Water soluble pro-drugs of propofol

This invention provides esters of propofol (2,6,-diisoprophenol). The propofol esters are soluble in water and metabolize rapidly to propofol in the body. The propofol esters are useful as pro-drugs for the same indications as propofol. This invention also provides methods of treating neurodegenerative diseases by administering as effective amount of propofol.

BACKGROUND OF THE INVENTION
 This invention relates to the field of pharmaceuticals. More specifically,
 this invention relates to pro-drugs of propofol that are water soluble and
 non-toxic.
 Propofol (2,6-diisopropylphenol) is a low molecular weight phenol that is
 widely used as an intravenous sedative-hypnotic agent in the induction and
 maintenance of anesthesia or sedation in humans and animals. Among its
 advantages as an anesthetic are rapid onset of anesthesia, rapid
 clearance, and minimal side effects.
 Propofol has a broad range of biological and medical applications. For
 example, it has been reported to be an anti-emetic (Castano et al., Rev.
 Esp. Anestesiol. Reanim. 42(7):257-60 (1995)), an anti-epileptic (Kuisma
 M. et al. Epilepsia 36(12):1241-1243 (1995)) and an anti-pruritic.
 (Borgeat, A. et al., Anesthesiology 80:642-56 (1994); Lawson, S. et al.,
 Brit. J. Anesthesia 64:59-63 (1990).)
 Propofol also has significant application as an antioxidant. (Sanchez et
 al., U.S. Pat. No. 5,308,874; Sanchez et al., U.S. Pat. No. 5,461,080; and
 Aarts L. et al. FEBS Let. 357(1):83-5 (1995).) In fact, it has been
 proposed that propofol can replace .alpha.-tocopherol as antioxidant.
 (Aarts, supra.) Oxidative processes in living materials can result in
 significant damage. For example, oxidizing agents in the environment, such
 as smoke or ozone, are inhaled and cause oxidative stress to tissues of
 the respiratory system. Exposure to sunlight causes damage to skin as a
 result of chain reactions which originate when the ultraviolet light
 promotes the production of free radicals, such as superoxide and hydroxyl,
 within the tissue surface. Other forms of energetic radiation can have the
 same effect.
 Propofol also has been shown to inhibit lipid peroxidation. (Misacchia et
 al., Pharmacol. Toxicol. (1991) 69:75-77.)
 Oxidation also is a component of inflammation. For example, cyclooxygenase
 oxidizes arachidonic acid into prostaglandins which act as inflammatory
 mediators. Therefore, inhibiting oxidation is useful in the treatment of
 conditions with an inflammatory component. In addition, oxidative damage
 is also caused by other inflammation mediators such as tumor necrosis
 factor (TNF) and IL-1.
 By inhibiting oxidation in tissues of the respiratory tract, propofol is
 useful in the prophylactic and therapeutic treatment of various pathologic
 respiratory conditions having an inflammatory component. These include,
 for example, acid aspiration, adult/infant respiratory distress syndrome,
 airway obstructive disease, asthma, bronchiolitis, bronchopulmonary
 dysplasia, cancer, chronic obstructive pulmonary disease ("COPD"), cystic
 fibrosis, emphysema, HIV-associated lung disease, idiopathic pulmonary
 fibrosis, immune-complex-mediated lung injury, exposure to an oxidizing
 agent, ischemia-reperfusion injury, mineral dust pneumoconiosis,
 drug-induced lung disease and silo-filler's disease.
 There is an extensive accumulation of evidence that either the pathogenesis
 or the subsequent damage pathways in various neurodegenerative diseases
 involve reactive oxygen species, and are therefore amenable to treatment
 with antioxidants. (A review of this subject is given by Simonian A. and
 Coyle J. T., "Oxidative Stress in Neurodegenerative Diseases", in Ann.
 Rev. Pharmacol. Toxicol. 36:83 (1996).) Examples of specific
 neurodegenerative diseases where oxidative damage may play a role include
 Friedrich's disease (Helveston et al., Clinical Neuropharnacology
 19(3):271 (1996)), Parkinson's disease (Jenner, Pathologie Biologie
 44(1):57 (1996)), Alzheimer's disease (Good et al., Am. J. Pathol.
 149(1):21 (1996)), Huntington's disease (Borlongan et al., Journal of the
 Florida Medical Association 83(5):335 (1996)), amyotrophic lateral
 sclerosis (ALS) (Cudkowicz, M. et al. "Free-Radical Toxicity in
 Amyotrophic Lateral Sclerosis," Ch. 16 in Glutathione in the Nervous
 System, Shaw, Ed. (1998); multiple sclerosis (MS) (Hooper, D. et al. "Uric
 acid, a natural scavenger of peroxynitrite, in experimental allergic
 encephalomyelitis and multiple sclerosis," Proc. Natl. Acad. Sci. USA
 95:675-680 (1998)); Pick disease (Castellani et al., Brain Research
 696(1-2):268 (1995)) and aging itself (Beal, Annals of Neurology 38(3):357
 (1995).)
 Similarly, the incidence of spinal cord injury in the United States is
 approximately 10,000 new cases per year. The human and financial costs of
 such injuries are devastating and therapies for treatment of these
 injuries are urgently needed. There is an accumulation of evidence that
 the pathogenesis of spinal cord injury, as well as injury to the brain,
 also involves reactive oxygen species and is therefore amenable to
 treatment with antioxidants (Castano et al., Rev. Esp. Anestesiol. Reanim.
 42(7):257-60 (1995)). Alpha-tocopherol (vitamin E), a well known
 antioxidant, has been shown to decrease post-traumatic spinal cord
 ischemia and to enhance chronic neurological recovery. However, vitamin E
 is taken up into the central nervous system very slowly, making it an
 impractical agent for the treatment of acute neural injury.
 A disadvantage to the use of propofol is that it is almost completely
 insoluble in water. Therefore, before it can be used for intravenous
 applications, such as anesthesia, it must be specially formulated in
 aqueous media using solubilizers or emulsifiers. The early developmental
 studies with intravenous propofol were performed with clear formulations
 containing the solubilizer Cremophor EL.RTM.. Later developmental studies
 and the current commercial products use an oil-in-water emulsion in which
 the emulsifier is the lecithin mixture Intralipid.RTM.. The commercial
 products are sold under various names including Diprivan.RTM.,
 Disoprofol.RTM., Disoprivan.RTM., and Rapinovet.RTM..
 Formulations that contain solubilizers or emulsifiers have been fraught
 with problems. Formulations containing the solubilizer Cremophor EL.RTM.
 have been reported to cause allergic complications (Briggs et al.,
 Anesthesis 37:1099 (1982)). Stable emulsions are technically difficult to
 prepare and are consequently more expensive. Microbial growth has
 sometimes been observed in such emulsions and is believed to be supported
 by the emulsifier components (McHugh et al., Can. J. Anaesth. 42(9):801-4
 (1995)).
 Other investigators have sought to overcome the problem of water
 insolubility by incorporating the propofol within a water-soluble carrier
 such as a cyclodextrin. Such a molecular complex allows delivery of
 propofol in a clear water solution and the eventual release of propofol in
 vivo. Unfortunately, the cyclodextrin complex produced cardiovascular
 complications in vivo, discouraging further study (Bielen et al., Anesth.
 Analg. 82(5):920-4 (1996)).
 Until now, there has been no pharmaceutical preparation of propofol
 formulated to deliver its beneficial effects without harmful side effects.
 Thus, the need exists for a water-soluble, stable, non-toxic
 pharmaceutical composition which is readily converted to propofol in vivo
 without the need for additives, solubilizers or emulsifiers.
 SUMMARY OF THE INVENTION
 This invention provides novel esters of propofol (2,6-diisopropylphenol)
 that are highly soluble in water and that metabolize rapidly into
 propofol. More specifically, this invention provides propofol
 hemisuccinate, propofol hemiglutarate, propofol hemiadipate,
 mono(propofol) phosphate, and di(propofol) phosphate. The esters of the
 present invention are at least one order of magnitude more soluble in
 water than propofol. The monophosphate and hemisuccinate esters are the
 most soluble.
 The pro-drugs of this invention have little or no direct antioxidant
 activity, as a consequence of blockage of the phenolic group of the
 propofol molecule. In an in vivo environment, biological enzymes cause the
 hydrolysis of the pro-drugs, resulting in the release of free propofol, a
 potent antioxidant. Therefore the pro-drugs of this invention, when used
 in biological environments, possess all of the therapeutic applications
 that have been demonstrated for propofol.
 These compositions offer advantages over propofol. First, the esters of
 propofol of this invention readily hydrolyze to propofol in vivo.
 Accordingly, they are useful as pro-drugs of propofol. Second, they are
 non-toxic. Accordingly, they have a high therapeutic-to-toxicity index.
 Third, they have a much higher water-solubility than propofol. Thus, they
 offer a safer means of administration than the current commercially
 available oil-in-water or cyclodextrin formulations. Fourth, they are more
 stable to oxidation than propofol because they protect the phenolic
 function from oxidation during formulation and storage. Phenols are well
 known to darken and decompose in the presence of air. Therefore, the
 esters of propofol of this invention offer all the therapeutic effects of
 propofol while avoiding the necessity of adding potentially harmful
 solubilizing or emulsifying agents.
 A soluble pro-drug facilitates formulation and administration of the drug.
 How fast the drug is released in vivo by hydrolysis is a function of the
 structure of the pro-drug; but it is also influenced by the carrier, the
 route of administration, and the tissues in which the pro-drug is located.
 The pro-drugs of this invention act in vivo as anti-oxidant and
 anti-inflammatory agents. They are useful in the treatment of oxidative
 tissue damage, diseases having an inflammatory component and cancer, in
 particular when co-administered with a chemotherapeutic agent. Propofol
 and the pro-drugs of this invention also have uses as hypnotic agents,
 anti-convulsives, anti-pruritics, and anti-emetics.
 In one aspect this invention provides a propofol pro-drug of the formula:
 ##STR1##
 wherein X is 2, 3 or 4, or a pharmaceutically acceptable salt of any of the
 foregoing.
 In another aspect this invention provides a pharmaceutical composition
 comprising a pharmaceutically acceptable carrier and a pharmacologically
 effective amount of a propofol pro-drug of this invention.
 In another aspect this invention provides a method for inhibiting oxidation
 of biological material comprising contacting the material with an
 effective amount of a propofol pro-drug of this invention.
 In another aspect this invention provides a method for the treatment of a
 pathologic condition having an inflammatory component in a subject
 comprising administering to the subject a pharmacologically effective
 amount of a propofol pro-drug of this invention.
 In another aspect this invention provides a method for the treatment of a
 pathologic condition of the nervous system having an inflammatory
 component in a subject comprising administering to the subject a
 pharmacologically effective amount of propofol or a propofol pro-drug of
 this invention.
 In another aspect this invention provides a method for the treatment of a
 pathologic respiratory condition in a subject comprising administering to
 the subject a pharmacologically effective amount of a propofol pro-drug of
 this invention.
 In another aspect this invention provides a method for inducing anaesthesia
 in a subject comprising administering to the subject a pharmacologically
 effective amount of a propofol pro-drug of this invention.
 In another aspect this invention provides a method for inhibiting nausea
 and vomiting in a subject comprising administering to the subject a
 pharmacologically effective amount of a propofol pro-drug of this
 invention.
 In another aspect this invention provides a method for the treatment of
 epileptic or convulsive disorders in a subject comprising administering to
 the subject a pharmacologically effective amount of a propofol pro-drug of
 this invention.
 In another aspect this invention provides a method for the treatment of
 pruritis in a subject in a subject comprising administering to the subject
 a pharmacologically effective amount of a propofol pro-drug of this
 invention.
 In another aspect this invention provides a method for the treatment of a
 cancer in a subject comprising administering to the subject a
 chemotherapeutic agent and a pharmacologically effective amount of a
 propofol pro-drug of this invention.
 In another aspect this invention provides a method for the treatment of a
 subject undergoing treatment with a chemotherapeutic agent having activity
 as an oxidizing agent comprising the step of administering a
 pharmacologically effective amount a propofol pro-drug of this invention
 to the subject.
 In another aspect, this invention provides the use of a water-soluble
 propofol pro-drug of this invention in the manufacture of a medicament for
 the treatment of a pathological condition having an inflammatory
 component.
 DETAILED DESCRIPTION OF THE INVENTION
 I. Water Soluble Esters of Propofol
 Propofol is rendered water soluble by the linking of hydrophilic groups to
 the molecule. Such covalent derivatization of propofol is possible only on
 the phenolic --OH group, which is flanked on both sides by bulky isopropyl
 groups. The --OH group is therefore spatially crowded ("sterically
 hindered") and would be expected to be resistant to the substitution of
 the hydrogen with a bulkier substituent such as an acyl group or a
 phosphoryl group.
 The synthesis of esters however was successfully achieved by the use
 activated diacids (as halides or anhydrides), and by simultaneous use of
 either catalysis by tertiary amines, or activation of the phenol by
 ionization of the phenolic proton.
 Preferred compounds in accordance with the present invention are those
 having the following formulae:
 ##STR2##
 In the above structure for carboxylic hemiesters of propofol, X=2 is the
 hemisuccinate ester of propofol; X=3 is the hemiglutarate ester of
 propofol; and X=4 is the hemiadipate ester of propofol.
 Preferred compounds of the present invention also include pharmaceutically
 acceptable salts of the compounds of the above formulae. A
 "pharmaceutically acceptable salt" is a salt that can be formulated into a
 compound for pharmaceutical use including, e.g., metal salts (sodium,
 potassium, magnesium, calcium, etc.) and salts of ammonia or organic
 amines.
 II. Prophylactic and Therapeutic Treatments
 Propofol and the pro-drugs of this invention are useful for the
 prophylactic and therapeutic treatment of subjects as described herein. A
 "subject" of treatment is an animal, such as a mammal, including a human.
 Non-human animals subject to treatment include, for example, fish, birds,
 and mammals such as cows, sheep, pigs, horses, dogs and cats. "Treatment"
 refers to prophylactic or therapeutic treatment. A "prophylactic"
 treatment is a treatment administered to a subject who does not exhibit
 signs of a disease or exhibits only early signs for the purpose of
 decreasing the risk of developing pathology. Thus, administration of the
 compound to a person who is exposed to an oxidant has a prophylactic
 effect in inhibiting oxidative tissue damage. A "therapeutic" treatment is
 a treatment administered to a subject who exhibits signs of pathology for
 the purpose of diminishing or eliminating those signs.
 III. Use as an Anti-Oxidant and Anti-Inflammatory
 Oxidation is a source of serious damage to biological molecules, including
 nucleic acids, proteins, lipids and carbohydrates. It is consequently also
 a source of damage to biological structures composed of such molecules,
 e.g., cell membranes, tissues and vasculature. The source of oxidants can
 be external to an organism, for example from the environment, or internal,
 as a result of the natural production of free radicals by, for example,
 the mitochondria, or as a result of the inflammatory response.
 Propofol and the pro-drugs of this invention are useful in methods of
 inhibiting oxidation in biological materials. The methods involve
 contacting the biological material with an effective amount of the
 compound. In the therapeutic methods of this invention, a
 pharmacologically effective amount of the compound is administered to a
 subject suffering from a pathological condition responsive to inhibition
 of oxidation. In the prophylactic methods of this invention a
 pharmaceutically effective amount of the compound is administered to a
 subject at risk of developing a disease as a result of exposure to
 oxidative stress.
 "Biological material" refers to cells, tissues, organs, extracts,
 homogenates, fluids or cultures both in vitro and in vivo. In one aspect,
 this invention provides methods of inhibiting oxidation of biological
 material in a subject by administering to the subject an amount of the
 compound effective to inhibit the oxidation. In another aspect, this
 invention provides methods of inhibiting oxidation to biological material
 in vitro by contacting the material with an amount of the compound
 effective to inhibit the oxidation.
 Inflammation is characterized at the cellular level by the production of
 inflammatory mediators, such as cytokines (e.g., TNF-.alpha., IL-1). The
 production of cytokines involves an oxidation step that is cyclooxygenase
 dependent. Inflammation at the cellular level is also characterized by the
 production of other inflammatory mediators, such as eicosanoids (e.g.,
 prostaglandins, prostacyclins, thromboxanes and leukiotrienes). The
 production of prostaglandins, prostacyclins and thromboxanes all involve
 an oxidation step that is cyclooxygenase dependent. At the tissue level,
 inflammation is characterized by invasion of leukocytes, especially
 neutrophils, macrophages and lymphocytes. Therefore, it appears that most
 or all inflammation involves an oxidative component. Because they inhibit
 oxidation, propofol and the pro-drugs of this invention are useful in the
 treatment or prevention of conditions having an inflammatory component. A
 pharmacologically effective amount of the compound is administered to a
 subject suffering from, or at risk of suffering from, a pathological
 condition which can be improved by inhibiting inflammation. In general, an
 effective dose is about 100 mg to about 1 gm taken orally per day.
 A. Arthritis
 Arthritis is an inflammatory condition. Accordingly, propofol and the
 pro-drugs of this invention are useful in treating arthritis, both
 rheumatoid arthritis and osteoarthritis. The compounds preferably are
 delivered orally or transdermally for this purpose. A pharmacologically
 effective amount of the agent taken orally is about 50 mg to about 2 g.
 daily.
 B. Respiratory Disorders
 Because they can be administered to the respiratory system via inhalation,
 propofol and the pro-drugs of this invention are useful in the treatment
 of respiratory disorders having an inflammatory component. The
 anti-oxidant compounds of this invention inhibit oxidation and its
 subsequent damage that result in or accompany such disorders. Accordingly,
 they are useful in the prophylactic or therapeutic treatment of
 respiratory disorders that involve an inflammatory component or that
 result from exposure to oxidizing agents.
 Respiratory diseases that can be treated with these compounds include acid
 aspiration, adult/infant respiratory distress syndrome, airway obstructive
 disease, asthma, bronchiolitis, bronchopulmonary dysplasia, cancer,
 chronic obstructive pulmonary disease ("COPD"), cystic fibrosis,
 emphysema, HIV-associated lung disease, idiopathic pulmonary fibrosis,
 immune-complex-mediated lung injury, exposure to an oxidizing agent,
 ischemia-reperfusion injury, mineral dust pneumoconiosis, drug-induced
 lung disease and silo-filler's disease.
 Exposure to oxidizing agents such as dust, ozone, hyperoxia, air pollution,
 nitric oxide, nitrogen dioxide, sulfur dioxide, tobacco smoke, diesel
 exhaust or other combustion byproducts also can be treated with propofol
 or the pro-drugs of this invention.
 In the treatment of respiratory conditions, the compound is preferably
 delivered by inhalation. The compound can be delivered as an aerosol, mist
 or powder. An effective amount for delivery by inhalation is about 0.1 mg
 to 10 mg per inhalation, several times daily. The compound also can be
 delivered orally in amounts of about 50 mg to about 2 g daily.
 C. Disorders Of The Central Nervous System
 Propofol and the pro-drugs of this invention are particularly useful in
 inhibiting oxidation and its resultant damage in disorders of the central
 nervous system that involve an inflammatory component. This results both
 from their anti-oxidant properties and because, once introduced into the
 system, they rapidly equilibrate in the various compartments, including
 the central nervous system. Also, lipophilicity and small size of propofol
 favor penetration into the nervous system and brain, which is why it can
 function as an anesthetic. Rapid and significant penetration is not a
 feature of many other antioxidants, such as alpha-tocopherol (Vitamin E)
 and ascorbic acid (vitamin C). Thus, these compounds are useful in the
 treatment of nervous system disorders.
 Neurodegenerative conditions of the nervous system include Friedrich's
 disease, Parkinson's disease, Alzheimer's disease, Huntington's disease,
 Pick disease, amyotrophic lateral sclerosis and multiple sclerosis.
 Propofol and the pro-drugs of this invention also are useful in treating
 trauma to the central nervous system. These include, for example, skull
 fracture and its resulting edema, concussion, contusion, brain
 hemorrhages, shearing lesions, subdural and epidural hematoma, and spinal
 cord injury (e.g., mechanical injury due to compression or flexion of the
 spinal cord).
 In the treatment of traumatic conditions of the central nervous system, the
 compound preferably is administered parenterally, such as by intravenous
 injection or injection directly into the central nervous system (i.e.,
 intrathecally (IT) or into the brain). A pharmacologically effective
 amount of the compound is about 25 mg to about 500 mg IV or IM and about 5
 mg to about 100 mg IT. The treatment of chronic neurodegenerative disease
 is best effected via oral administration of an effective amount of the
 compound, preferably 50 mg to 2 g daily.
 D. Cardiovascular Disorders
 Propofol and the pro-drugs of this invention are useful in
 preventing/treating cardiovascular disease, including but not limited to
 ischemia-reperfusion dysfunction, atherosclerosis and restenosis following
 angioplasty. Oral, enteral or intravenous administration is useful for
 this purpose.
 IV. Treatment of Cancer
 It is now recognized that co-administration of anti-oxidants improves the
 outcome of chemotherapy in subjects with cancer. (R. Chinery et al. Nature
 Medicine 3:1233-1241 (1997).) As an example, co-administration of
 pyrrolidine dithiocarbamate (PDTC) or vitamin E with 5-fluorouracil or
 doxorubicin inhibited the growth of colorectal cancer tumors in mice.
 Propofol and the pro-drugs of this invention, which function as
 anti-oxidants, are useful in the treatment of cancer or as adjuvants in
 the treatment of cancer. Co-administered with chemotherapeutic agents,
 they enhance cytotoxicity, thereby inhibiting the growth of tumors. In
 addition, they also inhibit oxidative damage that generally accompanies
 use of anticancer agents. Methods of treating cancer involve administering
 a pharmacologically effective amount of the compound to a subject prior
 to, during or after chemotherapy. The compounds are useful in the
 treatment of any cancer. However, they are particularly effective in the
 treatment of colorectal cancer and lung cancer. The compounds also are
 effective with chemotherapeutic agents that act by all known modes of
 action.
 The compounds preferably are delivered as a pharmaceutical composition in
 the form of an intravenous or intramuscular solution. However, other modes
 of delivery, such as enteral administration, also are useful. An effective
 amount of the agent is about 50 mg to about 2 g delivered daily over the
 course of the chemotherapy regimen.
 V. Use to Prevent/Ameliorate Chemotherapeutic Toxicity
 Propofol and the pro-drugs of this invention can be used to prevent or
 ameliorate the effects of chemotherapeutic agents that have oxidative
 damage as a significant side effect, e.g., bleomycin, doxorubicin and
 cisplatin. The methods involve administering a pharmacologically effective
 amount a compound of the invention to a subject undergoing chemotherapy
 treatment.
 VI. Use as a Hypnotic Agent and as a Sedative
 Propofol and the pro-drugs of this invention are useful as hypnotic agents
 for the same indications as propofol. These include inducing and/or
 maintaining general anaesthesia and use as a sedative. The compound is
 administered in an amount effective to induce hypnosis.
 For use as a general anaesthetic, the compounds are preferably administered
 as an intravenous solution. However, they also can be administered by
 inhalation. Compositions of propofol are presently administered as an
 injectable oil-in-water emulsion, due to the very low water solubility of
 propofol. The pro-drugs of this invention can be formulated in the same
 manner. However, the pro-drugs of this invention are more highly water
 soluble than propofol. Accordingly, they can be delivered as an aqueous
 solution or with significantly less emulsifiers or solubilizers.
 For use as a sedative (e.g., for the treatment of anxiety conditions), the
 compounds are preferably and effectively administered orally in amounts of
 about 10 mg to 2 g daily. However, they can also be administered by
 inhalation, intravenously or intramuscularly.
 The pro-drugs of this invention are administered in similar amounts and in
 the same schedule as injectable emulsions of propofol (e.g.,
 DIPRIVAN.RTM.). Dosage level of propofol for producing general anesthesia,
 both induction (for example about 2.0 to about 2.5 mg/kg for an adult) and
 maintenance (for example, about 4 to about 12 mg/kg/hr) and for producing
 a sedative effect (for example, about 0.3 to about 4.5 mg/kg/hr) may be
 derived from the very substantial literature on propofol. The actual
 dosages of the propofol pro-drugs, on a weight basis, will in many cases
 be higher than for propofol itself because (a) the molecular weights of
 the pro-drugs are higher and (b) release of propofol from the pro-drug
 occurs at a finite rate. Furthermore, the anesthetist and/or physician
 would modify the dose to achieve the desired effect in any particular
 patient, in accordance with normal skill in the art.
 VII. Use as a Anti-Emetic
 Propofol and the pro-drugs of this invention are useful as anti-emetics.
 Their administration is indicated in subjects at risk of vomiting or who
 feel nauseous. As an example, the compounds are usefully co-administered
 to subjects who are receiving treatments that induce nausea, such as
 various chemotherapy agents and surgical procedures. Accordingly, this
 invention provides methods for inhibiting nausea and vomiting by
 administering the compound to a subject in an amount effective to inhibit
 nausea and vomiting.
 In the prophylactic or therapeutic treatment of nausea or vomiting, the
 compounds preferably are delivered orally in a pharmaceutical composition.
 Accordingly, solid or liquid carriers are appropriate delivery vehicles.
 However, parenteral routes of administration, such as inhalation or
 injection, also are useful as well as topical and transdermal
 administration.
 For use as an anti-emetic, the compounds are effectively administered in
 amounts of about 50 mg to about 2 g.
 VIII. Use as a Anti-convulsive
 Propofol and the pro-drugs of this invention are useful as anti-convulsives
 to prevent or relieve seizures including, e.g., epileptic seizures. This
 invention provides methods for inhibiting convulsions comprising
 administering to a subject an amount of the compound effective to inhibit
 convulsions.
 In the prophylactic or therapeutic treatment of seizures the compounds
 preferably are delivered orally or parenterally.
 For use as an anti-convulsive, the compounds are effectively administered
 in amounts of about 50 mg to about 2 g daily.
 IX. Use as an Anti-pruritic
 Propofol and the pro-drugs of this invention are useful as anti-pruritics
 to prevent or relieve itching. This invention provides methods of
 inhibiting itching comprising administering the compound to a subject in
 an amount effective to inhibit itching. The compounds can treat both
 external and internal itching. The source of itching can be any disease or
 exposure to a pruritic agent, such as poison ivy.
 In the prophylactic or therapeutic treatment of itching, the compounds
 preferably are delivered topically in a pharmaceutical composition.
 Various creams and ointments are appropriate delivery vehicles.
 For use as an anti-pruritic, the compounds are effectively administered in
 amounts of about 50 mg to about 2 g daily or rubbed into the skin at about
 0.01 to about 5 mg/cm.sup.2. Sub-sedative dose for pruritus may be
 achieved at between about one-quarter and about one-tenth the anesthetic
 dose.
 X. Pharmaceutical Compositions and Modes of Delivery
 Propofol and the pro-drugs of this invention preferably are delivered as
 pharmaceutical compositions. "Pharmaceutical composition" refers to a
 composition suitable for pharmaceutical use in a subject. The
 pharmaceutical compositions of this invention comprise a pharmacologically
 effective amount of a compound of the invention and a pharmaceutically
 acceptable carrier. "Pharmacologically effective amount" refers to that
 amount of the compound effective to produce the intended pharmacological
 result, e.g., inhibit oxidation, induce anaesthesia, inhibit vomiting,
 inhibit convulsions, inhibit itching, or inhibit inflammation.
 "Pharmaceutically acceptable carrier" refers to any of the standard
 pharmaceutical carriers, buffers, and excipients, such as a phosphate
 buffered saline solution, aqueous solutions of dextrose, and emulsions,
 such as an oil/water or water/oil emulsion, and various types of wetting
 agents and/or adjuvants. Suitable pharmaceutical carriers and formulations
 are described in Remington's Pharmaceutical Sciences, 19th Ed. (Mack
 Publishing Co., Easton, 1995). Preferred pharmaceutical carriers depend
 upon the intended mode of administration of the active agent.
 The compounds of the invention can be formulated for administration in a
 variety of ways. Typical routes of administration include both enteral and
 parenteral. These include, without limitation, subcutaneous,
 intramuscular, intravenous, intraperitoneal, intramedullary,
 intrapericardiac, intrabursal, oral, sublingual, ocular, nasal, topical,
 transdermal, transmucosal, or anal. The mode of administration can be,
 e.g., via swallowing, inhalation, injection or topical application to a
 surface (e.g., eyes, mucus membrane, skin).
 Particular formulations typically are appropriate for specific modes of
 administration. Various contemplated formulations include, for example,
 aqueous solutions, solid formulations, aerosol formulations and
 transdermal formulations.
 A. Aqueous Solutions for Enteral, Parenteral Or Transmucosal Administration
 Examples of aqueous solutions include, for example, water, saline,
 phosphate buffered saline, Hank's solution, Ringer's solution,
 dextrose/saline, glucose solutions and the like. The compositions can
 contain pharmaceutically acceptable auxiliary substances as required to
 approximate physiological conditions or to improve stability, appearance
 or ease of administration, such as buffering agents, tonicity adjusting
 agents, wetting agents, detergents and the like. Additives can also
 include additional active ingredients such as bactericidal agents, or
 stabilizers. For example, the solution can contain sodium acetate, sodium
 lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan
 monolaurate or triethanolamine oleate. These compositions can be
 sterilized by conventional, well-known sterilization techniques, or can be
 sterile filtered. The resulting aqueous solutions can be packaged for use
 as is, or lyophilized, the lyophilized preparation being combined with a
 sterile aqueous solution prior to administration.
 Aqueous solutions are appropriate for injection and, in particular, for
 intravenous injection. Intravenous injection is a particularly appropriate
 means of delivery for using the compound as a hypnotic agent. The
 intravenous solution can include detergents and emulsifiers such as
 lipids. Aqueous solutions also are useful for enteral administration as
 tonics and administration to mucous or other membranes as, e.g., nose or
 eye drops. The composition can contain the compound in an amount of about
 1 mg/ml to 100 mg/ml, more preferably about 10 mg/ml.
 B. Solid and Other Non-Aqueous Compositions For Enteral Or Transdermal
 Delivery
 Solid compositions are appropriate for enteral administration. They can be
 formulated in the form of, e.g., pills, tablets, powders or capsules. For
 solid compositions, conventional nontoxic solid carriers can be used which
 include, for example, pharmaceutical grades of mannitol, lactose, starch,
 magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose,
 magnesium carbonate, and the like. For oral administration, a
 pharmaceutically acceptable nontoxic composition is formed by
 incorporating any of the normally employed excipients, such as those
 carriers previously listed, and generally 10%-95% of active ingredient.
 The carrier can be selected from various oils including those of petroleum,
 animal, vegetable or synthetic origin, for example, peanut oil, soybean
 oil, mineral oil, sesame oil, and the like. Suitable pharmaceutical
 excipients include starch, cellulose, talc, glucose, lactose, sucrose,
 gelatin, maltose, rice, flour, chalk, silica gel, magnesium stearate,
 sodium stearate, glycerol monostearate, sodium chloride, dried skim milk,
 glycerol, propylene glycol, water, ethanol, and the like.
 A unit dosage form, such as a tablet, can have about 10 mg to about 2 g of
 the compound.
 Solid compositions are particularly useful for using the compound as an
 anti-emetic.
 C. Topical Administration For Transdermal Or Transmucosal Delivery
 Systemic administration can also be by transmucosal or transdermal means.
 For transmucosal or transdermal administration, penetrants appropriate to
 the barrier to be permeated are used in the formulation. Such penetrants
 are generally known in the art, and include, for example, for transmucosal
 administration, bile salts and fusidic acid derivatives. In addition,
 detergents can be used to facilitate permeation. Transmucosal
 administration can be through nasal sprays, for example, or using
 suppositories.
 For topical administration, the agents are formulated into ointments,
 creams, salves, powders and gels. In one embodiment, the transdermal
 delivery agent can be DMSO.
 Transdermal delivery systems can include, e.g., patches.
 Topical administration is particularly useful for use of the compound as an
 anti-pruritic or in the treatment of wounds with an inflammatory component
 such as burns, rashes and sunburns. However, sustained administration can
 deliver the compound for use as an anti-oxidant and anti-inflammatory
 agent internally.
 D. Delivery By Inhalation
 For inhalation, the compound is preferably administered in the form of an
 aerosol, liquid or solid. For aerosol administration, the compound
 preferably is supplied in finely divided form along with a surfactant and
 propellant. A surfactant may be required if the agent is immiscible in the
 propellant.
 The surfactant preferably is soluble in the propellant. Representative of
 such agents are the esters or partial esters of fatty acids containing
 from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic,
 stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic
 polyhydric alcohol or its cyclic anhydride such as, for example, ethylene
 glycol, glycerol, erythritol, arabitol, mannitol, sorbitol, the hexitol
 anhydrides derived from sorbitol, and the polyoxyethylene and
 polyoxypropylene derivatives of these esters. Mixed esters, such as mixed
 or natural glycerides, can be employed. The surfactant can constitute
 0.1%-20% by weight of the composition, preferably 0.25%-5%.
 The balance of the composition is ordinarily propellant. Liquefied
 propellants are typically gases at ambient conditions, and are condensed
 under pressure. Among suitable liquefied propellants are the lower alkanes
 containing up to 5 carbons, such as butane and propane; and preferably
 fluorinated or fluorochlorinated alkanes. Mixtures of the above can also
 be employed. In producing the aerosol, a container equipped with a
 suitable valve is filled with the appropriate propellant, containing the
 agent as a solution or as finely divided particles and surfactant. The
 ingredients are thus maintained at an elevated pressure until released by
 action of the valve.
 A nebulizer or aerosolizer device for administering compounds typically
 delivers a dose of about concentration of between about 1 and 50 mg per
 inhalation.
 Delivery by inhalation is particularly effective for delivery to
 respiratory tissues for the treatment of respiratory conditions including
 an inflammatory component. Delivery of large doses by respiration also can
 induce sedation or anaesthesia. Anesthesia may be achieved by means of
 continuous inhalation such as occurs with propofol, ether, or other
 conventional anesthetics. Induction may occur at doses between about 200
 mg and about 400 mg inhaled over a period of a few minutes (e.g., about 5
 to about 15 minutes). Sedation may be maintained thereafter at a dose of
 about 200 mg to about 400 mg per hour for as long as is needed.
 E. Other Formulations
 In preparing pharmaceutical compositions of the present invention, it can
 be desirable to modify the complexes of the present invention to alter
 their pharmacokinetics and biodistribution. For a general discussion of
 pharmacokinetics, See, Remington's Phamaceutical Sciences, supra, Chapters
 37-39. A number of methods for altering pharmacokinetics and
 biodistribution are known to one of ordinary skill in the art. Examples of
 such methods include protection of the complexes in vesicles composed of
 substances such as proteins, lipids (for example, liposomes),
 carbohydrates, or synthetic polymers.
 F. Administration
 Single or multiple administrations of the compositions can be carried out
 with dose levels and pattern being selected by the treating physician. In
 any event, the pharmaceutical formulations should provide a quantity of a
 compound sufficient to treat the patient effectively.
 The total effective amount of a compound of the present invention can be
 administered to a subject as a single dose, either as a bolus or by
 infusion over a relatively short period of time, or can be administered
 using a fractionated treatment protocol, in which the multiple doses are
 administered over a more prolonged period of time. One skilled in the art
 would know that the concentration of a compound of the present invention
 required to obtain an effective dose in a subject depends on many factors
 including the age and general health of the subject, the route of
 administration, the number of treatments to be administered and the
 judgment of the prescribing physician. In view of these factors, the
 skilled artisan would adjust the dose so as to provide an effective dose
 for a particular use.
 The following examples are offered by way of illustration, not by way of
 limitation.

EXAMPLES
 Example 1
 Synthesis of propofol hemnisuccinate
 Succinic anhydride (14 g, 140 mmol) and dimethylaminopyridine (0.02 g, 0.16
 mmol) were added to a solution of 2,6-diisopropylphenol (20.8 ml, 112
 mmol) in triethylamine (50 ml) under nitrogen. After 16 hr at room
 temperature, solvents were removed under vacuum. The residue was dissolved
 in water and added to an iced solution of dilute hydrochloric acid. The
 precipitated product was filtered and recrystallized from ethanol-water to
 yield 25.0 g (80.2% yield) of 2,6-diisopropylphenyl hydrogen succinate
 (propofol hemisuccinate), mp 101-102.degree. C.
 High resolution nuclear magnetic resonance spectra are fully consistent
 with structure: .sup.1 H-NMR (500 MHz, CDCl.sub.3) .delta.L 1.207(d, 12H,
 J=6.9 Hz, di-I-Pr), 2.856(t, 2H, J=6.7 Hz, C3'--H.sub.2), 2.940(q, 2H,
 J=6-9 HZ, C.sub.7- H, C.sub.8 --H), 2.961 (t, 2H, J=6.7 Hz, C.sub.2'
 --H.sub.2), 7.173(d, 2H, J=7.8 HZ, C.sub.3- H, C.sub.5 --H), 7.224(d, 1H,
 J=7.8 Hz, C.sub.4- H .sup.31 P-NMR (500 Mhz, CDCl.sub.3) .iota.: -9.6994
 .sup.13 C-NMR (500 MHZ, CDCl.sub.3) .delta.: 22.929(C-3'), 23.916(C-2'),
 27.639(C-9, C-10, C-11, C-12), 28.815(CO7), 29.085(C-8), 124.122(C-3,
 C-5), 126.805(C-4), 140.456(C-2, C-6), 145.633(C-1), 171.000(C-1'),
 178.838(C-4')
 ##STR3##
 Example 2
 Synthesis of propofol hemiadipate Triethylamine (6.26 ml, 45 mmol) and
 4-dimethylaminopyridine (50 mg, 0.4 mmol) in methylene chloride (30 ml)
 were added to a solution of 2,6-diisopropylphenol (5.2 ml, 28 mmol) and
 adipoyl chloride (4.4 ml, 30 mmol) in methylene chloride (50) at 0.degree.
 C. The mixture was allowed to reach room temperature and stirred at that
 temperature for 2 hr. Water (50 ml) was added, and the two-phase mixture
 was stirred for 1 hr. The organic phase was washed with 3% aqueous HCl and
 then dried. Solvents were removed under vacuum, and the oily residue was
 chromatogrammed on a silica gel column using chloroform-methanol (10:0.1)
 and then chloroform-methanol-acetic acid (10:0.1:0.01). The fractions
 containing the ester were pooled and evaporated under vacuum to yield 3.4
 g (40% yield) of 2,6-diisopropylphenol hydrogen adipate (propofol
 hemiadipate) as an oil.
 The .sup.1 H-NMR and .sup.13 C-NMR spectra were very similar to those of
 the hemisuccinate ester (example 1) and fully consistent with structure.
 Splitting of signals however show that the compound exists as a mixture of
 rotamers, most likely the result of hindered rotation about the
 acyl-phenoxyl linkage.
 Example 3
 Synthesis of propofol hemisuccinate sodium salt
 A solution of propofol hemisuccinate (1.0 g, 3.6 mmol) in 10 ml of ethanol
 was neutralized with 3.6 ml of 1.0 N NaOH. The solvents were removed under
 vacuum, and water was fully removed by further addition and evaporation of
 acetonitrile under vacuum. The crystalline product was washed with
 acetonitrile and dried under high vacuum at 60.degree. C. The yield of
 propofol hemisuccinate sodium salt was 0.97 g (90%).
 The high resolution proton magnetic resonance spectrum and fast atom
 bombardment mass spectrum are fully consistent with structure: .sup.1
 H-NMR (500 MHz, D.sub.2 O).delta.: 1.13(d, 12H, J=6.8 Hz, di-i-Pr),
 2.622(t, 2H, J=6.7 Hz, C.sub.3 '--H2), 2.919(q, 2H, J=6.8 Hz, C.sub.7- H,
 C.sub.8- H), 2.937(t, 2H, J=6.7 Hz, C.sub.2' --H2), 7.275(m, 3H, C.sub.3-
 H, C.sub.4- H, C.sub.5- H) FAB-MS: [M+H].sup.+ 301.1410 M/Z, calculated
 for C.sub.16 H.sub.21 O.sub.4 Na+H formula 301.1417
 Example 4
 Synthesis of mono(propofol) phosphate disodium salt
 Butyllithium (2.24 ml of 2.5 M solution in hexanes; 5.6 mmol) was added
 dropwise to propofol (1.0 g, 5-6 mmol) in 10 ml of ether at -30.degree. C.
 under nitrogen. The solution was stirred at -30.degree. C. for 30 in then
 allowed to warm to room temperature. This solution was then added dropwise
 to a solution of phosphorus oxychloride (0.918 g, 6.0 mmol) in 10 ml of
 ether at -30.degree. C. The solution was allowed to warm to room
 temperature, then water (5 ml) was added and stirring was continued for 1
 hr. Sodium hydroxide (35 ml of 1 M) and 30 ml of hexanes was added. The
 aqueous phase was washed with hexanes, then acidified with HCl to pH 3 and
 extracted with ether. After evaporation of the solvents, the oily residue
 was dissolved in ethanol and neutralized to pH 7.4 with 1 M NaOH. After
 removal of the solvents in vacuo, the residue was suspended in
 acetonitrile, and the solid product was collected and dried. The yield of
 mono(propofol) phosphate disodium salt was 1.1 g (65%).
 The high resolution nuclear magnetic resonance spectra (proton, carbon and
 phosphorus) in water, and the fast atom bombardment mass spectrum are
 fully consistent with structure. The magnetic resonance spectra show the
 presence of two rotamers in a population ratio of 7:1: .sup.1 H-NMR (500
 MHz, D.sub.2 O).delta.: 1.184 and 1.205 (d,d, 12H, J=6.8 Hz, di-i-Pr),
 3.519 and 3.619 (m,m, 2H, C.sub.7 --H, C.sub.8 --H), 7.198 (m, 3H, C.sub.3
 --H, C.sub.4 --H, C.sub.5 --H) .sup.13 C-NMR (500 MHz, D.sub.2 O).delta.:
 21.986 and 22.083 (C-9, C-10, C-11, C-12), 22.212 and 25.826 (C-7, C-8),
 123.212 (C-3, C-5), 140.922 and 140.992 (C-2, C-6), 146.244, 146.315 and
 146.502 (C-1) 3'P-NMR (500 MHz, D.sub.2 O).delta.: -3.735 and -15.223
 FAB-MS: [M+H].sup.+ 303.0730 M/Z, calculated for C.sub.12 H.sub.17 O.sub.4
 PNa+H formula 303.0739
 Example 5
 Synthesis of di(propofol) phosphoric acid ester
 Butyllithium (2.24 ml of 2.5M solution in hexanes; 5.6 mmol) was added
 dropwise to propofol (1.0 g, 5.6 mmol) in 10 ml of ether at -30.degree. C.
 under nitrogen. The solute on was stirred at -30.degree. C. for 30 min
 then allowed to warm to room temperature. To this solution was then added
 dropwise a solution of phosphorus oxychloride (0.444 g, 2.9 mmol) in 5 ml
 of ether at -30.degree. C. The solution was allowed to warm to room
 temperature, then water (5 ml) was added and stirring was continued for 1
 hr. Sodium hydroxide (20 ml of 1 M) and 20 ml of hexanes was added. The
 organic phase was washed with 1 M NaOH, water, then dried over sodium
 sulfate. The solvents were removed and the residue was dissolved in
 acetone (10 ml) and treated with 10 ml of 1 M NaOH and stirred for 2 hr.
 Most of the acetone was removed and the aqueous residue was adjusted to pH
 5 with HCl, followed by extraction with hexanes. Evaporation of the
 hexanes left a white crystalline solid of di(propofol) phosphoric acid
 ester. The yield was 0.920 g (75%), mp 154.degree. C.
 The nuclear magnetic resonance spectra (proton and phosphorus) were
 consistent with structure: .sup.1 H-NMR (500 MHz, CDCl.sub.3).delta.:
 1.036(d, 24H, J=6.6 Hz, tetra-i-Pr), 3.342(m, 4H, J=6.6 Hz, C.sub.7 --H,
 C.sub.8 -H, C.sub.7' --H, C.sub.8' --H), 7.047 (d, 4H, J=7.5 Hz, C.sub.3
 --H, C.sub.5 --H, C.sub.3' --H, C.sub.5' --H), 10.400 (broad, 1H, P--OH)
 .sup.31 P-NMR (500 MHz, CDCl.sub.3).delta.: -9.6994
 Example 6
 Synthesis of di(propofol) phosphate monosodium salt
 A solution of di(propofol) phosphoric acid ester (300 mg, 0.7 mmol) in 5 ml
 of ethanol was neutralized to pH 7.4 with 0.7 ml of 1 M NaOH. After
 removal of the solvent under vacuum, the residue was dissolved in ether
 and again evaporated to yield di(propofol) phosphate disodium salt as a
 white solid, 300 mg, 100% yield.
 The fast atom bombardment mass spectrum was consistent with structure:
 FAB-MS: [M+H].sup.+ 436.1977 M/Z, calculated for C.sub.24 H.sub.34 O.sub.4
 PNa+Na formula 436.1979
 Example 7
 In vitro hydrolysis of propofol esters in various media
 General procedure: Propofol ester was dissolved in the test medium at room
 temperature, and samples were removed periodically for analysis. The
 samples were extracted with hexane, the extracts were evaporated to
 dryness, and the residues were taken up in methanol. Analysis was by HPLC
 using methanol solvent through an ODS column and UV detection at 260 nm.
 The approximate half-life for the hydrolysis of propofol hemisuccinate to
 propofol in various media were as follows:

Half-Life to
 Medium Hydrolysis
 water (PBS buffer pH 7.4) 2 weeks
 albumin 6 days
 human saliva 4 days
 human plasma 3 days
 human blood, whole 2 days
 rat blood, whole 2 hrs
 The approximate half-life for the hydrolysis of (mono)propofol phosphate to
 propofol in human saliva was about four days.
 Example 8
 In vivo hydrolysis of propofol hemisuccinate
 Propofol hemisuccinate sodium salt in aqueous solution was administered to
 adult male Sprague-Dawley rats by gavage. Blood was collected at 2, 4, 8
 and 24 hours after dosing, and analyzed by HPLC as described in example 3.
 Peak blood levels of propofol were seen at 2 to 4 hrs after dosing. At a
 dosage of 400 mg of propofol hemisuccinate per kg body weight, the blood
 level of propofol at 4 hrs was about 1 .mu.g/ml. All the animals remained
 healthy and active through the two day observation period following the
 dosing.
 Example 9
 Effect of propofol esters on LDL-oxidation by copper, hydrogen
 Peroxide/horseradish Peroxidase and Myeloperoxidase
 The following experiment is based on the use of low density lipoprotein
 (LDL) as an oxidizable substrate. LDL is one of the plasma lipoproteins
 whose oxidation is thought to contribute to the pathogenesis of
 atherosclerosis. The copper-promoted, the hydrogen peroxide-/horseradish
 peroxidase-promoted and the myeloperoxidase-promoted oxidation of LDL are
 models for the free radical-induced oxidation of LDL that occurs in vivo.
 LDL was isolated from heparinized plasma of normal human donors by
 ultracentrifugation. Most of the experiments described in this study were
 performed immediately after isolation. Examples and further details of the
 experimental procedures may be found in N. Santanam et al. J. Clin Invest.
 95(6):2594 (1995) and FEBS Leters, 414:549-551 (1997).
 The formation of conjugated dienes was measured in a spectrophotometer
 (model DB-3500; SLM-AMINCO, Urbana, Ill.) equipped with a 12 position
 sample changer. Samples and references were measured continuously for
 periods of up to several hours. Typically, 100 .mu.g/ml of LDL was
 incubated in PBS with 1 U horseradish peroxidase (type X, 260 U/mg) in the
 presence of 50 .mu.M H.sub.2 O.sub.2. For copper-mediated oxidation, 100
 .mu.g/ml LDL was incubated with 5 .mu.M copper sulfate solution.
 The copper-promoted oxidation of LDL was not significantly affected by the
 presence of the propofol pro-drugs (propofol phosphate, dipropofol
 phosphate, propofol hemisuccinate) at concentrations of 5 .mu.M. However,
 in the presence of 5 .mu.M propofol, the oxidation was almost totally
 inhibited.
 The oxidation of LDL in the presence of horseradish peroxidase/hydrogen
 peroxide was not significantly affected by the presence of either
 di(propofol)phosphate (5 .mu.M) or propofol monophosphate (5 .mu.M). In
 the presence of propofol hemisuccinate (5 .mu.M) the oxidation was
 slightly inhibited. In the presence of 5 .mu.M propofol, the oxidation was
 almost totally inhibited.
 The oxidation of LDL in the presence of myeloperoxidase was partly
 inhibited in the presence of propofol hemisuccinate.
 Human low density lipoprotein (huLDL) in the presence of myeloperoxidase
 undergoes oxidative modification. The oxidative damage may be measured by
 spectrophotometric detection of the resulting conjugated dienes (N.
 Santanam & S. Parthasarathy, J. Clin. Invest, 95(6):2594 (1995)).
 Following the procedures of Santanam et al., it was observed that the
 myeloperoxidase-mediated oxidation of huLDL was significantly inhibited in
 the presence of added propofol hemisuccinate.
 The present invention provides water soluble esters of
 2,6-diisopropylphenol and methods of using these compounds. While specific
 examples have been provided, the above description is illustrative and not
 restrictive. Many variations of the invention will become apparent to
 those skilled in the art upon review of this specification. The scope of
 the invention should, therefore, be determined not with reference to the
 above description, but instead should be determined with reference to the
 appended claims along with their full scope of equivalents.
 All publications and patent documents cited in this application are
 incorporated by reference in their entirety for all purposes to the same
 extent as if each individual publication or patent document were so
 individually denoted. Applicants do not admit by their citation of various
 references in this document that any particular reference is "prior art"
 to their invention.