Note: Descriptions are shown in the official language in which they were submitted.
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Patent Application
Neuroimmunophilins for selective neuronal radioprotection
Inventors: Marcus Keep (United States of America)
Eskil Elmer (Sweden)
Assignee: None.
Application number
Filed: 1998
Int. Cl.
U.S. Cl.
Field of search
References cited
U.S. Patent Documents:
4,117,118 Harri et al. Organic compounds.
5,648,351 Kelly et al. Use of macrolides for the treatment of cerebral
ischemia.
08/860,898 Keep et al. Treatment of cerebral ischemia and cerebral damage.
(pending)
5,795,908 Small molecule inhibitors of rotamase enzyme activity.
5,780,484 Methods for stimulating neurite growth with piperidine compounds.
5,654,332 Methods and compositions for stimulating neurite growth.
5,6I4,547 Small molecule inhibitors of rotamase enzyme.
Foreign Patent Documents:
0184162 6/1986 European Patent Office.
Other References:
Solomon H. Snyder, Michael M. Lai and Patrick E. Burnett. Immunophilins in the
Nervous System. 1998, Neuron 21, 283-294.
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Neuroimmunophilins for selective neuronal radioprotection
Description.
Neuroimmunophilin ligands.
Both cyclosporin and FK506 are neuroimmunophilin ligands, that is they bind
specifically to neuroimmunophilins. The neuroimmunophilins were previously
named
after their respective binding ligand i.e. they were defned as cyclophilins
and FK-
binding proteins. Because the effect of cyclosparin and FK506 on the immune
system
is so robust and well known in clinical transplantation, the cyclophilin and
FK-binding
protein families together became known as immunophilins. When it was
discovered
that neurons were 20 times more enriched in immunophilins than immune cells,
the
name became neuroimmunophilins. In addition, it was realized that
neuroimmunophilin
ligands were neuropi-otective.
However, it has never been proposed or realized that the differential
distribution of
neuroimmunophiiins could be exploited to improve the safety and eff cacy of
radiation
treatments of the brain, or radiation fields or rays that pass through the
brain. The
crucial realization is that neurons are highly enriched in neuroimmunophilins
and that
the glia or support cells of the brain contain little or no neuroimmunophilin
protein.
Neuroimmunophilin ligands are herein defined as all compounds that bind to the
neuroimmunophilins. NeuroimmunophiIin ligands include but are not limited to
the
immunosuppressants cyclosporin A, cyciosporins, FK506, ail their
immunosuppressant and non-immunosuppressant analogs, derivatives and variants,
as
well as small molecule immunophilin Iigands developed by the companies
Guilford
Pharmaceuticals Inc. and Vertex Pharmaceuticals Inc. and described in other
patent
applications. Treatment medication or treatment medications will be defined as
a
medicament comprising as its active ingredients not less than one
neuroimmunophilin
Iigand, and may contain a mixture of twa or more similar or different
neuroimmunophilin ligands. The three main classes of neuroimmunophiIin ligands
are
discussed below, including cyclosporins, FK506 and the small FK-binding
protein
neuroimmunophilins ligands ("FKBP-neuroimmunophilin ligands") of Guilford
Pharmaceuticals Inc. and Vertex Pharmaceuticals Inc.
Cyclosporin A and derivatives.
It is already known that cyclosporin A is an immunosuppressive drug. The above
mentioned treatment medication has already been described, in United States
Pat. No.
4,117,118 and numerous patents since, which relate to its production,
formulation and
immunosuppressive properties.
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Cyclosporin A is a product of the fungus Tolypocladium Inflatum Gams. It is a
cyclic
poly-amino acid molecule, consisting of 1 I amino acids. One of the amino
acids is unique
for cyclosporin A, a 13-hydroxyamino acid called butenyl-methyl-threonin
(MeBmt). The
molecular weight is 1202.6 and the chemical composition is C6zH~l,N"0,2.
The molecule is highly lipophilic, and therefore virtually insoluble in water.
The
bioavailability after an oral dose varies between 8 and 60% depending in part
on the bile
flow. The drug is absorbed mainly in the small intestine. The drug is
transported in the
blood within red blood cells to about 58%, and the remaining approximately 10-
20% in
leukocytes, and 33% bound to plasma proteins. In the plasma cyclosporin A is
bound
to high-density lipoprotein, low-density lipoproteins, very-low density
lipoproteins and
a small fraction to albumin. A very small fraction is free in plasma.
The drug undergoes extensive metabolism, mainly in the liver by the cytochrome
P450
system. There are at least 30 known metabolites of cyclosporin A, with various
chemical modifications, such as hydroxylation, demethylation, oxidation and
epoxide
formations. There are a number of variants of cyclosporin A, differing for
example in
one amino acid, which have similar pharmacological properties. Under normal
conditions, cyclosporin A and its metabolites do not pass the blood-brain
barrier.
When the glycoprotein-p transporter is poisoned, or the blood-brain barrier is
disrupted, cyclosporin is able to cross it and come into contact with neurons.
Several
analogs of cyclosporin are able to readily cross the blood-brain barrier.
Several analogs
of cyclosporin are not immunosuppressants. There is a subset of analogs of
cyclosporin
that both readily cross the blood-brain barrier and are not
immunosuppressants.
This entire family of cyclosporins, all derivatives, variants, amino acid
variants,
metabolites, including variations of mono-, di- and trihydroxylates, N-
demethylates,
aldehydes, carboxylates, conjugates, sulphates, glucuronides, intramolecular
cyclizations and those without a cyclic structure as well as shorter peptides
and amino
acids and their derivatives and salts with or without immunosuppressive
properties and
whether able to cross the blood brain barrier or not will hereinafter be
referred to as
cyclosporins. Cyclosporins will hereinafter be referred to as
"neuroimmunophiIin
ligand or ligands" based on their affinity and binding to the group of
neuroimmunophiIins called cyclophilins.
The present invention also discloses treatment medications of the family of
cyclosporins
and all known salts, variants, amino acid variants, derivatives, metabolites
and their
salts and derivatives for use in treatments of the conditions listed below, as
well as the
use of such treatment medications for the treatment of such conditions. This
includes
cyclosporin A, cyclosporin C, cyciosporin D, cyclosporin G. In addition, this
includes
all products of the fungus ToIypocladium Inflatum Gams. Some known metabolites
of
cyclosporin A include the following : (according to Hawk's Cay nomenclature)
AM I ,
AM9, AM 1 c, AM4N, AM 19, AM 1 c9, AM 1 c4N9, AM 1 A, AM I A4N, AM 1 Ac,
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AM 1 AL, AM 11 d, AM69, AM4N9, AM 14N, AM 14N9, AM4N69, AM99N, Dihydro-
CsA, Dihydro-CsC, Dihydro-CsD, Dihydro-CsG, M I7, AM lc-GLC, sulphate
conjugate of cyclosporin, BHI Ia, BHISa, B, G, E, (and with come overlap with
the
Hawk's above, according to Maurer's nomenclature) Ml, M2, M3, M4, M5, M6, M7,
M8, M9, M 10, M 11, M 12, M 13, M 14, M 15, M 16, M I 7, M i 8, M 19, M20, M2
I ,
M22, M23, M24, M25, M26, MUNDF1 and MeBMT. Some metabolites of
cyclosporin G include GM 1, GM9, GM4N, GM 1 c, GM I c9, and GM 19. Modified
cyciosporins include modified C-9 amino acid analogs, modified 8-amino acid
analogs,
modified 6-position analogs containing MeAIa or MeAbu residue, and SDZ 209-
313,
SDZ-205-549, SDZ-033-243, SDZ IMM 125 and SDZ-PSC-833.
FK506 and its derivatives.
FK506 is a macroiide compound, known and disclosed in European Patent
Publication
No. 0184162 and other documents. The known macrolide compounds include FR-
900506, FR-900520, FR-900523 and FR-900525 isolated from microorganisms of the
genus Streptomyces like Streptomyces tsukubensis No. 9993 and their related
compounds. Derivatives include ascornycin (C21-ethyl-FK506), CI8-OH-ascomycin,
9-deoxo-3I-o-demethy1FK506, 3I-o-demethyIFK506, C32-indolyl-ascomycin, A-
1 I9435, L-683,590, L-685,818, and L-688,6I7. These compounds were indicated
as
useful in treating rejection in transplantation, autoimmune diseases, and in
US Patent
5,648,351 as useful for preventing or treating cerebral ischemic disease.
FK506 and its
derivative macrolide compounds and salts with or without imrnunosuppressive
properties will hereinafter be referred to as FKs. FKs will hereinafter be
referred to as
a "neuroimmunophiIin ligand or ligands" based on their affinity and binding to
the
group of neuroimmunophilins called FK-binding proteins, especially FKBPI2, or
other
FKBPs.
Guilford and Vertex have discovered a series of small molecules which easily
enter the
brain and have been found to be neurotrophic and neuroprotective, by virtue of
their
ability to bind as ligands to FKBP12 and FKBPs, for which they hold a variety
of
patents including US Patent 5,780,484 and 5,614,547. However they do not claim
protection from. ionizing radiation damage. Further they do not claim that
using these
small molecule FKBP-type neuroimmunophilin ligands would be an improvement
over
current techniques of ionizing radiation treatment, or protection from
ionizing radiation
exposure. Small molecule FKBP-type neuroimmunophilin ligands will hereinafter
be
refereed to as a "neuroimmunophiIin ligand or ligands" based on their affinity
and
binding to the group of neuroimmunophilins called FK-binding proteins,
especially
FKBP12, or other FKBPs.
Currently under development are small molecules which easily enter the brain
which
have neurotrophic and neuroprotective properties by virtue of their ability to
bind to the
neuroimmunophilin cyclaphilin. It has not been claimed that using these small
molecule
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cyclophilin-type neuroimmunophilin ligands would be an improvement over
current
techniques of ionizing radiation treatment, or from ionizing radiation.
Cyclophilin-type
neuroimmunophilin ligands will hereinafter be referred to as
"neuroimmunophilin
ligand or ligands" based on their affinity and binding to the group of
neuroimmunophilins called cyclophilins.
A dose of ionizing radiation causes damage and kills cells primarily by
ionizing water or
oxygen into toxic hydroxyl, oxygen and/or other species of free radicals.
These
radicals then damage or kill the cell by their high reactivity against cell
proteins,
membranes and DNA. In addition, the free radicals themselves can induce a
mitochondria) permeability transition which incapacitates a cells ability to
make ATP to
carry out its normal functions and causes the mitochondria to release
mitochondria)
enzymes which activate nuclear caspases and other enzymes that cause
apoptosis, or
programmed cell death.
Cyclosporins, but not FK506, nor the FKBP-type neuroimmunophilin ligands,
blocks
the formation of this mitochondria) transition and thereby blocks apoptosis.
This will
make cyclosporins most likely the most effective of the neuroimmunophiIin
Iigands,
though a mixture with one ar more other ligands may have a synergistic effect.
Radiation therapy.
Below is a description of the art of radiation treatment for cancer and other
conditions.
Never before has it been suggested that radiation therapy could be improved by
the use
of a selective neuron-protecting drug. Never before has it been proposed that
by
administering a drug of the class of neuroimmunophilin ligands that it would
selectively
improve the resistance of normal neurons which are neuroirnmunophilin-rich in
brain,
spinal cord and peripheral nerves to the toxic effects of ionizing radiation,
compared to
all other types of cells which are neuroimmunophiIin-poor. Never before has it
been
realized that most primary brain cancers arise from neuroimmunophilin-poor
glial cells
(gliomas) or astrocytes {astrocytomas) or oligodendrocytes
(oligodendrogliomas), and
thus would not be protected from the toxic effects of ionizing radiation,
while normal
neuroimmunophilin-rich neurons would be protected from ionizing radiation by a
neuroimmunophilin ligand. Thus the person that is systemically treated with a
radioprotecting neuroimmunophilin ligand would have selective and improved .
protection of neurons, improving the art of radiation treatment in a non-
obvious and
novel way.
Ionizing radiation is frequently used in the medical field to treat disease.
Primary brain
tumors are often treated with radiotherapy, and are radiated with a wide field
including
much or all of the brain with an X-ray source such as a linear accellerator
over one or
many daily sessions typically over eight weeks. Sometimes the radiation is
from
gamma rays or proton and particle bearn._ This radiation slows the growth of
the brain
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tumor, but also kills normal neurons. Cystic brain tumors sometimes have
radioactive
liquids instilled into them. Sometimes radioactive pellets are temporarily or
permanently implanted.
Metastatic tumors from lung, breast, colon, skin and other organs often go to
the brain.
There are tumors of the head that are adjacent to brain, such as pituitary
tumors,
meningiomas and cra.niopharyngiomas. There are radiosensitive vascular
malformations in the brain. There are disorders of the brain which can be
helped with
partial or complete lesions of small brain structures including Parkinson's
disease,
epilepsy, obsessive compulsive disorder and trigeminal neuralgia, in which
radiation
passes through normal brain. These tumors and conditions are often treated
either with
radiotherapy as described above or radiosurgery. Radiosurgery uses either
gamma rays
or X-rays usually administering a high dose precisely localized in one
session, with
radiation passing through normal brain enroute and beyond the target
structure.
Tumors in the body, such as squamous cell, laryngeal, lung, breast, renal, or
prostate
cancers are often treated with radiation by linear accellerator, or
implantation of
radioactive pellets. The radiation fields treating these cancers sometimes
include neural
structures of the brain, spinal cord or peripheral nerves.
In addition to therapeutic medical uses for radiation, there are non-medical
instances of
radiation exposure. They include the accidental dosage or overdosage by
radioactive
substances, and suprath;erapeutic dosage using a medical radiation device.
Occasionally
there is the inadvertent expose of a pregnant person's fetus, and thus its
developing
nervous system, to X-ray radiation.
Occupational or accidental situations of radiation exposure such as nuclear
reactor
radiation leak, cause radiation of the brain in addition to the rest of the
body.
The Instant Invention.
There are side effects of radiation. It causes normal neurons to die, causing
nausea and
vomiting, lethargy, permanent decreased cognition, drop in intelligence, lost
endocrine
control, radiation necrosis and loss of function, spinal cord dysfunction and
necrosis
with resultant paralysis. The concern about these resulting side effects
reduces the
radiation doses that can be given by radiation oncologists, producing fewer
cures, or
faster recurrence than would be possible if higher doses could be given. In
addition,
the pediatric population is more susceptible to radiation effects of the
nervous system,
causing mental retardation. If neurons could be protected, these side effects
could be
decreased or prevented leading to more cancers cured or more effectively
treated
cancers.
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There is a need for a treatment that protects normal neurons from radiation,
while
leaving tumor cells susceptible. Treating a person exposed to radiation with
neuroimmunophiIin ligands would be a significant improvement over current
radiation
treatment. Being able to administer such a compound to patients has industrial
applicability.
The simultaneous realization of three factors leads to the non-obvious and
novel
inventive step that giving neuroimmunophiIin ligands to radiation therapy
patients
would selectively protect normal neurons over tumor cells and especially brain
tumor
cells, and thus improve radiation therapy - ( 1 } that neurons are more
enriched in
neuroimmunophilins than any other tissue (especially compared to brain cancer
or other
cancer cells}, (2) that drugs of the class of neuroimmunophilin ligands,
notably
cyclosporin and FK506, are protective to cells containing neuroimmunophilins
from
free radicals, and (3) that ionizing radiation kills cells via the production
of free radicals.
This also leads to the non-obvious inventive step that persons exposed to non-
medical
toxic doses of whole body radiation might better survive, or survive longer if
their
neurons were selectively protected compared to not being protected at all.
Medicament and administration.
Administration of the treatment medication may be by any suitable route
including oral,
sublingual, buccal, nasal, inhalation, parenteral (including intraperitoneal,
intraorgan,
subcutaneous, intradermal, intramuscular, infra-articular, venous (central,
hepatic or
peripheral), lymphatic, cardiac, arterial, including selective or
superselective cerebral
arterial approach, retrograde perfusion through cerebral venous system, via
catheter into
the brain parenchyma or ventricles), direct exposure or under pressure onto or
through the
brain or spinal tissue, or any of the cerebrospinal fluid ventricles,
injections into the
subarachnoid, brain cisternal, subdural or epiduraI spaces, via brain cisterns
or lumbar
puncture, infra and peri-ocular instillation including application by
injection around the
eye, within the eyeball, its structures and layers, as well as via enteral,
bowel, rectal, .
vaginal, urethral or bladder cistemal. Also for in utero and perinatal
indications then
injections into the matemaI vasculature, or through or into maternal organs,
and into
embryo, fetus, neonate and allied tissues and spaces such as the amniotic sac,
the umbilical
cord, the umbilical artery or veins and the placenta, with parenteral being
the preferred
route. The preferred route may vary depending on the condition of the patient.
Included in the invention is administration of the treatment medication via
any means with
purposeful disruption of brain or spinal parenchyma, or disrupting the blood-
brain barrier
via mechanical, thermal, cryogenic, chemical, toxic, receptor inhibitor or
augmentor, p-
glycoprotein transporter poisoning, inhibition or saturation, osmotic, charge
altering,
radiation, photon, electrical or other energy or process.
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This invention includes all methods of administering treatment medications
along with all
methods of opening, bypassing or disrupting the blood-brain barrier in
combination,
simultaneously or in sequence to get the treatment medication in contact with
nervous
tissues in order for it to exert neuro-radioprotection.
This invention includes the possibility of the timing and sequence of delivery
of treatment
medications to include pre-treatment and past-treatment, as well as
simultaneous with
treatment.
While it is possible for the treatment medication to be administered alone, it
is preferred to
present it as part of a pharmaceutical formulary drug. The formuIary drug of
this invention
comprise at least one administered treatment medication as defined above
together with one
or several appropriate carriers thereof and possibly other pharmaceutical
treatment
medications. The carriers must be appropriate in that they can readily coexist
with the
other agents of the formulary drug and are not detrimental to the receiver
thereof. This
treatment medication combined, as described in this paragraph, with other
appropriate
agents common to the art, is defined herein as the formulary drug.
The formulary drug includes those suitable for administration by the routes
including oral,
sublingual, buccal, nasal, inhalation, parenteral (including intraperitoneal,
intraorgan,
subcutaneous, intradermal, intramuscular, infra-articutar, venous (central,
hepatic or
peripheral), lymphatic, cardiac, arterial, including selective or
superselective cerebral
arterial approach, retrograde perfusion through cerebral venous system, via
catheter into
the brain parenchyma or ventricles), direct exposure or under pressure onto or
through the
brain or spinal tissue, or any of the cerebrospinal fluid ventricles,
injections into the
subarachnoid, brain cisternal, subdural or epidural spaces, via brain cisterns
or lumbar
puncture, infra and pert-ocular instillation including application by
injection around the
eye, within the eyeball, its structures and layers, as well as via enteral,
bowel, rectal,
vaginal, urethral or bladder cisternal. Also for in urero and perinatal
indications then
injections into the maternal vasculature, or through or into maternal organs
including the
uterus, cervix and vagina, and into embryo, fetus, neonate and allied tissues
and spaces
such as the amniotic sac, the umbilical cord, the umbilical artery or veins
and the placenta,
with parenteral being the preferred route.
The formulary drug may be distributed and made available in convenient unit
dose form
such as capsules and ampoules, containing the treatment medication of the
invention, and
may be manufactured and distributed by any of the methods known to the
pharmaceutical
arts. In addition to the treatment medication, the formulary drug can also
contain other
usual agents of the art relating to the type of formulary drug produced. The
formulary
drug may, by example, take the configuration of suspensions, solutions and
emulsions of
the treatment medication in lipid, non-aqueous or aqueous diIutents, solvents,
dissolving
agents, emulsifiers, syrups, granulates or powders, or mixtures of these. The
formulary
drug can also contain coloring agents, preservatives, perfumes, flavoring
additions and
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sweetening agents. In addition to the treatment medication, the formuIary drug
can also
contain other pharmaceutically active medications. The manufacture and
distribution of the
formulary drug is carried out by techniques known to the art, such as, evenly
and
intimately bringing together the treatment medication with liquids or fine
solids or both,
and then if needed, forming the formulary drug into a dose unit form. The
discrete dose,
portion and carrier vehicle constituting the formulary drug will generally be
adapted by
virtue of shape or packaging for medical administration and distributed for
this purpose.
The formulary drug acceptable for oral administration may be manufactured and
distributed
as individual dosage units such as capsules, pills, tablets, dragees,
dissolvable powders,
or cachets, each containing a known dose of the treatment medication; as
powder or .
granules; as solution or suspension in syrups, elixirs as a lipid, aqueous
liquid or~a non-
aqueous liquid; or as an oil-in-water emulsion or as a water-in-oil emulsion.
Tablets can be manufactured and distributed by compression or mould, from
treatment
medication possibly with one or more additional pharmaceutically active
compound.
Compressed tablets can be manufactured and distributed through compression in
a
machine typical to the art a known quantity of the treatment medication in a
dispersible
configuration such as powder or granules, possibly mixed with other agents
including
binders, lubricants, inert dilutents, preservatives, and dispersing agents.
Moulded tablets
can be manufactured and distributed by moulding in a machine typical to the
art a mix of
known quantity of treatment medication addition pharmaceutically active
compounds and
other additives moistened with a liquid dilutent. The tablets can possibly be
coated,
enveloped or covered, with substances including protective matrices, which can
contain
opacifiers or sweeteners and can be formulated to allow slow or controlled
release, or also
release within a certain part of the digestive system of the contained
treatment medications.
Capsules can be manufactured and distributed by placement of a known quantity
of
treatment medication, additional pharmaceutically active compounds and
additives within a
two part or sealed capsule of gelatin or other aqueous dissolvable substance.
The
treatment medication can also be manufactured and distributed as formulary
drug in
microencapsulated, microsomal, micellar and microemulsion forms.
The formuiary drug containing the treatment medication acceptable for
parenteral
administration can be manufactured and distributed from aqueous and non-
aqueous sterile
injection solutions, other pharmaceutically active compounds, additives
including anti-
oxidants, bacteriostats and solutes and sugars such as mannitol to make the
formulary drug
isotonic, hypotonic or hypertonic with the blood of the recipient; and also
aqueous and
non-aqueous sterile suspensions which can include suspenders and thickeners.
The
formuiary drug can be manufactured and distributed in unit-dose or mufti-dose
containers,
such as sealed glass or plastic ampoules, vials, bottles and bags as a liquid,
and in'a dry
state requiring only the addition of sterile liquid, for example water, saline
or dextrose
solutions, immediately prior to use. Extemporaneous solutions and suspensions
for
injection can be prepared from powders and tablets of the kind above
described.
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The formulary drug containing the treatment medication acceptable for
administration into
the brain and related structures, spinal cord and related structures,
ventricular system and
cerebrospinal fluid spaces can be manufactured and distributed from aqueous
and non-
aqueous sterile injection solutions, other pharmaceutically active compounds,
additives
including anti-oxidants, bacteriostats and solutes and sugars such as mannitol
to make the
formulary drug isotonic, hypotonic or hypertonic with the cerebrospinal fluid;
and also
aqueous and non-aqueous sterile suspensions including solvents which can
include
suspenders and thickeners. The formulary drug can be manufactured and
distributed in
unit-dose or mufti-dose containers, such as sealed glass or plastic ampoules,
vials, bottles
and bags as a liquid, and in a dry state requiring only the addition of
sterile liquid, for
example water, saline or dextrose solutions, immediately prior to use.
Extemporaneous
solutions and suspensions for injection can be prepared from powders and
tablets of the
kind above described.
The desired unit dose of formulary drug are those containing a daily dose or
ionizing
radiation treatment dose or an appropriate fraction thereof, of the
administered treatment
medication. Unit dose forms of the invention may also include more complex
systems
such as double barrelled syringes, syringes with sequential compartments one
of which
may contain the treatment medication, and the other any necessary dilutents or
vehicles, or
agents for opening the blood-brain barrier. The agents in the syringes would
be released
sequentially or as a mixture or combination of the two after the triggering of
the syringe
plunger. Such systems are known in the art.
The formulary drug generally contains from O.I to 90%a of the treatment
medication by
weight of the total composition. Amounts of from 0.0001 mg to 200 mg/kg, or
preferably
0.001 to 50 mg/kg, of body weight per day for parenteral administration and
0.001 to I50
mg/kg, preferably O.OI to 60mg/kg, of body weight per day for enteral
administration, can
be given to improve neuro-radioprotection. Nevertheless, it could be necessary
to alter
those dosage rates, depending on the condition, weight, and individual
reaction of. the
subject to the treatment, the type of formulary drug in which the treatment
medication is
administered and the mode in which the administration is carried out, and the
stage of the
disease process or interval of administration. It rnay thus be sometimes
adequate to use
less than the before stated minimum dose, while in other instances the upper
limit must be
surpassed to obtain therapeutic results.
The invention is for the use of the treatment medication in the conditions
described
throughout the application: The invention thus also includes all advertising,
labelling,
packaging, informational materials, inserts, product descriptions, advertising
materials, the
written word, including letter, pamphlet, brochures, magazines and books, as
well as
other media of communication including the spoken word, fax, phone, photos,
radio,
video, television, f im, Internet, e-mail or computer based, and proposals for
clinical trials
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and study protocols for clinical trials using the treatment medication for its
selective
neuronal protection from ionizing radiation.
Examples:
Examples 1-14 demonstrate typical situations where neuro-
radioprotection could be used.
Examples 15-27 demonstrate possible neuroimmunophilin Iigand
formulations for administering as neuro-radioprotective drugs.
Example 1
A patient has a primary brain tumor, such as an astrocytoma, oiigodendroglioma
or
ependymoma and is a candidate for clinical radiation therapy, radiosurgery or
brachytherapy. Four hours before radiation treatment, the patient has an
injection of an
neuroimmunophilin ligand into the vein, artery, thecal sac (via lumbar
puncture) or
ventricular catheter. The patient then has a session of clinical radiation
treatment.
Because the neuroimmunophilins are concentrated in neurons, but not glial
tumors, the
drug is concentrated in the neurons but not the tumor. Fewer neurons die
compared to
tumor at a given radiation dose compared to untreated patients, increasing the
safety of
higher radiation doses to kill tumor, and reducing the Ions of neurons.
Example 2
A patient with a primary brain tumor such as an astrocytoma, anapIastic
astrocytoma or
glioblastoma multiforme receives X-radiation therapy to the brain for a series
of daily
treatments over two months. This radiation field is wide and include large
areas of
normal brain in addition to the normal neurons adjacent to tumor. During the
period of
radiation therapy, to protect the brain neurons from radiation damage, or
allow the
administration of.larger doses of radiation than otherwise tolerated, the
patient is given a
series of doses of neuroimmunophilin Iigand. This reduces side effects of
cognitive
decline, brain swelling, nausea, headaches and radiation necrosis. This
increases the
chances for cure or control of tumor growth.
Example 3
A patient with a pituitary tumor is going to have radiation therapy or
radiosurgery. Part
of the radiation field includes the optic chiasm, optic nerve and optic tract.
To protect
the optic chiasm, nerve and tract neurons from radiation damage, and the
patient from
vision loss, or blindness, the patient is given a dose of neuroimmunophilin
ligand prior
to each session.
SUBSTITUTE SHEET (RULE 26)
CA 02345378 2001-03-23
WO OO/1b794 1~ PCT/US98/20040
Example 4
A patient with a craniopharyngioma is going to have radiation therapy or
radiosurgery.
Part of the radiation field includes the hypothalamus of the brain. To protect
the
hypothalamic neurons from radiation damage, the patient is given a dose of
neuroimmunophilin ligand prior to each session. This reduces the side effects
of
endocrine abnormalities or insufficiencies, diabetes insipidus, retardation or
mental
decline and radiation necrosis.
Example 5
An infant or child with a medulloblastoma brain tumor requires whole brain
radiation,
including the forebrain, midbrain, cerebellum, brain stem and spinal cord. To
protect
all the neurons in these locations, the infant or child is given a dose of
neuroimmunophilin ligand prior to each session. This reduces the common side
effects
of mental retardation, cognitive and functional decline, endocrine
abnormalities and
radiation necrosis. This allows the treatment to be given at an earlier age
than without
neuroradioprotection. This allows a higher radiation dose be given than would
be
allowed without neuroradioprotection.
Example 6
A patient with one or more metastatic tumors. from a lung, breast or other
primary
cancer to the brain has Gamma Knife, particle beam or Linear accellerator
based
stereotactic radiosurgery, with the gamma, particle beam or X-radiation fields
including
normal brain neurons. To protect the normal brain neurons in the path of the
radiation,
the patient is given a dose of neuroimmunophilin Iigand. This reduces the side
effects
of radiation necrosis and cognitive decline.
Example 7
A patient with a lung tumor is going to have lung radiation therapy. Part of
the
radiation field includes the spinal cord. To protect the spinal cord neurons
from
"bystander" radiation damage, the patient is given a dose of neuroimmunophilin
ligand
prior to each session.
Example 8
A patient with a kidney cancer is going to have kidney radiation therapy. Part
of the
radiation field includes the small and large bowel. To protect the autonomic
neurons in
the bowel from "bystander" radiation damage, the patient is given a dose of
neuroimmunophilin Iigand prior to each session.
SUBSTITUTE SHEET (RULE 26)
CA 02345378 2001-03-23
WO 00/16794 13 PCT/US98/20040
Example 9
A patient with prostate cancer is going to have radiation therapy or
brachytherapy
radioactive prostate implants. Part of the radiation field includes the
pudendal nerves
controlling penile sensation, erection and ejaculation. To protect the penile
nerves
passing adjacent to the prostate from "bystander" radiation damage, the
patient is given
a dose or doses of neuroimmunophilin Iigand. This reduces impotence.
Example 10
A patient with a breast tumor is going to have radiation therapy. Part of the
radiation
field includes the brachial plexus nerves. To protect the brachial plexus
nerves that
innervate the muscles and skin of the arm from "bystander" radiation damage,
the
patient is given a dose of neuroimmunophiiin Iigand prior to each session.
This reduces
the side effect of loss of sensorimotor function to the arm.
Example I1
Staff of a uranium processing plant is exposed to radiation. In order to
protect the
neurons of the people exposed, they are administered an intravenous dose of
cyclosporin A and/or FK506. This reduces radiation poisoning and increases
chances
for survival.
Example 12
A person is in an occupation or situation with high likelihood of radiation
exposure, or
has just received whole body radiation. The person is administered or self
administers
a dose of neuroimmunophilin Iigand to protect all the neurons in his or her
body and
increases chances for survival.
Example 13
A person is in earth orbit or space travel and receives cosmic radiation. The
person is
administered dose or doses of neuroimmunophilin ligand to protect all neurons
in his or
her body and increase chances for survival.
Example I4
A person is pregnant and the fetus is exposed to radiation. To reduce the
damage to
developing fetal neurons and brain, and reduce brain damage and mental
retardation of
the surviving child, a dose of neuroinnmanophilin iigand is administered.
SUBSTITUTE SHEET (RULE 26)
CA 02345378 2001-03-23
WO 00116794 ~ 4 PCT/US98/20040
Example i5
Sterile Injectable Concentrate Formulary Drug
Containing per ml:
Cyclosporin A 100 mg
Spiritus fords 280 mg
Polyoxyethylated castor oil b00 mg
The formulary drug is sterilized by heat or radiation and then placed in a
sealed
container such as glass in doses of 1 or 5 ml.
Sterile injectable concentrate formulary drug is diluted 1 mI in 20 m1 saline
so that it
may be administered by infusion or by injection into artery, vein, brain,
spine or
cerebrospinal fluid spaces.
Example 16
Sterile Injectable Concentrate Formulary Drug
Containing per ml:
Cyclosporin A 200 mg
Tween 80 $00 mg
The formulary drug is sterilized by heat or radiation and then placed in a
sealed
container such as glass in doses of I or 5 ml.
Sterile injectable concentrate formulary drug is diluted I ml in 10 ml saline
so that it
may be administered by infusion or by injection into artery, vein, brain,
spine or
cerebrospinal fluid spaces.
Example 17
Capsule Formulary Drug
Cyclosporin A 200 mg
Iron oxide E 172 . 1 mg
Titanium dioxide 3 mg
Ethanol 100 mg
Corn oil 415 mg
Gelatine 280 mg
Labrafil 300 mg
Andrisorb 105 mg
Glycero185!0 3 mg
A one or two part capsule is prepared by placing the formulary drug in a one
or two part
gelatine capsule.
SUBSTITUTE SHEET (RULE 26)
CA 02345378 2001-03-23
WO 00/16794 1 ~ PCT/US98/20040
Example 18
Liquid Oral Formulary Drug
Containing per 1 mi:
Cyclosporin A 200 mg
Ethanol 100 mg
Corn oil 430 mg
Labrafil 200 mg
Example 19
Sterile InjectabIe Concentrate Formulary Drug
Containing per ml
FK506 anhydrous S m
Polyoxyl 60 hydrogenated castor oil 200 mg
Dehydrated alcohol USP, 80% v/v.
The formulary drug is sterilized by heat or radiation and then placed in a
sealed
container such as glass in doses of I or 5 ml.
Sterile injectable concentrate formulary drug is diluted 1 ml in 10 ml saline
so that it
may be administered by infusion or by injection into artery, vein, brain,
spine or
cerebrospinal fluid spaces.
Example 20
Capsule Formulary Drug
FK506 anhydrous 5 mg
Lactose 100 mg
Hydroxypropyl methylcellulose 100 mg
Croscarmellose sodium 10 mg
Magnesium stearate IO mg
A one or two part capsule~is prepared by placing the formulary drug in a one
or two part
gelatine capsule.
Example 21
Sterile lnjectable Concentrate Formulary Drug
Containing per ml
Small molecule FKBP-type neuroimmunophilin ligand S mg
Polyoxyl 60 hydrogenated castor oil 200 mg
Dehydrated alcohol USP, 80% v/v.
The formulary drug is sterilized by heat or radiation and then placed in a
sealed
container such as glass in doses of 1 or S ml.
SUBSTITUTE SHEET (RULE 26)
CA 02345378 2001-03-23
WO 00/16794 ~ 6 PCT/US98/20040
Sterile injectable concentrate formuiary drug is diluted 1 ml in 10 ml saline
so that it
may be administered by infusion or by injection into artery, vein, brain,
spine or
cerebrospinal fluid spaces.
Example 22
Capsule Formulary Drug
Small rnolecule FKBP-type neuroimmunophiIin5 mg
ligand
Lactose 100 mg
Hydroxypropyl methyiceIlulose 100 mg
CroscanmelIose sodium 10 mg
Magnesium stearate 10 rng
A one or two part capsule is prepared by placing the formulary drug in a one
or two part
gelatine capsule.
Example 23
Sterile Injectabie Concentrate Formulary Drug
Containing per ml:
Cyclosporin A 200 mg
FK506 anhydrous 5 m
Small molecule FKBP-type neuroimmunophilin Iigand 5 mg
Tween 80 v/v
The formulary drug is sterilized by heat or radiation and then placed in a
sealed
container such as glass in doses of 1 or 5 ml.
Sterile injectable concentrate formulary drug is diluted 1 rni in 10 rnl
saline so that it
may be administered by infusion or by injection into artery, vein, brain,
spine or
cerebrospinal fluid spaces.
Example 24
Sterile Injectable Concentrate Formulary Drug
Containing per rnl
Small molecule cyclophiiin-type neuroimmunophiIin ligand 5 mg
Polyoxyl 60 hydrogenated castor oil 200 mg
Dehydrated alcohol LTSP, 80% vlv.
The formulary drug is sterilized by heat or radiation & then placed in a
sealed container
such as glass in doses of 1 or 5 ml. Sterile injectable concentrate formulary
drug is
diluted I ml in 10 ml saline so that it may be administered by infusion or by
injection
into artery, vein, brain, spine or cerebrospinal fluid spaces.
SUBSTITUTE SHEET (RULE 26)
CA 02345378 2001-03-23
WO 00/16794 ~ 7 PCT/US98I20040
Example 25
Capsule Formulary Drug
5ma11 molecule cyclophilin-type neuroimmunophilin5 mg
iigand
Lactose 100 mg
Hydroxypropyl methylcellulose 100 mg
Croscarmellose sodium 10 mg
Magnesium stearate I O mg
A one or two part capsule is prepared by placing the formulary drug in a one
or two part
gelatine capsule.
Example 26
Sterile Injeciable Concentrate Formulary Drug
Containing per mI:
Cyclosporin A 200 mg
FK506 anhydrous 5 mg
Small molecule FKBP-type neuroimmunophilin ligand 5 mg
Small molecule cyclophilin-type neuroimmunophilin ligand 5 mg
Tween 80 v/v
The formulary drug is sterilized by heat or radiation & then placed in a
sealed container
such as glass in doses of 1 or 5 ml. Sterile injectable concentrate farmuiary
drug is
diluted 1 ml in 10 ml saline so that it may be administered by infusion or by
injection
into artery, vein, brain, spine or cerebrospinal fluid spaces.
Example 27
Capsule Formulary Drug
Cyclosporin A 200
mg
FK506 anhydrous 5 mg
Small molecule FKBP-type neuroimmunophilin 5 mg
ligand
Small molecule cyclophilin-type neuroimmunophilin5 mg
ligand
Iron oxide E 172 1 mg
Titanium dioxide 3 mg
Ethanol 100 mg
Corn oil 41 S mg
Gelatine 280 mg
Labrafil 300 mg
Andrisorb 105 mg
Glycero185% 3 mg
A one or two part capsule is prepared by placing the formulary drug in a one
or two part
gelatine capsule.
SUBSTITUTE SHEET (RULE 26)
