. Rabbits were randomly assigned one experimental
and one control eye and received a single drop of topical 0.5% proparacaine HCl in each
eye prior to baseline pressure (baseline A) measurements.
Some of the rabbits received a second baseline pressure measurement, a half hour
later; these rabbits can be identified by a baseline B entry. The remaining rabbits only
had one baseline pressure prior to the experiment.
Immediately following the last baseline pressures (A or B, depending upon the
experiment), a mixture of 130 mM ECA and 130 mM cysteine was made in 120000
benzalkonium chloride and the pH was adjusted to pH 7. A total of 15 minutes elapsed
between the time the drugs were combined to the time they were administered. A total
of 8 drops of the ECA/Cysteine mixture were given to the experimental eye, each drop
separated by 2 minutes. The eyes were examined for corneal toxicity at 24 hours and
pressures were taken with 0.5% topical proparcaine HCl for anesthesia.
Results from the experiment, including observations of corneal edema, are
enclosed.
RABBI '1' TOPICAL l'DCPERIHEN'I'
No Pre—T:eatment
Topical (8 drops) 130 rub! ECA/Cysteine (pm)
$12 83
‘ C E E C E C
baseline A 22 22 23 23
baseline B 22 24 20 20 23 24
24 hours 23 19 16 20 10 21
$14 #5 '36
C E C E E C
baseline A 21 21 24 23 21 21
baseline 8 25 25 23 23 25 25
24 hr 24 23 19 20 26 25
56 (17 #8
E C E C E C
baseline A 22 22 29 28 28 28
baseline B 22 21 30 29 25 25
24 hr: 22 24 19 29 11 24
N9 #10 S11
E C C E C E
baseline A 21 23 35 34 27 25
baseline 8 21 21 25 24 23 22
24 1:: -‘ 13 20 24 17 22 21
3312 #13 814
C E E C E C
baseline A 26 30 22 21 22 22
baseline 8 23 20 - 26 24 25 21
24 hr 20 14 23 30 19 18
48 hr 23 30 19 18
N15 #16 #17
E C C E C E
baseline A 21 18 27 30 31 33
baseline E 20 20
24 hr 16 19 33 15 32 29
48 hr 23 23 25 24 29 25
I118 #19 6120
C E C E C E
baseline A 30 30 28 35 30 30
baseline B
24 hr 30 28 .34 27 30 20
48 hr 26 27 26 28 25 26
._.
U]
R)
LII
«:1 :22 #23
_ C E C E C E
baseline 19 26 30 30 34 36
baseline
24 hr 13 23 25 15 28 15
(8 hr 21 19 32 28 30 _30
E24 325 626»
'C~ E C E C E
baseline 35 33 32 29 34 33
baseline
24 hr 33 15 30 15 31 1S
(6 hr 30 .30 27 14 29 25
(2? G28 £29
C E C E C E
baseline 38 35 31 32 29 19
baseline 35 33 28 17
2t _hr 20 15 18 16 21 23
48 hr 29 32 ‘
l30~ H31 H32
C E E C E C
baseline 31 -33 26 25 26 26
baseline 29 30
24 hr 26 ll 18 23 21 20
«as G34 #35
E C E C E C
baseline 26 - 26 21 23 24 23
baseline
26 hr 24 23 18 22 17 22
636
E C
baseline 26 27
baseline
24 hr 11 25
AVG E STD AVG C STD
baseline 27.4 4.7 27.2 4.7
baseline 24.5 3.8 24.3 3.7
2‘ hr 18.0 5.0 24.8 4.4
48 hr 24.8 (.6 27.0 3.5
NOITS: 16/3'1 NORMAL 6/37 2+ EDDUK
/37 TRACE EDEHR
/37 MILD EDEMA
/37 DIFFUSE EDEMA
«/37 RED CONJUNCTIVA
1/37 cnmosxs
Claims (32)
- Claims Use of a masking agent (a) in the manufacture of a medicament, for use in the treatment or prevention of glaucoma with a molecule (b) having one or more groups capable of reacting with sulfhydryl groups in the trabecular meshwork of the eye, to increase aqueous humor outflow, said masking agent (a) being biocompatible and capable of undergoing a michael addition reaction with the sulfhydryl reactive group(s) in the molecule (b) and thereby preventing said molecule (b) from causing a medically unacceptable side effect.
- A use as claimed in claim 1, wherein the molecule (b) is not present in the medicament.
- A use as claimed in claim 1 or 2, wherein the masking agent (a) fonns an adduct with the molecule (b) in the medicament.
- A use as claimed in any of the preceding claims, wherein the masking agent (a) is used in molar excess relative to the molecule (b).
- A use as claimed in any of claims 1-3, wherein the molecule (b) is used in molar excess relative to the masking agent (a).
- A use as claimed in any of the preceding claims, wherein the molecule (b) is ethacrynic acid or an analog thereof.
- A use as claimed in claim 6, wherein the molecule (b) is ethacrynic acid.
- A use as claimed, in any of the preceding claims, wherein the masking agent (a) is selected from the group comprising cysteine, B-mercaptoethylamine (cysteamine), thiosalicylic acid, 3-mercaptopropionic acid, N-acetyl-(B—mer-captoethylamine, thiophenol, 4-mercaptophenol, 2,5 ,-dichlorobenzenethiol, 3,4— dichlorobenzenethiol, methanethiol, methanesulfinic acid, tertiary butylithiol, 3- chloropropanethiol, allylthiol, benzylthiol, 1-hydroxymethylethan—edithiol, mercaptoacetic acid, N—acetylcysteine, 4—mercapto-2—aminobutanoic acid, glutathione, thioacetic acid, benzyloxythiol, dihydrogen sulfide, dimethylamine, pyridine, pyrazole, imidazole, and theophylline.
- A use as claimed in claim 8, wherein the masking agent (a) is selected from the group comprising cysteine, cysteamine, N—acetylcysteine, N-acetylcysteamine, glutathione and thiosalicylic acid.
- A use as claimed in claim 9, wherein the masking agent (a) is selected from the group consisting of cysteine and N-acetylcysteine.
- A use as claimed in any of the preceding claims, wherein the medicament further comprises a delivery enhancing agent.
- A use as claimed in claim 1 wherein the medicament is for topical administration to the eye.
- A use as claimed in claim 1, wherein the medicament is for administration to the eye prior to the adduct.
- A composition for use in the treatment or prevention of glaucoma comprising a molecule (b) having one or more groups capable of reacting with sulfhydryl groups in the trabecular meshwork of the eye to increase aqueous humor outflow, characterised by further comprising a biocompatible masking agent (a) capable of undergoing a michael addition reaction with the sulfhydryl reactive group(s) in the molecule (b) in a sufficient amount to thereby prevent said molecule (b) from causing a medically unacceptable side effect.
- A composition as claimed in claim 14, comprising an adduct of the masking agent (a) and molecule (b).
- A composition as claimed in claim 14 or 15, wherein the masking agent (a) is present in molar excess relative to the molecule (b).
- A composition as claimed in claim 14 or 15, wherein the molecule (b) is present in molar excess relative to the masking agent (a).
- A composition as claimed in any of claims 14-17, wherein the molecule (b) is ethacrynic acid or an analog thereof.
- A composition as claimed in claim 18, wherein the molecule (b) is ethacrynic acid.
- A composition as claimed in any of claims 14-19, wherein the masking agent (b) is selected from the group comprising cysteine, [3-mercaptoethylamine (cysteamine), thiosalicylic acid, 3-mercaptopropionic acid, N-acetyl—B— mercaptoethylamine, thiophenol, 4—mercaptophenol, 2,5 ,-dichlorobenzenethiol, 3,4-dichlorobenzenethiol, methanethiol, methanesulfinic acid, tertiary butylthiol, 3—chloropropanethiol, allylthiol, benzylthiol, 1—hydroxymethylethanedithiol, mercaptoacetic acid, N—acetylcysteine, 4-mercaptoaminobutanoic acid, gluthathione, thioacetic acid, benzyloxythiol, dihydrogen sulfide, dimethylamine, pyridine, pyrazole, imidazole, and theophylline.
- A composition as claimed in claim 20, wherein the masking agent (a) is selected from the group comprising cysteine, cysteamine, N—acetylcysteine, N- acetylcysteamine, glutathione and thiosalicylic acid.
- A composition as claimed in claim 21, wherein the masking agent (a) is selected from the group consisting of cysteine and N-acetylcysteine.
- A composition as claimed in any of claims 14-22, further comprising a delivery enhancing agent.
- A composition as claimed in any of claims 14-23, for use in a method for treating or preventing glaucoma wherein the composition is for topical administration to the eye.
- A device for delivering a composition as claimed in claim 15, or and any one of claims 16-24 when dependent from claim 15, comprising a container constructed and arranged to deliver an ophthalmic preparation topically to the eye and an opthalmic preparation contained in the container, wherein the ophthalmic preparation includes the composition or precursors thereof in an amount sufficient for delivering a therapeutically effective dose.
- A device as claimed in claim 25, wherein the container is a syringe and contains the ophthalmic preparation including the composition or precursors thereof.
- A kit comprising a container housing a molecule (b), having one or more groups capable of reacting with sulfhydryl groups in the trabecular meshwork of the eye, and a container housing a masking agent (a), being biocompatable and capable of undergoing a michael addition reaction with the sulfhydryl reactive group(s) in the molecule (b), as a combined preparation for simultaneous, separate, or sequential use in the treatment or prevention of glaucoma.
- A kit comprising a container housing the masking agent (a), being biocompatable and capable of undergoing a michael addition reaction with the sulfliydryl reactive group(s) in a molecule (b), wherein molecule (b) has one or more groups capable of reacting with sulfhydryl groups in the trabecular meshwork of the eye, and a container housing an adduct of the masking agent (a) and molecule (b), as a combined preparation for simultaneous, separate, or sequential use in the treatment or prevention of glaucoma.
- Use as defined in claim 1 substantially as described herein with reference to the examples.
- A composition as defined in claim 14 substantially as described herein with reference to the examples.
- A device as defined in claim 25 substantially as described herein with reference to the examples. 26
- 32. A kit as defined in claim 27 or claim 28 substantially as described herein with reference to the examples. TOMKINS & CO. sgec/291'
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
USUNITEDSTATESOFAMERICA14/03/19910 | |||
US07/669,381 US5306731A (en) | 1985-06-14 | 1991-03-14 | Method and products for treating the eye |
Publications (2)
Publication Number | Publication Date |
---|---|
IE83778B1 true IE83778B1 (en) | |
IE920817A1 IE920817A1 (en) | 1992-09-23 |
Family
ID=24686133
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE081792A IE920817A1 (en) | 1991-03-14 | 1992-03-13 | Method and products for treating the eye |
Country Status (10)
Country | Link |
---|---|
US (1) | US5306731A (en) |
EP (1) | EP0575524B1 (en) |
JP (1) | JPH06508607A (en) |
AT (1) | ATE233554T1 (en) |
AU (1) | AU665756B2 (en) |
CA (1) | CA2104868C (en) |
DE (1) | DE69232942T2 (en) |
HU (1) | HU221846B1 (en) |
IE (1) | IE920817A1 (en) |
WO (2) | WO1992016198A2 (en) |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5506226A (en) * | 1993-04-19 | 1996-04-09 | Alcon Laboratories, Inc. | Ethacrynic acid-like compounds and use thereof to treat glaucoma |
SE9303627D0 (en) * | 1993-11-03 | 1993-11-03 | Kabi Pharmacia Ab | Method and means for the prevention of cataract |
US5458883A (en) * | 1994-01-12 | 1995-10-17 | Duke University | Method of treating disorders of the eye |
WO1995033456A2 (en) * | 1994-06-07 | 1995-12-14 | Telor Ophthalmic Pharmaceuticals, Inc. | Reducing intraocular pressure using aryloxy- and aryl-acetic acids |
US5798380A (en) * | 1996-02-21 | 1998-08-25 | Wisconsin Alumni Research Foundation | Cytoskeletal active agents for glaucoma therapy |
US6586425B2 (en) | 1996-02-21 | 2003-07-01 | Wisconsin Alumni Research Foundation | Cytoskeletal active agents for glaucoma therapy |
US5654335A (en) * | 1996-02-23 | 1997-08-05 | University Of Iowa Research Foundation | Topical use of ethyl ethacrynate for glaucoma treatment |
US5565434A (en) * | 1996-02-23 | 1996-10-15 | University Of Iowa Research Foundation | Hexose and pentose prodrugs of ethacrynic acid |
US6573299B1 (en) | 1999-09-20 | 2003-06-03 | Advanced Medical Instruments | Method and compositions for treatment of the aging eye |
US8993627B2 (en) * | 2005-04-21 | 2015-03-31 | Sentient Lifesciences, Inc. | N-acetylcysteine amide (NAC amide) for the treatment of diseases and conditions associated with oxidative stress |
US7282225B1 (en) | 2006-09-27 | 2007-10-16 | Occular Technologies, Inc. | Composition and methods for improving retinal health |
JP6035009B2 (en) | 2007-08-22 | 2016-11-30 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | Activable binding polypeptides and methods for identification and use thereof |
US20100189727A1 (en) * | 2008-12-08 | 2010-07-29 | Tegopharm Corporation | Masking Ligands For Reversible Inhibition Of Multivalent Compounds |
EP2385955B1 (en) | 2009-01-12 | 2020-08-12 | CytomX Therapeutics, Inc. | Modified antibody compositions, methods of making and using thereof |
JP5861223B2 (en) | 2009-02-23 | 2016-02-16 | サイトムエックス セラピューティクス, インク.CytomX Therapeutics, Inc. | Proprotein and its use |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA883792A (en) * | 1971-10-19 | C. Mezey Kalman | Ethacrynic acid suppositories | |
GB1141422A (en) * | 1967-01-27 | 1969-01-29 | Merck & Co Inc | Diuretics |
US4590210A (en) * | 1979-03-09 | 1986-05-20 | Langham Maurice E | Compositions for treatment of ocular hypertension |
US4596771A (en) * | 1982-09-27 | 1986-06-24 | Research Corporation | Monoclonal antibodies to vitamin B-6 and immunossay method |
US4777130A (en) * | 1984-12-05 | 1988-10-11 | Andra Biologicals | Isolation of mycobacterial a 60 antigen for diagnostic purposes |
ATE89726T1 (en) * | 1985-06-14 | 1993-06-15 | Massachusetts Eye & Ear Infirm | INCREASE IN BODY WATER OUTLET. |
JPH0696521B2 (en) * | 1986-01-31 | 1994-11-30 | 千寿製薬株式会社 | Ocular hypotensive agent for topical ocular administration |
US4891324A (en) * | 1987-01-07 | 1990-01-02 | Syntex (U.S.A.) Inc. | Particle with luminescer for assays |
US4829011A (en) * | 1987-08-27 | 1989-05-09 | Biotrack, Inc. | Agglutination assay |
US4847209A (en) * | 1987-11-09 | 1989-07-11 | Miles Inc. | Latex agglutination immunoassay in the presence of hemoglobin |
-
1991
- 1991-03-14 US US07/669,381 patent/US5306731A/en not_active Expired - Lifetime
-
1992
- 1992-03-12 WO PCT/US1992/002046 patent/WO1992016198A2/en not_active Application Discontinuation
- 1992-03-13 IE IE081792A patent/IE920817A1/en not_active IP Right Cessation
- 1992-03-16 WO PCT/US1992/002061 patent/WO1992016199A1/en active IP Right Grant
- 1992-03-16 AT AT92908766T patent/ATE233554T1/en not_active IP Right Cessation
- 1992-03-16 AU AU15783/92A patent/AU665756B2/en not_active Ceased
- 1992-03-16 JP JP4508339A patent/JPH06508607A/en active Pending
- 1992-03-16 DE DE69232942T patent/DE69232942T2/en not_active Expired - Fee Related
- 1992-03-16 EP EP92908766A patent/EP0575524B1/en not_active Expired - Lifetime
- 1992-03-16 HU HU9302590A patent/HU221846B1/en not_active IP Right Cessation
- 1992-03-16 CA CA002104868A patent/CA2104868C/en not_active Expired - Fee Related
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