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EP1890729A2 - Utilisation de carotenoides et/ou de derives/analogues de carotenoides dans la reduction/inhibition de certains effets negatifs des inhibiteurs de cox - Google Patents

Utilisation de carotenoides et/ou de derives/analogues de carotenoides dans la reduction/inhibition de certains effets negatifs des inhibiteurs de cox

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Publication number
EP1890729A2
EP1890729A2 EP06758837A EP06758837A EP1890729A2 EP 1890729 A2 EP1890729 A2 EP 1890729A2 EP 06758837 A EP06758837 A EP 06758837A EP 06758837 A EP06758837 A EP 06758837A EP 1890729 A2 EP1890729 A2 EP 1890729A2
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EP
European Patent Office
Prior art keywords
alkyl
cox
hydrogen
aryl
composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06758837A
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German (de)
English (en)
Inventor
Samuel F. Lockwood
R. Preston Mason
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Cardax Pharmaceuticals Inc
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Cardax Pharmaceuticals Inc
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Publication date
Application filed by Cardax Pharmaceuticals Inc filed Critical Cardax Pharmaceuticals Inc
Publication of EP1890729A2 publication Critical patent/EP1890729A2/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • TITLE USE OF CAROTENOIDS AND/OR CAROTENOID DERTVATIVES/ANALOGS FOR REDUCTION/INHIBITION OF CERTAIN NEGATIVE EFFECTS OF COX INHIBITORS
  • the present invention generally relates to the fields of medicinal and synthetic chemistry. Specifically, the invention relates to the use of carotenoids, and in particular xanthophyll carotenoids, including analogs, derivatives, and intermediates thereof, as therapeutic agents that reduce or inhibit side effects associated with the administration of COX-2 selective inhibitors.
  • COX-2 inducible cyclooxygenase-2
  • NSAIDs such as aspirin, indomethacin, ibuprofen, and naproxen
  • selective COX-2 inhibitor drags relieve pain with minimal gastric erosion that can result from the inhibition of cytoprotective COX-I -dependent synthesis of prostaglandin E 2 (PGE 2 ) in the gastric mucosa.
  • oxidized COX-2 selective inhibitor drags were found to increase the production and levels of certain oxidized phospholipids, low density lipoprotein (LDL) and F 2 - isprostanoids, the levels of which are correlated with the development of adverse cardiovascular conditions, such as atherosclerosis. Moreover, it was demonstrated that sulfone COX-2 inhibitor drags could reduce the oxygen radical antioxidant capacity (ORAC) of human plasma. Although the magnitude of lipid peroxidation events (in particular the oxidative lag time of LDL cholesterol in the presence of a radical initiator) is somewhat reduced in the presence of a vitamin-E analog, the oxidation potential of COX-2 selective inhibitor drags could not be fully reversed with this agent (Walter et al., 2004).
  • ORAC oxygen radical antioxidant capacity
  • New methods of reducing or inhibiting one or more of the negative cardiovascular complications associated with therapeutic administration of COX-2 selective inhibitors in a subject would provide useful therapeutic agents.
  • Carotenoids are a group of natural pigments produced principally by plants, yeast, and microalgae. The family of related compounds now numbers greater than 750 described members, exclusive of Z and E isomers. Humans and other animals cannot synthesize carotenoids de novo and must obtain them from their diet. All carotenoids share common chemical features, such as a polyisoprenoid structure, a long polyene chain forming the chromophore, and near symmetry around the central double bond. Tail-to-tail linkage of two C 2 o geranyl-geranyl diphosphate molecules produces the parent C 40 carbon skeleton.
  • Carotenoids without oxygenated functional groups are called “carotenes", reflecting their hydrocarbon nature; oxygenated carotenes are known as “xanthophylls.”
  • Parent carotenoids may generally refer to those natural compounds utilized as starting scaffold for structural carotenoid analog synthesis. Carotenoid derivatives may be derived from a naturally occurring carotenoid.
  • Naturally occurring carotenoids may include lycopene, lycophyll, lycoxanthin, astaxanthin, beta-carotene, lutein, zeaxanthin, and/or canthaxanthin to name a few.
  • Carotenoids with chiral centers may exist either as the R (rectus) or S (sinister) configurations.
  • astaxanthin (with 2 chiral centers at the 3 and 3' carbons) may exist as 4 possible stereoisomers: 3S, 3'S; 3R, 3'S and 3S, 3'R (identical meso forms); or 3R, 3'R.
  • the relative proportions of each of the stereoisomers may vary by natural source.
  • Haematococcus pluvialis microalgal meal is 99% 3S, 3'S astaxanthin, and is likely the predominant human evolutionary source of astaxanthin.
  • Krill (3R,3'R) and yeast sources yield different stereoisomer compositions than the microalgal source.
  • Synthetic astaxanthin produced by large manufacturers such as Hoffmann-LaRoche AG, Buckton Scott (USA), or BASF AG, are provided as defined geometric isomer mixtures of a 1:2:1 stereoisomer mixture [3S, 3'S; 3R, 3'S, 3'R,3S (meso); 3R, 3 'R] of non-esterified, free astaxanthin.
  • Natural source astaxanthin from salmonid fish is predominantly a single stereoisomer (3S,3'S), but does contain a mixture of geometric isomers. Astaxanthin from the natural source Haematococcus pluvialis may contain nearly 50% Z isomers.
  • the Z conformational change may lead to a higher steric interference between the two parts of the carotenoid molecule, rendering it less stable, more reactive, and more susceptible to reactivity at low oxygen tensions.
  • the Z forms in relation to the all-is 1 form, the Z forms: (1) may be degraded first; (2) may better suppress the attack of cells by reactive oxygen species such as superoxide anion; and (3) may preferentially slow the formation of radicals. Overall, the Z forms may initially be thermodynamically favored to protect the lipophilic portions of the cell and the cell membrane from destruction.
  • the all-is 1 form of astaxanthin unlike ⁇ -carotene, retains significant oral bioavailability as well as antioxidant capacity in the form of its dihydroxy- and diketo-substitutions on the ⁇ -ionone rings, and has been demonstrated to have increased efficacy over ⁇ -carotene in most studies.
  • the all-is 1 form of astaxanthin has also been postulated to have the most membrane-stabilizing effect on cells in vivo. Therefore, it is likely that the all-i? form of astaxanthin in natural and synthetic mixtures of stereoisomers is also extremely important in antioxidant mechanisms, and may be the form most suitable for particular pharmaceutical preparations.
  • the antioxidant mechanism(s) of carotenoids includes singlet oxygen quenching, direct radical scavenging, and lipid peroxidation chain-breaking.
  • the polyene chain of the carotenoid absorbs the excited energy of singlet oxygen, effectively stabilizing the energy transfer by derealization along the chain, and dissipates the energy to the local environment as heat. Transfer of energy from triplet-state chlorophyll (in plants) or other porphyrins and proto-porphyrins (in mammals) to carotenoids occurs much more readily than the alternative energy transfer to oxygen to form the highly reactive and destructive singlet oxygen ( 1 O 2 ).
  • Carotenoids may also accept the excitation energy from singlet oxygen if any should be formed in situ, and again dissipate the energy as heat to the local environment. This singlet oxygen quenching ability has significant implications in cardiac ischemia, macular degeneration, porphyria, and other disease states in which production of singlet oxygen has damaging effects. In the physical quenching mechanism, the carotenoid molecule may be regenerated (most frequently), or be lost. Carotenoids are also excellent chain-breaking antioxidants, a mechanism important in inhibiting the peroxidation of lipids. Astaxanthin can donate a hydrogen (H) to the unstable polyunsaturated fatty acid (PXIFA) radical, stopping the chain reaction.
  • H hydrogen
  • PXIFA unstable polyunsaturated fatty acid
  • Peroxyl radicals may also, by addition to the polyene chain of carotenoids, be the proximate cause for lipid peroxide chain termination.
  • the appropriate dose of astaxanthin has been shown to completely suppress the peroxyl radical chain reaction in liposome systems. Astaxanthin shares with vitamin E this dual antioxidant defense system of singlet oxygen quenching and direct radical scavenging, and in most instances (and particularly at low oxygen tension in vivo) is superior to vitamin E as a radical scavenger and physical quencher of singlet oxygen.
  • Carotenoids and in particular astaxanthin, are potent direct radical scavengers and singlet oxygen quenchers and possess all the desirable qualities of such therapeutic agents for inhibition or amelioration of ischemia-reperfusion (I/R) injury.
  • Synthesis of novel carotenoid derivatives with "soft-drug” properties i.e. activity in the derivatized form), with physiologically relevant, cleavable linkages to pro-moieties, can generate significant levels of free carotenoids in both plasma and solid organs.
  • Lipid soluble in natural form may be modified to become more water soluble
  • antioxidants which are potent singlet oxygen quenchers and direct radical scavengers, particularly of superoxide anion, should limit hepatic fibrosis and the progression to cirrhosis by affecting the activation of hepatic stellate cells early in the fibrogenetic pathway. Reduction in the level of ROS by the administration of a potent antioxidant can therefore be crucial in the prevention of the activation of both HSC and Kupffer cells.
  • This protective antioxidant effect appears to be spread across the range of potential therapeutic antioxidants, including water-soluble (e.g., vitamin C, glutathione, resveratrol) and lipophilic (e.g., vitamin E, ⁇ - carotene, astaxanthin) agents. Therefore, a co-antioxidant derivative strategy in which water-soluble and lipophilic agents are combined synthetically is a particularly useful embodiment.
  • Vitamin E is generally considered the reference antioxidant.
  • carotenoids are more efficient in quenching singlet oxygen in homogenenous organic solvents and in liposome systems. They are better chain-breaking antioxidants as well in liposomal systems. They have demonstrated increased efficacy and potency in vivo. They are particularly effective at low oxygen tension, and in low concentration, making them extremely effective agents in disease conditions in which ischemia is an important part of the tissue injury and pathology.
  • These carotenoids also have a natural tropism for the liver after oral administration. Therefore, therapeutic administration of carotenoids should provide a greater benefit in limiting fibrosis than vitamin E.
  • inhibiting, reducing or ameliorating at least some of the side effects associated with the administration of COX-2 inhibitors to a subject may include administering to the subject an effective amount of a pharmaceutically acceptable formulation including a xanthophyll or other carotenoid or a synthetic analog or derivative thereof.
  • the formulation may include astaxanthin, lutein and/or zeaxanthin.
  • Negative consequences associated with therapeutic administration of COX-2-selective inhibitors that may be reduced by administering the xanthophyll carotenoids or synthetic derivatives or analogs thereof may include reducing lipid peroxidation and other measures of enzymatic and non-enzymatic oxidative stress, reducing radical flux, and reducing membrane de-stabilization caused by the presence of the COX-2 inhibitor.
  • carotenoid analogs or carotenoid derivatives suited for use in the embodiments described herein include those derivatives or analogs that undergo chemical and/or enzymatic breakdown in a subject's body, in the digestive tract, in the serum, in the plasma, or in a cell, wherein at least one of the breakdown products is astaxanthin, or a derivative or an analog of astaxanthin.
  • COX-2 selective inhibitors whose negative cardiovascular effects may be reduced may include sulfone-based COX-2 inhibitors such as, for example, rofecoxib and etoricoxib.
  • COX-2 selective inhibitors whose negative cardiovascular effects may be reduced may include sulfonamide-based COX-2 inhibitors such as, for example, celecoxib, valdecoxib, or COX-2 selective inhibitors that are neither sulfone- nor sulfonamide-based, such as, for example, lumiracoxib.
  • xanthophyll carotenoids or synthetic derivatives or analogs thereof may be administered to a subject concurrently with COX-2 selective inhibitor drug therapy, either as a co-formulation, or with separate pharmaceutical and/or nutraceutical agents.
  • xanthophyll carotenoids or synthetic derivatives or analogs thereof may be administered to a subject prior to the commencement of COX-2 selective inhibitor drug therapy. In an embodiment, xanthophyll carotenoids or synthetic derivatives or analogs thereof may be administered to a subject following the commencement of COX-2 selective inhibitor drug therapy.
  • Administration of xanthophyll carotenoids or a synthetic analogs or derivatives thereof according to the preceding embodiments may at least partially inhibit and/or influence the complications, particularly those complications associated with the cardiovascular system, associated with chronic administration of COX-2 selective inhibitor drugs such as rofecoxib, etoricoxib, celecoxib, and valdecoxib.
  • the administration of carotenoids, xanthophyll carotenoids or structural analogs or derivatives of carotenoids by one skilled in the art - including consideration of the pharmacokinetics and pharmacodynamics of therapeutic drug delivery - is expected to inhibit and/or ameliorate disease conditions associated with administering xanthophyll carotenoid or a synthetic analog or derivative thereof to a subject, including but not limited to the production of oxidixed lipids, and LDL.
  • analogs or derivatives of carotenoids administered to cells may be at least partially water-soluble.
  • Water-soluble structural carotenoid analogs or derivatives are those analogs or derivatives that may be formulated in aqueous solution, either alone or with one or more excipients.
  • Water-soluble carotenoid analogs or derivatives may include those compounds and synthetic derivatives that form molecular self-assemblies, and may be more properly termed "water dispersible” carotenoid analogs or derivatives. Water-soluble and/or “water- dispersible” carotenoid analogs or derivatives may be preferred in some embodiments.
  • Water-soluble carotenoid analogs or derivatives may have a water solubility of greater than about 1 mg/mL in some embodiments. In certain embodiments, water-soluble carotenoid analogs or derivatives may have a water solubility of greater than about 5 mg/ml - 10 mg/mL. In certain embodiments, water-soluble carotenoid analogs or derivatives may have a water solubility of greater than about 20 mg/mL. In certain embodiments, water-soluble carotenoid analogs or derivatives may have a water solubility of greater than about 25 mg/mL. In some embodiments, water-soluble carotenoid analogs or derivatives may have a water solubility of greater than about 50 mg/mL.
  • water-soluble analogs or derivatives of carotenoids maybe administered to a subject alone or in combination with additional xanthophyll carotenoids or structural analogs or derivatives. In some embodiments, water-soluble analogs or derivatives of carotenoids maybe administered to a subject alone or in combination with other antioxidants.
  • a method of inhibiting or reducing at least some of the side effects associated with therapeutic administration of COX-2 selective inhibitors may include administering to the subject an effective amount of a pharmaceutically acceptable formulation including a carotenoid.
  • a carotenoid may have the structure:
  • each R 3 is independently hydrogen or methyl, and where each R 1 and R 2 are independently:
  • R 4 is hydrogen, methyl, or -CH 2 OH; and where each R 5 is independently hydrogen or -OH.
  • a method of inhibiting or reducing at least some of the side effects associated with therapeutic administration of COX-2 selective inhibitors may include administering to the subject an effective amount of a pharmaceutically acceptable formulation including a synthetic analog or derivative of a carotenoid.
  • the synthetic analog or derivative of the carotenoid may have the structure
  • each R 3 is independently hydrogen or methyl, and where each R and R 2 are independently:
  • R 4 is hydrogen or methyl; where each R 5 is independently hydrogen, -OH, or -OR 6 wherein at least one R 5 group is -OR 6 ; wherein each R 6 is independently: alkyl; aryl; -alkyl-N(R 7 ) 2 ; -aryl-N(R 7 ) 2 ; -alkyl-CO 2 H; -aryl-CO 2 H; -O-C(O)-R 8 ;-P(O)(OR 8 ) 2 ; -S(O)(OR S ) 2 ; an amino acid; a peptide, a carbohydrate; -C(O)-(CH 2 ) n -CO 2 R 9 ; -C(O)-OR 9 ; a nucleoside residue, or a co-antioxidant; where R 7 is hydrogen, alkyl, or aryl; wherein R 8 is hydrogen, alkyl, aryl, benzyl, or a co-antioxidant;
  • Each co-antioxidant may be independently Vitamin C, Vitamin C analogs, Vitamin C derivatives, Vitamin E, Vitamin E analogs, Vitamin E derivatives, flavonoids, flavonoid derivatives, or flavonoid analogs.
  • Flavonoids include, but are not limited to, quercetin, xanthohumol, isoxanthohumol, or genistein. Selection of the co- antioxidant should not be seen as limiting for the therapeutic application of the current invention.
  • a pharmaceutical composition may include one or more carotenoids ("a co-formulation" strategy), or synthetic derivatives or analogs thereof, in combination with one or more COX-2 selective inhibitor drugs. Certain embodiments may further directed to pharmaceutical compositions that include combinations two or more carotenoids or synthetic analogs or derivatives thereof.
  • a pharmaceutical composition may include cliiral astaxanthin in combination with a COX-2 selective inhibitor drug.
  • the COX-2 selective inhibitor drug may be a sulfone-based compound, such as rofecoxib or etoricoxib.
  • COX-2 selective inhibitor drug may be a sulfonamide-based compound such as celecoxib or valdecoxib.
  • a pharmaceutical composition suitable for use with the embodiments described herein may include at least one chiral astaxanthin, or a derivative or an analog thereof, and rofecoxib.
  • the pharmaceutical compositions may be adapted to be administered orally, or by one or more parenteral routes of administration.
  • the pharmaceutical composition may be adapted such that at least a portion of the dosage of carotenoid or synthetic de ⁇ vative or analog thereof is delivered prior to at least a portion of the COX- 2 selective inhibitor drug being delivered.
  • separate pharmaceutical compositions are provided, such that the COX-2 inhibitor is delivered separately from carotenoid, or synthetic derivatives or analogs thereof (sometimes referred to in the art as a "co-administration" strategy).
  • the pharmaceutical compositions may be adapted to be administered orally, or by one or more parenteral routes of administration.
  • the pharmaceutical composition may be adapted such that at least a portion of the dosage of the carotenoid or synthetic derivative or analog thereof is delivered prior to, during, or after at least a portion of the COX-2 selective inhibitor drag is delivered to the subject.
  • Embodiments directed to pharmaceutical compositions may further include appropriate vehicles for delivery of said pharmaceutical composition to a desired site of action (i.e., the site a subject's body where the biological effect of the pharmaceutical composition is most desired).
  • a desired site of action i.e., the site a subject's body where the biological effect of the pharmaceutical composition is most desired.
  • Pharmaceutical compositions including xanthophyll carotenoids or analogs or derivatives of astaxanthin, lutein or zeaxanthin that may be administered orally or intravenously may be particularly advantageous for and suited to embodiments described herein.
  • an injectable astaxanthin formulation or a structural analog or derivative may be administered with a astaxanthin, zeaxanthin or lutein structural analog or derivative and/or other carotenoid structural analogs or derivatives, or in formulation with antioxidants and/or excipients that further the intended purpose.
  • one or more of the xanthophyll carotenoids or synthetic analogs or derivatives thereof may be at least partially water-soluble.
  • FIG. 1 depicts a graphic representation of several examples of the structures of several xanthophyll carotenoids and synthetic derivatives or analogs that may be used according to some embodiments.
  • A astaxanthin; (B) lutein; (C) zeaxanthin; (D) disuccinic acid astaxanthin ester; (E) disodium disuccinic acid ester astaxanthin salt (CardaxTM); and (F) divitamin C disuccinate astaxanthin ester; (G) tetrasodium diphosphate astaxanthin ester.
  • FIG. 2 depicts a time series of the UV/Vis absorption spectra of the disodium disuccinate derivative of natural source lutein in water.
  • FIG. 5 depicts a time series of the UV/Vis absorption spectra of the disodium diphosphate derivative of natural source lutein in water.
  • FIG. 8 depicts a mean percent inhibition ( ⁇ SEM) of superoxide anion signal as detected by DEPMPO spin-trap by the disodium disuccinate derivative of natural source lutein (tested in water).
  • FIG. 9 depicts a mean percent inhibition ( ⁇ SEM) of superoxide anion signal as detected by DEPMPO spin-trap by the disodium diphosphate derivative of natural source lutein (tested in water).
  • FIG. 1OA depicts compartive effects of NSAIDs onrates of conjugated diene formation in human LDL.
  • FIG. 1OB depicts comparative effects of NSAIDs on formation of TBARS in human LDL.
  • FIG. 1 IA depicts the effects of rofecoxib and etoricoxib on isoprostane formation from lipid vesicles enriched with arachidonic acid.
  • FIG. 1 IB depicts comparative effects of COX-2 inhibitors on the antioxidant capacity of human plasma.
  • FIG. 12 depicts the effects of COX-2 inhibitors and carotenoids on lipid hydroperoxide formation in lipid vesicles enrinched with arachidonic acid.
  • FIG. 13 depicts a schematic illustration of structure changes in a membrane with rofecoxib.
  • FIG. 14 depicts a summary of the cardiotoxic mechanisms for rofecoxib.
  • FIGS. 15A and 15B depict the effects of carotenoids on the structure of POPC membrane as different C/P ratios.
  • FIGS. 16A and 16B depict the effects of carotenoids on the membrane structure and peroxidation at different C/P ratios.
  • xanthophyll carotenoid generally refers to a naturally occurring or synthetic 40- carbon polyene chain with a carotenoid structure that contains at least one oxygen-containing functional group.
  • the chain may include terminal cyclic end groups.
  • xanthophyll carotenoids include astaxanthin, zeaxanthin, lutein, echinenone, lycophyll, canthaxanthin, and the like.
  • Non-limiting examples of carotenoids that are not xanthophyll carotenoids include ⁇ -carotene and lycopene.
  • carotenoid analog and carotenoid derivative generally refer to chemical compounds or compositions derived from a naturally occurring or synthetic carotenoid. Terms such as carotenoid analog and carotenoid derivative may also generally refer to chemical compounds or compositions that are synthetically derived from non-carotenoid based parent compounds; however, which ultimately substantially resemble a carotenoid derived analog. Non-limiting examples of carotenoid analogs and derivatives that may be used according to some of the embodiments described herein are depicted schematically in FIG. 1, D-G.
  • organ when used in reference to a part of the body of an animal or of a human generally refers to the collection of cells, tissues, connective tissues, fluids and structures that are part of a structure in an animal or a human that is capable of performing some specialized physiological function. Groups of organs constitute one or more specialized body systems. The specialized function performed by an organ is typically essential to the life or to the overall well-being of the animal or human.
  • Non-limiting examples of body organs include the heart, lungs, kidney, ureter, urinary bladder, adrenal glands, pituitary gland, skin, prostate, uterus, reproductive organs (e.g., genitalia and accessory organs), liver, gall-bladder, brain, spinal cord, stomach, intestine, appendix, pancreas, lymph nodes, breast, salivary glands, lacrimal glands, eyes, spleen, thymus, bone marrow.
  • Non- limiting examples of body systems include the respiratory, circulatory, cardiovascular, lymphatic, immune, musculoskeletal, nervous, digestive, endocrine, exocrine, hepato-biliary, reproductive, and urinary systems.
  • the organs are generally made up of several tissues, one of which usually predominates, and determines the principal function of the organ.
  • tissue when used in reference to a part of a body or of an organ, generally refers to an aggregation or collection of morphologically similar cells and associated accessory and support cells and intercellular matter, including extracellular matrix material, vascular supply, and fluids, acting together to perform specific functions in the body.
  • tissue There are generally four basic types of tissue in animals and humans including muscle, nerve, epithelial, and connective tissues.
  • modulate generally refers to a change or an alteration in the magnitude of a be used herein to biological parameter such as, for example, foci formation, tumorigenic or neoplastic potential, apoptosis, growth kinetics, expression of one or more genes or proteins of interest, metabolism, oxidative stress, replicative status, intercellular communication, or the like.
  • Modulation may refer to a net increase or a net decrease in the biological parameter.
  • reducing when used in the context of modulating a pathological or disease state, generally refers to the prevention and/or reduction of at least a portion of the negative consequences of the disease state.
  • the term(s) When used in the context of an adverse side effect associated with the administration of a drug to a subject, the term(s) generally refer to a net reduction in the severity or seriousness of said adverse side effects.
  • side effects associated with the administration of COX-2 inhibitors generally refers to one or more unintended, although not necessarily unexpected, biological events associated with COX-2 inhibitor administration to a subject that are generally unrelated to the biological response(s) typically desired by said administration, namely, inhibition of the biological activity of the COX-2 enzyme in the subject.
  • a side effect associated with the administration of COX-2 inhibitors is generally said to be “adverse" when the side effect can cause harm to the subject.
  • Some of the adverse side effects associated with the administration of COX-2 inhibitors to a subject can occur systernically or at the level of one or more organ systems and include: increased incidences of edema, cnanges in systolic DIOOQ pressuic chat are greater than approximately 20 mm Hg, risk of stroke, risk of myocardial infacrtion, and increased risk of thrombotic events.
  • Additional side effects that may occur at the level of biochemical reactions in an individual being administered COX-2 inhibitors include, by way of non-limiting example, the spontaneous development of pro-oxidant and toxic properties of the administered drug, increased production of certain oxidized phospholipids, LDL and F 2 isoprostanoids, reduced oxygen radical antioxidant capacity (ORAC), and increased lipid peroxidation events.
  • COX-2 selective inhibitors or "COX-2 inhibitor” generally refers to a compound belonging to a class of non-steroidal anti-inflammatory drags (NS AIDs) that inhibit inducible cyclooxygenase (COX) enzymes, in particular COX-2.
  • COX-2 inhibitors embraces those compounds that selectively inhibit cyclooxygenase-2 over cyclooxygenase- 1.
  • COX-2 and COX-I inhibitory activities may be determined employing the human whole blood COX-I assay and the human whole blood COX-2 assay described in C. Brideau et. Al., Inflamm. Res. 45: 68-74 (1996), herein incorporated by reference.
  • the compounds may have a cyclooxygenase-2 IC 50 of less than about 2 ⁇ M in the human whole blood COX-2 assay, yet have a COX-I IC 50 of greater than about 5 ⁇ M in the human whole blood COX-I assay. Also, the compounds have a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase- 1 inhibition of at least 5, or at least 30.
  • COX-2 selective inhibitor may refer to sulfone drugs, such as rofecoxib or etoricoxib. COX-2 inhibitor may also refer to a sulfonamide drug such as celecoxib and valdecoxib. A variety of selective "COX-2 inhibitors" are known in the art.
  • COX-2 inhibitors are prodrugs of selective COX-2 inhibitors, and exert their action by conversion in vivo to the active and selective COX-2 inhibitors.
  • the active and selective COX-2 inhibitors formed from the above-identified COX-2 inhibitor pro-drags are described in detail in WO 95/00501, published Jan. 5, 1995, WO 95/18799, published JuI. 13, 1995 and U.S. Pat. No. 5,474,995, issued Dec. 12, 1995. Given the teachings of U.S. Pat. No.
  • administering when used in the context of providing a pharmaceutical or nutraceutical composition to a subject generally refers to providing to the subject one or more pharmaceutical, “over-the-counter” (OTC) or nutraceutical compositions in combination with an appropriate delivery vehicle by any means such that the administered compound achieves one or more of the intended biological effects for which the compound was administered.
  • OTC over-the-counter
  • a composition may be administered parenteral, subcutaneous, intravenous, intracoronary, rectal, intramuscular, intraperitoneal, transdermal, or buccal routes of delivery. Alternatively, or concurrently, administration may be by the oral route.
  • the dosage administered will be dependent upon the age, health, weight, and/or disease state of the recipient, kind of concurrent treatment, if any, frequency of treatment, and/or the nature of the effect desired.
  • the dosage of pharmacologically active compound that is administered will be dependent upon multiple factors, such as the age, health, weight, and/or disease state of the recipient, concurrent treatments, if any, the frequency of treatment, and/or the nature and magnitude of the biological effect that is desired.
  • phrases such as "pharmaceutical composition,” “pharmaceutical formulation,” “pharmaceutical preparation,” or the like generally refer to formulations that are adapted to deliver a prescribed dosage of one or more pharmacologically active compounds to a cell, a group of cells, an organ or tissue, an animal or a human. Methods of incorporating pharmacologically active compounds into pharmaceutical preparations are widely known in the art. The determination of an appropriate prescribed dosage of a pharmacologically active compound to include in a pharmaceutical composition in order to achieve a desired biological outcome is within the skill level of an ordinary practitioner of the art.
  • a pharmaceutical composition may be provided as sustained-release or timed-release formulations.
  • Such formulations may release a bolus of a compound from the formulation at a desired time, or may ensure a relatively constant amount of the compound present in the dosage is released over a given period of time.
  • Terms such as “sustained release,” “controlled release,” or “timed release” and the like are widely used in the pharmaceutical arts and are readily understood by a practitioner of ordinary skill in the art.
  • Pharmaceutical preparations may be prepared as solids, semi-solids, gels, hydrogels, liquids, solutions, suspensions, emulsions, aerosols, powders, or combinations thereof.
  • a pharmaceutical preparation may be one or more carriers, preservatives, flavorings, excipients, coatings, stabilizers, binders, solvents and/or auxiliaries that are, typically, pharmacologically inert. It will be readily appreciated by an ordinary practitioner of the art that, included within the meaning of the term are pharmaceutically acceptable salts of compounds. It will further be appreciated by an ordinary practitioner of the art that the term also encompasses those pharmaceutical compositions that contain an admixture of two or more pharmacologically active compounds, such compounds being administered, for example, as a combination therapy.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N -dibenzylethylenediamine, diethylamine, 2-dibenzylethylenediamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylarnine, tripropylamine, tromethamine, and the
  • the terms “subject” generally refers to a mammal, and in particular to a human.
  • the terms “in need of treatment” or “in need thereof when used in the context of a subject being administered a pharmacologically active composition, generally refers to a judgment made by an appropriate healthcare provider that an individual or animal requires or will benefit from a specified treatment or medical intervention. Such judgments may be made based on a variety of factors that are in the realm of expertise of healthcare providers, but include knowledge that the individual or animal is ill, will be ill, or is at risk of becoming ill, as the result of a condition that may be ameliorated or treated with the specified medical intervention.
  • terapéuticaally effective amount is meant an amount of a drug or pharmaceutical composition that will elicit at least one desired biological or physiological response of a cell, a tissue, a system, animal or human that is being sought by a researcher, veterinarian, physician or other caregiver.
  • prophylactically effective amount is meant an amount of a pharmaceutical composition that will substantially prevent, delay or reduce the risk of occurrence of the biological or physiological event in a cell, a tissue, a system, animal or human that is being sought by a researcher, veterinarian, physician or other caregiver.
  • pharmacologically inert generally refers to a compound, additive, binder, vehicle, and the like, that is substantially free of any pharmacologic or "drug-like" activity.
  • a "pharmaceutically or nutraceutically acceptable formulation,” as used herein, generally refers to a non- toxic formulation containing a predetermined dosage of a pharmaceutical and/or nutraceutical composition, wherein the dosage of the pharmaceutical and/or nutraceutical composition is adequate to achieve a desired biological outcome.
  • the meaning of the term may generally include an appropriate delivery vehicle that is suitable for properly delivering the pharmaceutical composition in order to achieve the desired biological outcome.
  • antioxidant may be generally defined as any of various substances (as beta- carotene, vitamin C, and ⁇ -tocopherol) that inhibit oxidation or reactions promoted by Reactive Oxygen Species (ROS) and other radical and non-radical species.
  • ROS Reactive Oxygen Species
  • co-antioxidant may be generally defined as an antioxidant that is used and that acts in combination with another antioxidant (e.g., two antioxidants that are chemically and/or functionally coupled, or two antioxidants that are combined and function with each another in a pharmaceutical preparation).
  • the effects of co-antioxidants may be additive (i.e., the anti-oxidative potential of one or more anti-oxidants acting additively is approximately the sum ot ttte oxidative potential of each component anti-oxidant) or synergistic (i.e., the anti- oxidative potential of one or more anti-oxidants acting synergistically may be greater than the sum of the oxidative potential of each component anti-oxidant).
  • the presently described embodiments provide for a novel method for the treatment or prophylaxis of at least some of the adverse side effects associated with the administration of COX-2 inhibitors in patients comprising administering to said patients a therapeutically or prophylactically effective amount of a xanthophyll carotenoid, or a carotenoid derivative or analog, and/or a COX-2 selective inhibitor and a xanthophyll carotenoid, or a carotenoid derivative or analog.
  • the present invention also provides for pharmaceutical compositions comprising a therapeutically or prophylactically effective amount of a COX-2 inhibitor and a xanthophyll carotenoid, or a carotenoid derivative or analog, and a pharmaceutically acceptable carrier in unit dosage form.
  • the present invention also provides a pharmaceutical product comprising (1) a therapeutically or prophylactically effective amount of a COX-2 selective inhibitor in a first oral unit dosage form, (2) a xanthophyll carotenoid, or a carotenoid derivative or analog, in a second oral unit dosage form, and (3) instructions for concurrent or sequential administration of said pharmaceutical product to a patient in need thereof.
  • Clinical studies have demonstrated a correlation between the therapeutic use of certain cyclooxygenase-2
  • COX-2 inhibitor drugs and increased risk for adverse cardiovascular events.
  • This increased risk appears to be slightly more biased toward sulfone COX-2 selective inhibitor drugs such as refocoxib and etoricoxib than sulfonamide COX-2 inhibitors such as celecoxib and valdecoxib, suggesting that the mechanism by which the drugs increase the susceptibility of developing cardiovascular complication is independent of the ability of the drug to inhibit COX-2 enzyme function. While the mechanism by which COX-2 inhibitors exert adverse cardiovascular effects on subjects under treatment is not completely understood, emerging data suggest that sulfone COX-2 inhibitor class (e.g.
  • rofecoxib and etoricoxib exert non-enzymatic pro-oxidant effects in addition to the class effect that results from unopposed systemic inhibition of COX-2.
  • the relative contribution of each of the aforementioned mechanisms is currently unclear, however, the net effect is that subjects under long term therapy with COX-2 inhibitors show an approximately a 5-fold increase in the incidence of clinical coronary events.
  • a method that substantially reduces at least a portion of the adverse cardiovascular side effects side effects associated with the administration of COX-2 inhibitor to a subject.
  • the method may include administering to a subject hi need thereof an effective amount of a pharmaceutically acceptable formulation that includes a xanthophyll carotenoid or a synthetic analog or derivative of a xanthophyll carotenoid.
  • the formulation may include astaxantbin, lutein and/or zeaxanthin or a structural analog or a derivative thereof.
  • the formulation may include homochiral (“chiral") astaxanthin, or a synthetic analog or derivative of a homochiral astaxanthin.
  • the formulation may include mixtures of varying proporations of different homochiral forms of astaxanthin.
  • a synthetic analog or derivative of a chiral astaxanthin may be administered to a subject, wherein the synthetic chiral asatxanthin, when present in the subject's body, undergoes chemical or enzymatic breakdown, wherein at least one breakdown product is chiral asatxanthin.
  • the various synthetic and/or naturally occurring forms of astaxanthin (stereoisomers, geometric isomers, monoesters, diesters) maybe administered to a subject to achieve the intended purpose.
  • astaxanthin therefore includes its various chemical forms, and may include a certain preferred isomeric or ester form for a particular use.
  • Exemplary though non-limiting xanthophyll carotenoids or structural derivatives or analogs thereof that may be suitable for use in the embodiments disclosed herein are depicted schematically in FIG. 1
  • administering to a subject who is undergoing, who is expected to undergo, or who has undergone therapy with one or more COX-2 inhibitors may substantially inhibit or reduce the risk that the subject experiences adverse side effects associated with COX-2 inhibitors.
  • a subject may be administered xanthophyll carotenoids or structural derivatives or analogs thereof that are embodied herein to reduce the likelihood that the subject experiences edema, changes hi systolic blood pressure that are greater than approximately 20 mm Hg, risk of stroke, myocardial infarction, or thrombotic events.
  • a subject may be administered xanthophyll carotenoids or structural derivatives or analogs thereof embodied herein to inhibit or reduce certain adverse biochemical reactions, or complications arising from ceratin adverse biochemical reactions, that may occur hi an idividual being administered COX-2 inhibitors, such as, for example, the spontaneous development of prooxidant and toxic properties COX-2 inhibitors, increased production of certain oxidized phospholipids, LDL and F 2 isoprostanoids, reduced oxygen radical antioxidant capacity (ORAC), and increased lipid peroxidation events.
  • administering a xanthophyll carotenoid or a structural derivative or an analog of a carotenoid may reduce the rate of lipid peroxidation resulting from the administration of COX-2 selective inhibitor drugs.
  • COX-2 selective inhibitors whose negative cardiovascular effects may be reduced may include sulfone-based COX-2 inhibitors such as, for example, rofecoxib and etoricoxib.
  • COX-2 selective inhibitors whose negative cardiovascular effects may be reduced may include sulfonamide-based COX-2 inhibitors such as, for example, celecoxib, valdecoxib, or COX-2 selective inhibitors that are neither sulfone- nor sulfonamide-based, such as, for example, lumiracoxib.
  • sulfonamide-based COX-2 inhibitors such as, for example, celecoxib, valdecoxib, or COX-2 selective inhibitors that are neither sulfone- nor sulfonamide-based, such as, for example, lumiracoxib.
  • carotenoids or synthetic derivatives or analogs thereof may be administered to a subject concurrently with COX-2 selective inhibitor drug therapy.
  • carotenoids or synthetic derivatives or analogs thereof may be administered to a subject prior to the commencement of COX-2 selective inhibitor drug therapy.
  • xanthophyll carotenoids or synthetic derivatives or analogs thereof may be administered to a subject following the commencement of COX-2 selective inhibitor drug therapy.
  • the carotenoids or synthetic derivatives or analogs thereof may be provided in a single pharmaceutical preparation together with a COX-2 selective inhibitor drug.
  • the carotenoids or synthetic derivatives or analogs thereof may be provided may be administered to a subject in a pharmaceutical preparation that is distinct from that which includes the COX-2 selective inhibitor.
  • the pharmaceutical preparation may be administered orally, in the form of a tablet, a capsule, an emulsion, a liquid, or the like. Alternatively, the pharmaceutical preparation may be administered via a parenteral route.
  • a more detailed description of the types of pharmaceutical preparations that may be suitable for some embodiments is described in below.
  • Some embodiments may be particularly suited timed or sustained release pharmaceutical preparations, in which the preparation is adapted to deliver a known dosage of xanthophyll carotenoids or synthetic derivatives or analogs thereof at or over a predetermined time.
  • a pharmaceutical preparation may be adapted to one drug, or a portion thereof, before delivering the second drug.
  • a pharmaceutical preparation may be adapted in such a way that at least a portion of the xanthophyll carotenoid or structural analog or derivative thereof is released into the body of a subject before the COX-2 inhibitor drug is released.
  • Such formulations may ensure that pro-oxidant capacity of COX-2 selective inhibitor drugs is maximally reduced.
  • a pharmaceutical composition may further include one or more co-antioxidant compounds.
  • co-antioxidant compounds that may be suitable for inclusion in a pharmaceutical preparation together with the xanthophyll carotenoids disclosed herein, or structural analogs or derivatives thereof, may include ascorbic acid or vitamin-E ( ⁇ -toco ⁇ herol).
  • the co-antioxidant compounds may improve the ability of xanthophyll carotenoids or structural derivatives or analogs thereof to reduce the pro-oxidant capacity of COX-2 selective inhibitor drugs.
  • co- antioxidant compounds may be covalently linked to the xanthophyll carotenoids or structural analogs or derivatives.
  • co-antioxidant compounds may be mixed with the xanthophyll carotenoids or structural analogs or derivatives.
  • Administration of xanthophyll carotenoids or a synthetic analogs or derivatives thereof according to the preceding embodiments may at least partially inhibit and/or influence the complications, particularly those complications associated with the cardiovascular system, associated chronic administration of COX-2 selective inhibitor drugs such as rofecoxib, etoricoxib, celecoxib, and valdecoxib.
  • me administration of xanthophyll carotenoids or structural analogs or derivatives of carotenoids by one skilled in the art - including consideration of the pharmacokinetics and pharmacodynamics of therapeutic drag delivery - is expected to inhibit and/or ameliorate disease conditions associated with administering xanthophyll carotenoid or a synthetic analog or derivative thereof to a subject, including but not limited to the production of oxidized lipids, isoprostanes and LDL.
  • analogs or derivatives of carotenoids administered to a subject may be adapted to be at least partially water-soluble.
  • the xanthophyll carotenoids or structural carotenoid analogs or derivatives may at least partially counteract or reverse the ability of certain COX-2 selective inhibitor drags to reduce the electron density of the hydrocarbon core of phospholipids.
  • Restoring the electron density of the hydrocarbon core of phospholipids may render phospholipids present in cell membranes or LDL less susceptible to peroxidation by ROS.
  • Reduced lipid peroxidation may, in turn, substantially prevent or reduce the occurrence of atherosclerosis or other adverse cardiovascular effects in subjects undergoing COX-selective inhibitor drug therapy.
  • the xanthophyll carotenoid or structural derivative or analog may be adapted or chosen such that the hydrophobic carotenoid backbone of the molecule incorporates into the plasma membrane of a cell in a plane that is substantially perpendicular the plane of the phospholipid bilayer.
  • Such a configuration may allow the oxygen-containing functional groups of the xanthophyll carotenoid or structural analog or derivative thereof to anchor the molecule in a plane perpendicular to the phospholipids bilayer of the plasma membrane.
  • a xanthophyll carotenoids or structural analogs or derivatives thereof may, at least in part, restore the electron density of the hydrocarbon core of phospholipids exposed to COX-2 selective inhibitor drags.
  • a xanthophyll carotenoid or structural analog or derivative thereof may be selected such that the distance between the oxygen-containing function groups on opposing ends of the molecule is substantially similar to the thickness of the phospholipid bilayer of plasma membranes (e.g., between about 25 A to about 55 A, or between about 40 A to about 50 A).
  • oxygen-containing function groups on opposing ends of the molecule may substantially prevent the molecule from adopting a configuration that is planar, and thus disruptive, to the plasma membrane.
  • the inclusion of oxygen-containing function groups on opposing ends of the molecule may substantially prevent the molecule from adopting a configuration that is non-random, and thus also disruptive, to the plasma membrane.
  • a second class is the tricyclic inhibitor class, which can be further divided into the sub-classes of tricyclic inhibitors with a central carbocyclic ring (examples include SC-57666, 1, and 2); those with a central monocyclic heterocyclic ring (examples include DuP 697, SC-58127, SC-58635, and 3, 4 and 5; and those with a central bicyclic heterocyclic ring (examples include 6, 7, 8, 9 and 10).
  • Compounds 3, 4 and 5 are described in U.S. Pat. No.
  • the third identified class can be referred to as those which are structurally modified NSAIDs, and includes
  • One class of COX-2 inhibitors includes pyrazolyl-benzenesulfonamides.
  • methods of reducing the negative cardiovascular effects associated with therapeutic administration of pyrazolyl- benzenesulfonamides COX-2 inhibitors in a subject may include administering to the subject an effective amount of a pharmaceutically acceptable formulation including a xanthophyll or other carotenoid or a synthetic analog or derivative of a xanthophyll carotenoid and one or more pyrazolyl-benzenesulfonamides COX-2 inhibitors. Any of the carotenoids or carotenoid derivatives described herein may be used to reduce the negative cardiovascular effects associated with therapeutic administration of pyrazolyl-benzenesulfonamides COX-2 inhibitors.
  • R 21 is selected from S(O) 2 N(R 26 )R 27 , halo, alkyl, alkoxy, hydroxyl and haloalkyl; wherein R 26 is hydrogen or alkoxycarbonylalkyl; wherein R 27 is hydrogen, alkyl, carboxyalkyl, acyl, alkoxycarbonyl, heteroarylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylcarbonyl, amino acid residue, or alkylcarbonylaminoalkylcarbonyl; wherein R 22 is selected from hydrido, halo, haloalkyl, cyano, nitro, formyl, carboxyl, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, amidino, cyanoamidino, amido, alkoxy, amidoalkyl, N-monoalkylamido, N-monoarylamido, N,N-dialkylamido,
  • R 25 is one or more radicals selected from halo, alkylthio, alkylsulf ⁇ nyl, alkylsulfonyl, cyano, carboxyl, alkoxycarbonyl, amido, N-monoalkylamido, N-monoarylamido, alkyl, N,N-dialkylamido, N-alkyl-N-arylamido, haloalkyl, hydrido, hydroxyl, alkoxy, hydroxyalkyl, haloalkoxy, sulfamyl, N-alkylsulfamyl, amino, alkylamino, heterocyclic, nitro and acylamino; or a pharmaceutically-acceptable salt thereof.
  • pyrazolyl-benzenesulfonamides described herein would be useful to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthopathies, gouty arthritis, systemic lupus erythematosus, osteoarthritis and juvenile arthritis.
  • Such pyrazolyl-benzenesulfonamides described herein would be useful in the treatment of asthma, bronchitis, menstrual cramps, tendinitis, bursitis, and skin-related conditions such as psoriasis, eczema, burns and dermatitis.
  • a sub-class of pyrazolyl-benzenesulfonamides includes those compounds having the structure shown in Formula II below:
  • R 22 is haloalkyl; wherein R 23 is hydrido; and wherein R 24 is selected from aryl, cycloalkyl, and cycloalkenyl; wherein R 24 is optionally substituted at a substitutable position with one or more radicals selected from halo, alkylthio, alkylsulfonyl, cyano, nitro, haloalkyl, alkyl, hydrido, alkoxy, haloalkoxy, sulfamyl, heterocyclic and amino; or a pharmaceutically-acceptable salt thereof.
  • a specific example of a pyrazolyl-benzenesulfonamide includes the compound depicted in formula III below:
  • Another class of COX-2 inhibitors includes isoxazoles.
  • methods of reducing the negative cardiovascular effects associated with therapeutic administration of isoxazole COX-2 inhibitors in a subject may include administering to the subject an effective amount of a pharmaceutically acceptable formulation including a xanthophyll or other carotenoid or a synthetic analog or derivative of a xanthophyll carotenoid and one or more isoxazole COX-2 inhibitors. Any of the carotenoids or carotenoid derivatives described herein may be used to reduce the negative cardiovascular effects associated with therapeutic administration of isoxazole COX-2 inhibitors.
  • isoxazole COX-2 inhibitors useful in treating inflammation and other COX-2 related disorders are defined by Formula IV:
  • R 31 is selected from R-, RO-, RS-, RO-alkyl, RS-alkyl, carboxyl, cyano, hydroxyl, amino, halo, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkoxyalkyloxyalkyl, aryl(hydroxylalkyl), haloalkylsulfonyloxy, arylcarbonyloxyalkyl, arylcarbonylthioalkyl, alkoxycarbonyloxyalkyl, alkylaminocarbonyloxyalkyl, alkylaminocarbonylthioalkyl, RS(O)-; RS(O)alkyl-; RC(O)-; RC(O)alkyl-; ROC(O)-; ROC(O)alkyl-; RNH-; RNHalkyl-; R 2 N-; R 2 Nalkyl-; RS(O) 2 alky
  • Compounds of Formula IV would be useful for, but not limited to, the treatment of inflammation in a subject, and for treatment of other cyclooxygenase-2 mediated disorders, such as, as an analgesic in the treatment of pain and headaches, or as an antipyretic for the treatment of fever.
  • compounds of the invention would be useful to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis.
  • a sub-class of isoxazole COX-2 inhibitors includes those compounds defined by Formula V:
  • R 34 is selected from hydroxyl, alkyl, carboxyl, halo, carboxyalkyl, alkoxycarbonylalkyl, aralkyl, methoxy, ethoxy, butoxy, alkylthio, alkoxyalkyl, aryloxyalkyl, arylthioalkyl, haloalkyl, hydroxylalkyl, aralkoxyalkyl, aryl(hydroxylalkyl), carboxyalkoxyalkyl, carboxyaryloxyalkyl, alkoxycarbonylaryloxyalkyl, cycloalkyl and cycloalkylalkyl; wherein R 35 is N(R 39 )R 40 ; wherein R 39 is hydrogen; wherein R 40 is hydrogen, alkyl or -C(O)alkyl; and wherein R 36 is phenyl; wherein R 36 is optionally substituted at a substitutable position with one or more radicals independently selected from alkylsulfinyl,
  • a further sub-class of isoxazole COX-2 inhibitors includes those compounds defined by Formula VI:
  • R 37 is selected from hydroxyl, alkyl, carboxyl, halo, carboxyalkyl, alkoxycarbonylalkyl, alkoxyalkyl, carboxyalkoxyalkyl, haloalkyl, alkylthio, alkylsulfinyl, (hydroxy)alkoxyalkyl, carboxyalkylaryloxyalkyl, haloalkylsulfonyloxy, hydroxylalkyl, aryl(hydroxylalkyl), carboxyaryloxyalkyl, cycloalKyl, cycioai ⁇ yiai ⁇ yi, ana araiKyi; and wherein R 38 is one or more radicals independently selected from hydrido, alkylsulfinyl, alkyl, cyano, carboxyl, alkoxycarbonyl, haloalkyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino,
  • a specific example of an isoxazole COX-2 inhibitor includes the compound depicted in formula VII below:
  • Another class of COX-2 inhibitors includes various phenyl heterocycles.
  • methods of reducing the negative cardiovascular effects associated with therapeutic administration of phenyl heterocycle COX-2 inhibitors in a subject may include administering to the subject an effective amount of a pharmaceutically acceptable formulation including a xanthophyll or other carotenoid or a synthetic analog or derivative of a xanthophyll carotenoid and one or more phenyl heterocycle COX-2 inhibitors.
  • Any of the carotenoids or carotenoid derivatives described herein may be used to reduce the negative cardiovascular effects associated with therapeutic administration of phenyl heterocycle COX-2 inhibitors.
  • Examples of phenyl heterocycle COX-2 inhibitors useful in treating inflammation and other COX-2 related disorders are defined by Formula VIII or pharmaceutically acceptable salts of the compounds defined by Formula VHI:
  • X-Y-Z- is: (a) -CH 2 CH 2 CH 2 -; (b) -C(O)CH 2 CH 2 -; (c) -CH 2 CH 2 C(O)-;
  • R 41 is: (a) S(O) 2 CH 3 ; (b) S(O) 2 NH 2 ; (c) S(O) 2 NHC(O)CF 3 ; (d) S(O)(NH)CH 3 ; (e) S(O)(NH)NH 2 ; (f) S(O)(NH)NHC(O)CF 3 ; (g) P(O)(CH 3 )OH; (h) P(O)(CH 3 )NH 2 ; (i) S(O) 2 NH-alkyl; G) S(O) 2 NH-aryl; (k) S(O) 2 NHC(O)-alkyl; or (1) S(O) 2 NHC(O)aryl;
  • R 42 is (a) C 1-6 alkyl; (b) C 3 , C 4 , C 5 , C 6 , or C 7 cycloalkyl; (c) mono-, di- or tri-substituted phenyl or naphthyl wherein possible substituents include hydrogen, halo, C 1-6 alkoxy, Ci. 6 alkylthio, CN, CF 3 , Cj -6 alkyl, N 3 , -CO 2 H, -CO 2 -C M alkyl, -C(R 45 )(R 4(5 )-OH, -C(R 45 )(R 46 )-O-d.
  • each R 43 is: (a) hydrogen; (b) CF 3; (c) CN; (d) C 1-6 alkyl; (e) hydroxy Ci -6 alkyl;
  • R 44 and R 44' are each independently: (a) hydrogen; (b) CF 3 ; (c) CN; (d) Ci -6 alkyl; (e) -Q; (f) -0-Q; (g) -S-Q, or (h) optionally substituted (1) -Ci -5 alkyl-Q, (2) -0-C x-5 alkyl-Q, (3) -S-C 1-5 alkyl-Q, (4) -C 1-3 alkyl-O-Ci.
  • R 45 , R 45' , R 46 , R 47 and R 48 are each independently: (a) hydrogen; (b) Cj -6 alkyl; or R 45 and R 46 or R 47 and R 48 together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms;
  • Q is CO 2 H, CO 2 -C 1-4 alkyl, tetrazolyl-5-yl, C(R 47 )(R 48 )(OH), or C(R 47 )(R 48 )(O-C 1-4 alkyl).
  • Compounds of Formula VIII would be useful for, but not limited to, the treatment of cyclooxygenase-2 mediated disorders, such as, the relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, injuries, and following surgical and dental procedures.
  • cyclooxygenase-2 mediated disorders such as, the relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgi
  • a sub-class of phenyl heterocycle COX-2 inhibitors includes those compounds defined by Formula IX:
  • R 41 is: (a) S(O) 2 CH 3 ; (b) S(O) 2 NH 2 ; (c) S(O) 2 NHC(O)CF 3 ; (d) S(O)(NH)CH 3 ; (e) S(O)(NH)NH 2 ; (f) S(O)(NH)NHC(O)CF 3 ; (g) P(O)(CH 3 )OH; (h) P(O)(CH 3 )NH 2 ; (i) S(O) 2 NH-alkyl; Q) S(O) 2 NH-aryl; (k) S(O) 2 NHC(O)-alkyl; or (1) S(O) 2 NHC(O)aryl;
  • R 42 is (a) Ci -6 alkyl; (b) C 3 , C 4 , C 5 , C 6 , or C 7 cycloalkyl; (c) mono-, di- or tri-substituted phenyl or naphthyl wherein possible substituents include hydrogen, halo, C 1-6 alkoxy, C 1-6 alkylthio, CN, CF 3 , C 1-6 alkyl, N 3 , -CO 2 H, -CO 2 -C 1-4 alkyl, -C(R 45 )(R 46 )-OH, -C(R 45 )(R 46 )-O-C 1-4 alkyl, and (13) -C 1-6 alkyl-CO 2 -R 45 ; (d) mono-, di- or tri-substituted heteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, the monocyclic ring having one heteroatom wnicn is a, u
  • R 45 and R 46 are each independently: (a) hydrogen; (b) Ci -6 alkyl; or R 45 and R 46 together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms;
  • a further sub-class of phenyl heterocycle COX-2 inhibitors includes those compounds defined by Formula IX:
  • R 41 is S(O) 2 CH 3 , S(O) 2 NH 2 , S(O)NHCH 3 , S(O)NHNH 2 , S(O) 2 NH ⁇ alkyl, S(O) 2 NH-aryl, S(O) 2 NHC(O)-alkyl, or S(O) 2 NHC(O)aryl;
  • R 42 is C 1-6 alkyl; C 3 , C 4 , C 5 , C 6 , and C 7 , cycloalkyl; (c) heteroaryl
  • R 45 , R 45' and R 46 are each independently (a) hydrogen; (b) C 1-6 alkyl; or R 45 and R 46 together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms.
  • phenyl heterocycle COX-2 inhibitor includes the compound depicted below:
  • Another class of COX-2 inhibitors includes benzothiazine derivatives.
  • methods of reducing the negative cardiovascular effects associated with therapeutic administration of phenyl heterocycle COX-2 inhibitors in a subject may include administering to the subject an effective amount of a pharmaceutically acceptable formulation including a xanthophyll or other carotenoid or a synthetic analog or derivative of a xanthophyll carotenoid and one or more benzothiazine COX-2 inhibitors.
  • a pharmaceutically acceptable formulation including a xanthophyll or other carotenoid or a synthetic analog or derivative of a xanthophyll carotenoid and one or more benzothiazine COX-2 inhibitors.
  • Any of the carotenoids or carotenoid derivatives described Herein may De use ⁇ ra reuuce me negative cardiovascular effects associated with therapeutic administration of benzothiazine COX-2 inhibitors.
  • benzothiazine COX-2 inhibitors useful in treating inflammation and other COX-2 related disorders are defined by Formula X or pharmaceutically acceptable salts of the compounds defined by Formula X:
  • R 51 is hydrogen, methyl or ethyl
  • R 52 is methyl, ethyl or n- ⁇ ro ⁇ yl
  • Compounds of Formula X would be useful for, but not limited to, the treatment of cyclooxygenase-2 mediated disorders, such as, the relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, bums, injuries, and following surgical and dental procedures.
  • cyclooxygenase-2 mediated disorders such as, the relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neural
  • benzothiazine COX-2 inhibitor includes the compound depicted below:
  • Another class of COX-2 inhibitors includes substituted pyridines.
  • methods of reducing the negative cardiovascular effects associated with therapeutic administration of substituted pyridine COX- 2 inhibitors in a subject may include administering to the subject an effective amount of a pharmaceutically acceptable formulation including a xanthophyll or other carotenoid or a synthetic analog or derivative of a xanthophyll carotenoid and one or more substituted pyridine COX-2 inhibitors. Any of the carotenoids or carotenoid derivatives described herein may be used to reduce the negative cardiovascular effects associated with therapeutic administration of substituted pyridine COX-2 inhibitors.
  • substituted pyridine COX-2 inhibitors useful in treating inflammation and other COX-2 related disorders are defined by Formula XI or pharmaceutically acceptable salts of the compounds defined by Formula XI:
  • R 61 is: (a) CH 3 ; (b) NH 2 ; (c) NHC(O)CF 3 ; (d) NH-alkyl; (e) NH-aryl; (f) NHC(O)-alkyl; or (g) S(O) 2 NHC(O)aryl;
  • Ar is a mono-, di-, or trisubstituted phenyl or pyridinyl (or the N-oxide thereof), wherein substituents include hydrogen, halogen, C 1-6 alkoxy, Ci -6 alkylthio, CN, Ci -6 alkyl, C 1-6 fluoroalkyl, N 3 , -CO 2 R 63 , hydroxy, -C(R 64 )(R 65 )-OH, -C 1-6 alkyl-CO 2 -R 66 , or C 1-6 fluoroalkoxy;
  • R 62 is: (a) halo; (b) C 1-6 alkoxy; (c) Ci -6 alkylthio; (d) CN; (e) C] -6 alkyl; (f) C 1-6 fluoroalkyl; (g) N 3 ; (h) -CO 2 R 67 ; (i) hydroxy; (j) -C(R 68 )(R 69 )-OH; (k) -C 1-6 alkyl-CO 2 -R 70 ; (1) C 1-6 fluoroalkoxy; (m) NO 2 ; (n) NR 53 R 54 ; and (o) NHCOR 55 ;
  • R 63 , R 64 , R 65 , R 66 , R 67 , R 68 , R 69 , R 70 , R 53 , R 54 , R 55 are each independently hydrogen or C 1-6 alkyl, or R 64 and R 65 , R 68 and R 69 or R 53 and R 54 together with the atom to which they are attached form a saturated monocyclic ring of 3, 4, 5, 6 or 7 atoms.
  • Compounds of Formula XI would be useful for, but not limited to, the treatment of cyclooxygenase-2 mediated disorders, such as, the relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, injuries, and following surgical and dental procedures.
  • a mruier suD-ciass oi suostituted pyridine COX-2 inhibitors includes those compounds defined by Formula
  • R 61 is: (a) CH 3 ; (b) NH 2 ; (c) NHC(O)CF 3 ; (d) NH-alkyl; (e) NH-aryl; (f) NHC(O)-alkyl; or (g) S(O) 2 NHC(O)aryl;
  • R 62 is: (a) halo; (b) C 1-3 alkoxy; (c) Ci -3 alkylthio; (d) C 1-3 alkyl; (e) N 3 ; (f) -CO 2 H; (g) hydroxy; (h) C 1-3 fluoroaU ⁇ xy; (i) NO 2 ; O) NR 53 R 54 and (k) NHCOR 55 ;
  • X is methyl, ethyl, n-propyl, i-propyl or cyclopropyl.
  • a further sub-class of substituted pyridine COX-2 inhibitors includes those compounds defined by Formula XIII:
  • R 61 is: (a) CH 3 ; (b) NH 2 ; (c) NHC(O)CF 3 ; (d) NH-alkyl; (e) NH-aryl; (f) NHC(O)-alkyl; or (g) S(O) 2 NHC(O)aryl;
  • R 62 is chloro or methyl
  • each X group is independently: hydrogen, halogen, C 1-4 alkoxy, Cj -4 alkylthio, CN, C 1-4 alkyl, or CF 3 .
  • benzothiazine COX-2 inhibitor includes the compound depicted below:
  • COX-2 inhibitors includes substituted arylaniinophenylacetic acids.
  • methods of reducing the negative cardiovascular effects associated with therapeutic administration of substituted arylaniinophenylacetic acid COX-2 inhibitors in a subject may include administering to the subject an effective amount of a pharmaceutically acceptable formulation including a xanthophyll or other carotenoid or a synthetic analog or derivative of a xanthophyll carotenoid and one or more arylaniinophenylacetic acid COX-2 inhibitors. Any of the carotenoids or carotenoid derivatives described herein may be used to reduce the negative cardiovascular effects associated with therapeutic administration of substituted arylaniinophenylacetic acid COX-2 inhibitors.
  • substituted arylaniinophenylacetic acid COX-2 inhibitors useful in treating inflammation and other COX-2 related disorders are defined by Formula XTV or pharmaceutically acceptable salts of the compounds defined by Formula XIV:
  • R is methyl or ethyl; R 71 is chloro or fluoro; R 72 is hydrogen or fluoro; R 73 is hydrogen, fiuoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy; R 74 is hydrogen or fluoro; and R 75 is chloro, fluoro, trifluoromethyl or methyl; pharmaceutically acceptable salts thereof; and pharmaceutically acceptable prodrug esters thereof.
  • Pharmaceutically acceptable prodrug esters are ester derivatives which are convertible by solvolysis or under physiological conditions to the free carboxylic acids of formula XTV. Such esters are e.g.
  • ester prodrugs include 5-alkyl substituted 2- arylaminophenylacetoxyacetic acids.
  • Pharmaceutically acceptable salts represent metal salts, such as alkaline metal salts, e.g. sodium, potassium, magnesium or calcium salts, as well as ammonium salts, which are formed e.g.
  • Compounds of Formula XIV would be useful for, but not limited to, the treatment of cyclooxygenase-2 mediated disorders, such as, the relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, injuries, and following surgical and dental procedures.
  • cyclooxygenase-2 mediated disorders such as, the relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neural
  • R 74 is hydrogen; and R 75 is chloro; pharmaceutically acceptable salts thereof; and pharmaceutically acceptable prodrug esters thereof.
  • arylaminophenylacetic acid COX-2 inhibitor includes the compound depicted below:
  • COX-2 selective inlibitors of the present invention include rofecoxib (Vioxx®), celecoxib (Celebrex®), valdecoxib (Bextra®), meloxicam (Mobic®), lumiracoxib (Prexige®), parecoxib (Dynastat®), and etoricoxib (Arcoxia®).
  • methods of reducing the negative cardiovascular effects associated with the specific above-listed COX-2 inhibitors in a subject may include administering to the subject an effective amount of a pharmaceutically acceptable formulation including a xanthophyll or other carotenoid or a synthetic analog or derivative thereof. Any of the carotenoids or carotenoid derivatives described herein may be used to reduce the negative cardiovascular effects associated with therapeutic administration of the specific above-listed COX-2 inhibitors.
  • a composition may include one or more carote ⁇ oids and one or more COX-2 inhibitors.
  • Carotenoids may include carotenes and xanthophyll carotenoids.
  • carotenoids that may be combined with one or more COX-2 inhibitors include carotenoids having the general structure:
  • each R 3 is independently hydrogen or methyl, and where each R and R 2 are independently:
  • R 4 is hydrogen, methyl, or -CH 2 OH; and where each R 5 is independently hydrogen or -OH.
  • Sources of some of these carotenoids can be found, for exmple, in the reference “Key to Cartenoids", Otto Straub, 2 nd Ed., Birkhauser Verlag, Boston, 1987, which is incorporated herein by reference.
  • carotenoids that may be combined with one or more COX-2 inhibitors include carotenoids having the general structure:
  • carotenoids that may be combined with one or more COX-2 inhibitors include xanthophyll carotenoids having the general structure:
  • R 1 and R 2 are independently:
  • R 4 is -CH 2 -OH; and where each R 5 is independently hydrogen or -OH.
  • carotenoid analogs or derivatives may be employed in "self-formulating" aqueous solutions, in which the compounds spontaneously self-assemble into macromolecular complexes. These complexes may provide stable formulations in terms of shelf life. The same formulations may be parenterally administered, upon which the spontaneous self-assembly is overcome by interactions with serum and/or tissue components in vivo.
  • Some specific embodiments may include phosphate derivatives, succinate derivatives, co-antioxidant derivatives (e.g., Vitamin C, Vitamin C analogs, Vitamin C derivatives, Vitamin E, Vitamin E analogs, Vitamin E derivatives, flavonoids, flavonoid analogs, or flavonoid derivatives), or combinations thereof derivatives or analogs of carotenoids.
  • Flavonoids may include, for example, quercetin, xanthohumol, isoxanthohumol, or genistein.
  • Vitamin E may generally be divided into two categories including tocopherols having a general structure
  • the second category of Vitamin E may include tocotrienols having a general structure
  • Quercetin a flavonoid
  • one or more co-antioxidants may be coupled to a carotenoid or carotenoid derivative or analog.
  • Derivatives of one or more carotenoid analogues may be formed by coupling one or more free hydroxy groups of the co-antioxidant to a portion of the carotenoid.
  • Derivatives or analogs may be derived from any known carotenoid (naturally or synthetically derived).
  • specific examples of naturally occurring carotenoids which compounds described herein maybe derived from include for example zeaxanthin, lutein, lycophyll, astaxanthin, and lycopene.
  • carotenoid analogs or derivatives may have increased water solubility and/or water dispersibility relative to some or all known naturally occurring carotenoids. Contradictory to previous research, improved results are obtained with derivatized carotenoids relative to the base carotenoid, wherein the base carotenoid is derivatized with substituents including hydrophilic substituents and/or co-antioxidants.
  • me caro ⁇ enoid derivatives may include compounds having a structure including a polyene chain (i.e., backbone of the molecule). The polyene chain may include between about 5 and about 15 unsaturated bonds. In certain embodiments, the polyene chain may include between about 7 and about 12 unsaturated bonds. In some embodiments a carotenoid derivative may include 7 or more conjugated double bonds to achieve acceptable antioxidant properties.
  • decreased antioxidant properties associated with shorter polyene chains may be overcome by increasing Ihe dosage administered to a subject or patient.
  • a chemical compound including a carotenoid derivative or analog may have the general structure:
  • Each R 11 may be independently hydrogen or methyl.
  • R 9 and R 10 may be independently H, an acyclic alkene with one or more substituents, or a cyclic ring including one or more substituents.
  • y may be 5 to 12. In some embodiments, y may be 3 to 15. In certain embodiments, the maximum value of y may only be limited by the ultimate size of the chemical compound, particularly as it relates to the size of the chemical compound and the potential interference with the chemical compound's biological availability as discussed herein.
  • substituents may be at least partially hydrophilic. These carotenoid derivatives may be included in a pharmaceutical composition.
  • a method of inhibiting or reducing the at least some of the side effects associated with therapeutic administration of COX-2 selective inhibitors may include administering to the subject an effective amount of a pharmaceutically acceptable formulation including one or more synthetic analogs or derivatives of a carotenoid.
  • the synthetic analog or derivative of the carotenoid may have the structure
  • each R 3 is independently hydrogen or methyl, and where each R 1 and R 2 are independently:
  • R is hydrogen or methyl; where each R 5 is independently hydrogen, -OH, or -OR 6 wherein at least one R 5 group is -OR 6 ; wherein each R 6 is independently: alkyl; aryl; -alkyl-N(R 7 ) 2 ; -aryl-N(R 7 ) 2 ; -alkyl-CO 2 H; -aryl-CO 2 H; -0-C(O)-R 8 ; -P(O)(OR 8 ) 2 ; -S(O)(OR 8 ) 2 ; an amino acid; a peptide, a carbohydrate; -C(O)-(CH 2 ) n -CO 2 R 9 ; a nucleoside reside, or a co-antioxidant; where R 7 is hydrogen, alkyl, or aryl; wherein R 8 is hydrogen, alkyl, aryl, benzyl or a con-antioxidant; where R 9 is hydrogen; alkyl; aryl
  • Each co-antioxidant may be independently Vitamin C, Vitamin C analogs, Vitamin C derivatives, Vitamin E, Vitamin E analogs, Vitamin E derivatives, fiavonoids, flavonoid derivatives, or flavonoid analogs.
  • Flavonoids include, but are not limited to, quercetin, xanthohumol, isoxanthohurnol, or genistein. Selection of the co- antioxidant should not be seen as limiting for the therapeutic application of the current invention.
  • a method of inhibiting or reducing the at least some of the side effects associated with therapeutic administration of COX-2 selective inhibitors may include administering to the subject an effective amount of a pharmaceutically acceptable formulation including one or more synthetic analogs or derivatives of a carotenoid.
  • the synthetic analog or derivative of the carotenoid may have the structure
  • each R 5 is independently hydrogen, -OH, or -OR 6 wherein at least one R 5 group is -OR 6 ; wherein each R 6 is independently: alkyl; aryl; -alkyl-N(R 7 ) 2 ; -aryl-N(R 7 ) 2 ; -alkyl-CO 2 H; -aryl-CO 2 H; -0-C(O)-R 8 ; - P(O)(OR 8 ) 2 ; -S(O)(OR 8 ) 2 ; an amino acid; a peptide, a carbohydrate; -C(O)-(CH 2 ) n -CO 2 R 9 ; a nucleoside reside, or a co-antioxidant; where R 7 is hydrogen, alkyl, or aryl; wherein R 8 is hydrogen, alkyl, aryl, benzyl, or a co-antioxidant; and where R 9 is hydrogen; alkyl; aryl; -P(O
  • R 6 is an amino acid derivative or a peptide
  • coupling of the amino acid or the peptide is accomplished through an ester linkage.
  • the ester linkage may be formed between a free hydroxyl of the xanthophyll carotene and the carboxylic acid of the amino acid or peptide.
  • R 9 is an amino acid derivative or a peptide
  • coupling of the amino acid or the peptide is accomplished through an amide linkage.
  • the amide linkage may be formed between the terminal carboxylic acid group of the linker attached to the xanthophyll carotene and the amine of the amino acid or peptide.
  • R 6 is a sugar
  • R 6 includes, but is not limited to the following side chains:
  • R 13 is hydrogen or -OH.
  • R 6 may have the structure: HO R 13 where R 12 is a purine or pyrimidine base, and R 13 is hydrogen or -OH.
  • the carotenoid analog or derivative may have the structures
  • Each R may be independently H, alkyl, aryl, benzyl, Group IA metal, or a co-antioxidant.
  • Each co-antioxidant may be independently Vitamin C, Vitamin C analogs, Vitamin C derivatives, Vitamin E, Vitamin E analogs, Vitamin E derivatives, flavonoids, flavonoid analogs, or flavonoid derivatives.
  • Flavonoids may include, for example, quercetin, xanthohumol, isoxanthohumol, or genistein.
  • the carotenoid analog or derivative may have the structures
  • Each R may be independently H, alkyl, aryl, benzyl, Group IA metal (e.g., sodium), or a co-antioxidant.
  • Each co- antioxidant may be independently Vitamin C, Vitamin C analogs, Vitamin C derivatives, Vitamin E, Vitamin E analogs, Vitamin E derivatives, flavonoids, flavonoid analogs, or flavonoid derivatives.
  • Flavonoids may include, for example, quercetin, xanthohumol, isoxanthohumol, or genistein.
  • R includes Vitamin C, Vitamin C analogs, or Vitamin C derivatives, some embodiments may include carotenoid analogs or derivatives having the structure
  • Each R may be independently H, alkyl, aryl, benzyl, or Group IA metal.
  • the carotenoid derivative may have the structure:
  • Each R 14 may be independently O or H 2 .
  • Each R may be independently H, alkyl, benzyl, Group IA metal, co-antioxidant, or aryl.
  • carotenoid derivatives include, but are not limited to, the following compounds:
  • Water-soluble carotenoid analogs or derivatives may have a water solubility of greater than about 1 mg/mL in some embodiments. In certain embodiments, water-soluble carotenoid analogs or derivatives may have a water solubility of greater than about 5 mg/mL. In certain embodiments, water-soluble carotenoid analogs or derivatives may have a water solubility of greater than about 10 mg/mL. In certain embodiments, water-soluble carotenoid analogs or derivatives may have a water solubility of greater than about 20 mg/mL. In some embodiments, water- soluble carotenoid analogs or derivatives may have a water solubility of greater than about 50 mg/mL.
  • Naturally occurring carotenoids such as xanthophyll carotenoids of the C40 series, which includes commercially important compounds such as lutein, zeaxanthin, and astaxanthin, have poor aqueous solubility in the native state. Varying the chemical structure(s) of the esterified moieties may vastly increase the aqueous solubility and/or dispersibility of derivatized carotenoids.
  • highly water-dispersible C40 carotenoid derivatives may include natural source i ⁇ itR-lutein ( ⁇ , ⁇ -carotene-3,3'-diol) derivatives.
  • Derivatives may be synthesized by esterification with inorganic phosphate and succinic acid, respectively, and subsequently converted to the sodium salts. Deep orange, evenly colored aqueous suspensions were obtained after addition of these derivatives to USP-purified water.
  • Aqueous dispersibility of the disuccinate sodium salt of natural lutein was 2.85 mg/mL; the diphosphate salt demonstrated a > 10-fold increase in dispersibility at 29.27 mg/mL.
  • Aqueous suspensions may be obtained without the addition of heat, detergents, co-solvents, or other additives.
  • the direct aqueous superoxide scavenging abilities of these derivatives were subsequently evaluated by electron paramagnetic resonance (EPR) spectroscopy in a well-characterized in vitro isolated human neutrophil assay.
  • the derivatives may be potent (millimolar concentration) and nearly identical aqueous-phase scavengers, demonstrating dose-dependent suppression of the superoxide anion signal (as detected by spin-trap adducts of DEPMPO) in the millimolar range.
  • Cellular membranes may be particularly co-evolved with molecules of a length of approximately 30 nm.
  • carotenoid derivatives may be greater than or less than about 30 nm in size.
  • carotenoid derivatives may be able to change conformation and/or otherwise assume an appropriate shape, which effectively enables the carotenoid derivative to efficiently interact with a cellular membrane.
  • alkenes in the E configuration this should not be seen as limiting.
  • Compounds discussed herein may include embodiments where alkenes are in the Z configuration or include alkenes in a combination of Z and E configurations within the same molecule.
  • the compounds depicted herein may naturally convert between the Z and E configuration and/or exist in equilibrium between the two configurations.
  • Carotenoid analogs or derivatives may have increased water solubility and/or water dispersibility relative to some or all known naturally occurring carotenoids.
  • one or more co- antioxidants may be coupled to a carotenoid or carotenoid derivative or analog.
  • carotenoid analogs or derivatives may be employed in "self-formulating" aqueous solutions, in which the compounds spontaneously self-assemble into macromolecular complexes. These complexes may provide stable formulations in terms of shelf life.
  • the same formulations may be parenterally administered, upon which the spontaneous self-assembly is overcome by interactions with serum and/or tissue components in vivo.
  • Some specific embodiments may include phosphate, succinate, co-antioxidant (e.g., Vitamin C, Vitamin C analogs, Vitamin C derivatives, Vitamin E, Vitamin E analogs, Vitamin E derivatives, or flavonoids), or combinations thereof derivatives or analogs of carotenoids.
  • Flavonoids may include, for example, quercetin, xanthohumol, isoxanthohumol, or genistein. Derivatives or analogs may be derived from any known carotenoid (naturally or synthetically derived).
  • carotenoids which compounds described herein may be derived from include for example zeaxanthin, lutein, lycophyll, astaxanthin, and lycopene.
  • the synthesis of water-soluble and/or water-dispersible carotenoids (e.g., C40) analogs or derivatives — as potential parenteral agents for clinical applications may improve the injectability of these compounds as therapeutic agents, a result perhaps not achievable through other formulation methods.
  • the methodology may be extended to carotenoids with fewer than 40 carbon atoms in the molecular skeleton and differing ionic character.
  • the methodology may be extended to carotenoids with greater than 40 carbon atoms in the molecular skeleton.
  • the methodology may be extended to non-symmetric carotenoids.
  • the aqueous dispersibility of these compounds allows proof-of-concept studies in model systems (e.g. cell culture), where the high lipophilicity of these compounds previously limited their bioavailability and hence proper evaluation of efficacy.
  • Esterification or etherification may be useful to increase oral bioavailability, a fortuitous side effect of the esterification process, which can increase solubility in gastric mixed micelles.
  • These compounds upon introduction to the mammalian GI tract, are rapidly and effectively cleaved to the parent, non-esterified compounds, and enter the systemic circulation in that manner and form.
  • the eilect of the intact ester and/or ether compound on the therapeutic endpoint of interest can be obtained with parenteral administration of the compound(s).
  • the net overall effect is an improvement in potential clinical utility for the lipophilic carotenoid compounds as therapeutic agents.
  • a subject may be administered a pharmaceutical composition comprising a carotenoid analog or derivative.
  • the analog or derivative may be broken down according to the following reaction:
  • the principles of retrometabolic drug design may be utilized to produce novel soft drugs from the asymmetric parent carotenoid scaffold (e.g., i ⁇ ?2?-lutein ( ⁇ , ⁇ -carotene-3,3'-diol)).
  • lutein scaffold for derivatization was obtained commercially as purified natural plant source material, and was primarily the if/LR-stereoisomer (one of 8 potential stereoisomers).
  • Lutein (Scheme 1) possesses key characteristics — similar to starting material astaxanthin — which make it an ideal starting platform for retrometabolic syntheses: (1) synthetic handles (hydroxyl groups) for conjugation, and (2) an excellent safety profile for the parent compound.
  • lutein is available commercially from multiple sources in bulk as primarily the RRR- stereoisomer, the primary isomer in the human diet and human retinal tissue.
  • carotenoid analogs or derivatives may have increased water solubility and/or water dispersibiliry relative to some or all known naturally occurring carotenoids.
  • the carotenoid derivatives may include compounds having a structure including a polyene chain (i.e., backbone of the molecule).
  • the polyene chain may include between about 5 and about 15 unsaturated bonds.
  • the polyene chain may include between about 7 and about 12 unsaturated bonds.
  • a carotenoid derivative may include 7 or more conjugated double bonds to achieve acceptable antioxidant properties.
  • decreased antioxidant properties associated with shorter polyene chains may be overcome by increasing the dosage administered to a subject or patient.
  • Some embodiments may include solutions or pharmaceutical preparations of carotenoids and/or carotenoid derivatives combined with co-antioxidants, in particular vitamin C and/or vitamin C analogs or derivatives.
  • Pharmaceutical preparations may include about a 2:1 ratio of vitamin C to carotenoid respectively.
  • co-antioxidants may increase solubility of the chemical compound.
  • co-antioxidants e.g., vitamin C
  • co-antioxidants may decrease toxicity associated with at least some carotenoid analogs or derivatives.
  • co-antioxidants e.g., vitamin C
  • co-antioxidants may increase the potency of the chemical compound synergisiically.
  • Co-antioxidants may be coupled (e.g., a covalent bond) to the carotenoid derivative.
  • Co-antioxidants may be included as a part of a pharmaceutically acceptable formulation.
  • structural carotenoid analogs or derivatives may be generally defined as carotenoids and the biologically active structural analogs or derivatives thereof.
  • “Derivative” in the context of this application is generally defined as a chemical substance derived from another substance either directly or by modification or partial substitution.
  • “Analog” in the context of this application is generally defined as a compound that resembles another in structure but is not necessarily an isomer. Typical analogs or derivatives include molecules which demonstrate equivalent or improved biologically useful and relevant function, but which differ structurally from the parent compounds.
  • Parent carotenoids are selected from the more than 700 naturally occurring carotenoids described in the literature, and their stereo- and geometric isomers.
  • Such analogs or derivatives may include, but are not limited to, esters, ethers, carbonates, amides, carbamates, phosphate esters and ethers, sulfates, glycoside ethers, with or without spacers (linkers).
  • the synergistic combination of more than one xanthophyll carotenoid or structural analog or derivative or synthetic intermediate of carotenoids may be generally defined as any composition including one xanthophyll carotenoid or a structural carotenoid analog or derivative or synthetic intermediate combined with one or more different xanthophyll carotenoids or structural carotenoid analogs or derivatives or synthetic intermediates or co-antioxidants, either as derivatives or in solutions and/or formulations.
  • Certain embodiments may include administering a xanthophyll carotenoid or a structural carotenoid analogs or derivatives or synthetic intermediates alone or in combination to a subject such that at least a portion of the adverse effects of COX-2 selective inhibitor drugs are thereby reduced, inhibited and/or ameliorated.
  • the xanthophyll carotenoid or a structural carotenoid analogs or derivatives or synthetic intermediates may be water- soluble and/or water dispersible derivatives.
  • the carotenoid derivatives may include any substituent that substantially increases the water solubility of the naturally occurring carotenoid.
  • the carotenoid derivatives may retain and/or improve the antioxidant properties of the parent carotenoid.
  • the carotenoid derivatives may retain the non-toxic properties of the parent carotenoid.
  • the carotenoid derivatives may have increased bioavailability, relative to the parent carotenoid, upon administration to a subject.
  • the parent carotenoid may be naturally occurring.
  • compositions may include the administering a composition comprised of the synergistic combination of more than one xanthophyll carotenoids or structural carotenoid analogs or derivatives or synthetic intermediates to a subject such that at least a portion of the adverse effects of COX-2 selective inhibitor drugs are thereby reduced, inhibited and/or ameliorated.
  • the composition may be a "racemic" (i.e. mixture of the potential stereoisomeric forms) mixture of carotenoid derivatives.
  • pharmaceutical compositions comprised of structural analogs or derivatives or synthetic intermediates of carotenoids in combination with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier may be serum albumin.
  • structural analogs or derivatives or synthetic intermediates of carotenoids may be complexed with human serum protein such as, for example, human serum albumin (i.e., HSA) in a solvent.
  • HSA human serum albumin
  • HSA may act as a pharmaceutically acceptable carrier.
  • a single stereoisomer of a structural analog or derivative or synthetic intermediate of carotenoids may be administered to a human subject in order to ameliorate a pathological condition.
  • Administering a single stereoisomer of a particular compound (e.g., as part of a pharmaceutical composition) to a human subject may be advantageous (e.g., increasing me potency of the pharmaceutical composition).
  • Administering a single stereoisomer may be advantageous due to the fact that only one isomer of potentially many may be biologically active enough to have the desired effect.
  • nutraceuticals generally refers to dietary supplements, foods, or medical foods that: 1. possess health benefits generally defined as reducing the risk of a disease or health condition, including the management of a disease or health condition or the improvement of health; and 2. are safe for human consumption in such quantity, and with such frequency, as required to realize such properties.
  • a nutraceutical is any substance that is a food or a part of a food and provides medical or health benefits, including the prevention and treatment of disease.
  • Such products may range from isolated nutrients, dietary supplements and specific diets to genetically engineered designer foods, herbal products, and processed foods such as cereals, soups and beverages.
  • this definition applies to all categories of food and parts of food, ranging from dietary supplements such as folic acid, used for the prevention of spina bifida, to chicken soup, taken to lessen the discomfort of the common cold.
  • This definition also includes a bio-engineered designer vegetable food, rich in antioxidant ingredients, and a stimulant functional food or pharmafood.
  • nutraceuticals may also be composed, used, and/or delivered in a similar manner where appropriate.
  • the xanthophyll carotenoid, carotenoid derivative or analog may be administered at a dosage level up to conventional dosage levels for xanthophyll carotenoids, carotenoid derivatives or analogs, but will typically be less than about 2 gmper day. Suitable dosage levels may depend upon the overall systemic effect of the chosen xanthophyll carotenoids, carotenoid derivatives or analogs, but typically suitable levels will be about 0.001 to 50 mg/kg body weight of the patient per day, from about 0.005 to 30 mg/kg per day, or from about 0.05 to 10 mg/kg per day.
  • the compound may be administered on a regimen of up to 6 times per day, between about 1 to 4 times per day, or once per day.
  • a suitable dosage range is, e.g. from about 0.01 mg to about 100 mg of a xanthophyll carotenoid, carotenoid derivative or analog per kg of body weight per day, preferably from about 0.1 mg to about 10 mg per kg and for cytoprotective use from 0.1 mg to about 100 mg of a xanthophyll carotenoid, carotenoid derivative or analog per kg of body weight per day.
  • compositions may include all compositions of 1.0 gram or less of a particular structural carotenoid analog, in combination with 1.0 gram or less of one or more other structural carotenoid analogs or derivatives or synthetic intermediates and/or co-antioxidants, in an amount which is effective to achieve its intended purpose. While individual subject needs vary, determination of optimal ranges of effective amounts of each component is with the skill of the art.
  • a structural carotenoid analog or derivative or synthetic intermediates may be administered to mammals, in particular humans, orally at a dose of 5 to 100 mg per day referenced to the body weight oi tne mammal or human being treated for a particular disease.
  • a structural carotenoid analog or derivative or synthetic intermediate may be administered to mammals, in particular humans, parenterally at a dose of between 5 to 1000 mg per day referenced to the body weight of the mammal or human being treated for a particular disease.
  • about 100 mg of a structural carotenoid analog or derivative or synthetic intermediate is either orally or parenterally administered to treat or prevent disease.
  • the unit oral dose may comprise from about 0.25 mg to about 1.0 gram, or about 5 to 25 mg, of a structural carotenoid analog.
  • the unit parenteral dose may include from about 25 mg to 1.0 gram, or between 25 mg and 500 mg, of a structural carotenoid analog.
  • the unit intracoronary dose may include from about 25 mg to 1.0 gram, or between 25 mg and 100 mg, of a structural carotenoid analog.
  • the unit doses may be administered one or more times daily, on alternate days, in loading dose or bolus form, or titrated in a parenteral solution to commonly accepted or novel biochemical surrogate marker(s) or clinical endpoints as is with the skill of the art.
  • the compounds may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers, preservatives, excipients and auxiliaries which facilitate processing of the structural carotenoid analog or derivative or synthetic intermediates which may be used pharmaceutically.
  • preparations particularly those preparations which may be administered orally and which may be used for the preferred type of administration, such as tablets, softgels, lozenges, dragees, and capsules, and also preparations which may be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally or by inhalation of aerosolized preparations, may be prepared in dose ranges that provide similar bioavailability as described above, together with the excipient. While individual needs may vary, determination of the optimal ranges of effective amounts of each component is within the skill of the art.
  • the COX-2 selective inhibitor and the xanthophyll carotenoid, carotenoid derivative or analog may be administered separately in separate dosage forms or together in a single unit dosage form.
  • the xanthophylls carotenoid, carotenoid derivative or analog and the COX-2 selective inhibitor can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e, sequentially, and in any order.
  • the xanthophyll carotenoid, carotenoid derivative or analog and the COX-2 selective inhibitor can be co-administered concurrently on a once-a-day (QD) dosing schedule; however, varying dosing schedules, such as the xanthophyll carotenoid, carotenoid derivative or analog once per day and the COX-2 selective inhibitor once, twice or more times per day, or the COX-2 selective inhibitor once per day and the xanthophyll carotenoid, carotenoid derivative or analog once, twice or more times per day, is also encompassed herein.
  • QD once-a-day
  • a single oral dosage formulation comprising the xanthophyll carotenoid, carotenoid derivative or analog and the COX-2 selective inhibitor may be preferred.
  • a single dosage formulation will provide convenience for the patient.
  • the COX-2 selective inhibitor may be administered at a dosage level up to conventional dosage levels for NSAIDs. Suitable dosage levels will depend upon the anti-inflammatory effect of the chosen inhibitor of cyclooxygenase-2, but typically suitable levels will be between about 0.001 to 50 mg/kg body weight of the patient per day, between about 0.005 to 30 mg/kg per day, or between about 0.05 to 10 mg/kg per day. In some embodiments, the compound may De administered on a regimen of up to 6 times per day, from 1 to 4 times per day, or once per day.
  • a suitable dosage range is, e.g. from about 0.01 mg to about 100 mg of a COX-2 selective inhibitor per kg of body weight per day, or from about 0.1 mg to about 10 mg per kg of a COX-2 selective inhibitor per kg of body weight per day.
  • Any suitable route of administration may be employed for providing a patient with an effective dosage of drags of the present invention.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like maybe employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compositions may include those compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (aerosol inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
  • the drugs used in the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulisers.
  • the compounds may also be delivered as powders which may be formulated and the powder composition may be inhaled with the aid of an insufflation powder inhaler device.
  • Suitable topical formulations for use in the present embodiments may include transdermal devices, aerosols, creams, ointments, lotions, dusting powders, and the like.
  • drugs used can be combined as the active ingredient in ultimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • oral liquid preparations such as, for example, suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • the pharmaceutical preparauo ⁇ s may be manufactured in a manner which is itself known to one skilled in the art, for example, by means of conventional mixing, granulating, dragee-making, softgel encapsulation, dissolving, extracting, or lyophilizing processes.
  • pharmaceutical preparations for oral use may be obtained by combining the active compounds with solid and semi-solid excipients and suitable preservatives, and/or co- antioxidants.
  • the resulting mixture may be ground and processed.
  • the resulting mixture of granules may be used, after adding suitable auxiliaries, if desired or necessary, to obtain tablets, softgels, lozenges, capsules, or dragee cores.
  • Suitable excipients may be fillers such as saccharides (e.g., lactose, sucrose, or mannose), sugar alcohols (e.g., mannitol or sorbitol), cellulose preparations and/or calcium phosphates (e.g., tricalcium phosphate or calcium hydrogen phosphate).
  • binders may be used such as starch paste (e.g., maize or corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylniethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone).
  • Disintegrating agents may be added (e.g., the above- mentioned starches) as well as carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof (e.g., sodium alginate).
  • Auxiliaries are, above all, flow-regulating agents and lubricants (e.g., silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol, or PEG).
  • Dragee cores are provided with suitable coatings, which, if desired, are resistant to gastric juices.
  • Softgelatin capsules are provided with suitable coatings, which, typically, contain gelatin and/or suitable edible dye(s).
  • animal component-free and kosher gelatin capsules may be particularly suitable for the embodiments described herein for wide availability of usage and consumption.
  • concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol (PEG) and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures, including dimethylsulfoxide (DMSO), tetrahydrofuran (THF), acetone, ethanol, or other suitable solvents and co-solvents.
  • DMSO dimethylsulfoxide
  • THF tetrahydrofuran
  • acetone acetone
  • ethanol or other suitable solvents and co-solvents.
  • cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate
  • Dye staffs or pigments may be added to the tablets or dragee coatings or softgelatin capsules, for example, for identification or in order to characterize combinations of active compound doses, or to disguise the capsule contents for usage in clinical or other studies.
  • compositions that may be used orally include push-fit capsules made of gelatin, as well as soft, thermally sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.
  • the push-fit capsules may contain the active compounds in the form of granules that may be mixed with fillers such as, for example, lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers and/or preservatives.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils such as rice bran oil or peanut oil or palm oil, or liquid paraffin.
  • stabilizers and preservatives may be added.
  • pulmonary administration of a pharmaceutical preparation may be desirable.
  • Pulmonary administration may include, for example, inhalation of aerosolized or nebulized liquid or solid particles of the pharmaceutically active component dispersed in and surrounded by a gas.
  • Possible pharmaceutical preparations which may be used rectally, include, for example, suppositories, which consist of a combination of the active compounds with a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons.
  • gelatin rectal capsules that consist ot a combination of the active compounds -with a base.
  • Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
  • Suitable formulations for parenteral administration include, but are not limited to, aqueous solutions of the active compounds in water-soluble and/or water dispersible form, for example, water-soluble salts, esters, carbonates, phosphate esters or ethers, sulfates, glycoside ethers, together with spacers and/or linkers.
  • Suspensions of the active compounds as appropriate oily injection suspensions may be administered, particularly suitable for intramuscular injection.
  • Suitable lipophilic solvents, co-solvents (such as DMSO or ethanol), and/or vehicles including fatty oils, for example, rice bran oil or peanut oil and/or palm oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides, may be used.
  • Aqueous injection suspensions may contain substances that increase the viscosity of the suspension including, for example, sodium carboxymethyl cellulose, sorbitol, dextran, and/or cyclodextrins. Cyclodextrins (e.g., ⁇ -cyclodextrin) may be used specifically to increase the water solubility for parenteral injection of the structural carotenoid analog.
  • Liposomal formulations in which mixtures of the structural carotenoid analog or derivative with, for example, egg yolk phosphotidylcholine (E-PC), may be made for injection.
  • the suspension may contain stabilizers, for example, antioxidants such as BHT, and/or preservatives, such as benzyl alcohol.
  • the compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • the dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.
  • a physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress or the development of cardiovascular complications associated with the a administration of COX-2 selective inhibitor drugs.
  • the daily oral dosage of each active ingredient when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, between about 0.01 to 100 mg/kg of body weight per day, or between about 1.0 to 20 mg/kg/day.
  • Intravenously administered doses may range from about 1 to about 10 mg/kg/minute during a constant rate infusion.
  • Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four or more times daily.
  • the pharmaceutical compositions described herein may further be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as "pharmacologically inert carriers") suitably selected with respect to the intended form of administration, teat is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • suitable pharmaceutical diluents, excipients, or carriers suitably selected with respect to the intended form of administration, teat is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • the pharmacologically active component may be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;
  • an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like
  • the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • the compounds of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • soluble polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyhnethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with pahnitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
  • Dosage forms suitable for administration may contain from about 1 milligram to about 100 milligrams or more of active ingredient per dosage unit.
  • the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
  • Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
  • citric acid and its salts and sodium EDTA are also used.
  • parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
  • Natural source lutein (90%) was obtained from ChemPacific, Inc. (Baltimore, MD) as a red-orange solid and was used without further purification. All other reagents and solvents used were purchased from Acros (New Jersey, USA) and were used without further purification. All reactions were performed under N 2 atmosphere. All flash chromatographic purifications were performed onNatland International Corporation 230-400 mesh silica gel using the indicated solvents.
  • Tribenzyl phosphite 4. To a well-stirred solution of phosphorus trichloride (1.7 mL, 19.4 mmol) in Et 2 O (430 mL) at 0 0 C was added dropwise a solution of triethylamine (8.4 mL, 60.3 mmol) in Et 2 O (20 mL), followed by a solution of benzyl alcohol (8.1 mL, 77.8 mmol) in Et 2 O (20 mL). The mixture was stirred at 0 0 C for 30 min and then at RT overnight. The mixture was filtered and the filtrate concentrated to give a colorless oil.
  • Dibenzyl phosphoroiodidate 5.
  • UV/Vis spectroscopy at 436 nm, and the absorbance was compared to a standard curve compiled from 4 standards of known concentration.
  • concentration of the original supernatant was calculated to be 2.85 mg/mL and the absorptivity was 36.94 AU*mL/cm*mg. Slight error may have been introduced by the small size of the original aliquot.
  • 30.80 mg of 9 was added to 1 mL of USP-purified water. The sample was rotated for 2 hours, then centrifuged for 5 minutes. After centrifuging, solid was visible in the bottom of the tube. A 125- ⁇ L aliquot of the solution was then diluted to 25 mL.
  • the sample was analyzed by UV/Vis spectroscopy at 411 nm, and the absorbance was compared to a standard curve compiled from 4 standards of known concentration.
  • concentration of the original supernatant was calculated to be 29.27 mg/mL and the absorptivity was 2.90 AU*mL/cm*mg. Slight error may have been introduced by the small size of the original aliquot.
  • Leukocyte Isolation and Preparation Human polymorphonuclear leukocytes (PMNs) were isolated from freshly sampled venous blood of a single volunteer (S.F.L.) by Percoll density gradient centrifugation as described previously.
  • each 10 mL of whole blood was mixed with 0.8 mL of 0.1 M EDTA and 25 mL of saline.
  • the diluted blood was then layered over 9 mL of Percoll at a specific density of 1.080 g/mL. After centrifugation at 400 x g for 20 min at 20 0 C, the plasma, mononuclear cell, and Percoll layers were removed. Erythrocytes were subsequently lysed by addition of 18 mL of ice-cold water for 30 s, followed by 2 mL of 10x PIPES buffer (25 mM PIPES, 110 mM NaCl, and 5 mM KCl, titrated to pH 7.4 with NaOH).
  • FIG. 2 depicts a tune series of the UV/Vis absorption spectra of the disodium disuccinate derivative of natural source lutein in water.
  • Existence of head-to-tail (J-type) aggregation in solution cannot be ruled out.
  • DMSO more polarizable solvent
  • the ⁇ 3x increases to 446 nm at an EtOH concentration ot ⁇ -47O, at wmcn point u ⁇ iui ther shift of the absorption maximum occurs (i.e. a molecular solution has been achieved), identical to that obtained in 100% EtOH (See FIG. 3).
  • FIG. 5 depicts a time series of the UV/Vis absorption spectra of the disodium diphosphate derivative of natural source lutein in water. Loss of vibrational fine structure (spectral distribution beginning to approach unimodality) and the blue-shifted lambda max relative to the lutein chromophore in EtOH suggested that card-pack aggregation was present immediately upon solvation.
  • the ⁇ max (428 run) obtained at time zero did not appreciably blue-shift over the course of 24 hours, and the spectra became slightly more hypochromic over time (i.e. decreased in absorbance intensity), indicating additional time-dependent supramolecular assembly (aggregation) of the card-pack type during this time period. This spectrum was essentially maintained over the course of 24 hours (compare with FIG. 2, disuccinate lutein sodium salt).
  • a red-shift was observed (X m3x to 446 nm), as was observed with the disuccinate derivate.
  • Wetting of the diphosphate lutein derivative with a small amount of water was required to obtain appreciable solubility in organic solvent (e.g. EtOH and DMSO).
  • Spectra were obtained at time zero.
  • the expected bathochromic shift (in this case to 459 nm) of the spectrum in the more polarizable solvent (95% DMSO) is seen. Increased vibrational fine structure and red-shifting of the spectra were observed in the organic solvents.
  • Direct superoxide anion scavenging by EPR spectroscopy The mean percent inhibition of superoxide anion signal ( ⁇ SEM) as detected by DEPMPO spin-trap by the disodium disuccinate derivative of natural source lutein (tested in water) is shown in FIG. 8.
  • a 100 ⁇ M formulation (0.1 niM) was also tested in 40% EtOH, a concentration shown to produce a molecular (i.e. non-aggregated) solution.
  • concentration of the derivative increased, inhibition of superoxide anion signal increased in a dose-dependent manner.
  • approximately % (75%) of the superoxide anion signal was inhibited.
  • No significant scavenging (0% inhibition) was observed at 0.1 mM in water.
  • Addition of 40% EtOH to the derivative solution at 0.1 mM did not significantly increase scavenging over that provided by the EtOH vehicle alone (5% inhibition).
  • the mean percent inhibition of superoxide anion signal ( ⁇ SEM) as detected by DEPMPO spin-trap by the disodium diphosphate derivative of natural source lutein (tested in water) is shown in FIG. 9.
  • a 100 ⁇ M formulation (0.1 mM) was also tested in 40% EtOH, a concentration also shown to produce a molecular (i.e. non- aggregated) solution of this derivative.
  • concentration of the derivative increased, inhibition of the superoxide anion signal increased in a dose-dependent manner.
  • 5 mM slightly more than 90% of the superoxide anion signal was inhibited, (versus /D7o ior me uisuccinate lutein sodium salt).
  • disuccinate lutein sodium salt As for the disuccinate lutein sodium salt, no apparent scavenging (0% inhibition) was observed at 0.1 mM in water. However, a significant increase over background scavenging by the EtOH vehicle (5%) was observed after the addition of 40% EtOH , resulting in a mean 18% inhibition of superoxide anion signal. This suggested that disaggregation of the compound lead to an increase in scavenging ability by this derivative, pointing to slightly increased scavenging ability of molecular solutions of the more water-dispersible diphosphate derivative relative to the disuccinate derivative. Again, the millimolar concentration scavenging by the derivative was accomplished in water alone, without the addition of organic co-solvent (e.g., acetone, EtOH), heat, detergents, or other additives.
  • organic co-solvent e.g., acetone, EtOH
  • Table IL Descriptive statistics of mean % inhibition of superoxide anion signal for aqueous and ethanolic (40%) formulations of disodium diphosphate derivatives of natural source lutein tested in the current study. Sample sizes of 3 were evaluated for each formulation, with the exception of lutein diphosphate in water at 100 ⁇ M (0.1 mM) where N I. Mean % inhibition of superoxide anion signal increased in a dose-dependent manner as the concentration of lutein diphosphate was increased in the test assay. At 100 ⁇ M in water, no inhibition of scavenging was seen.
  • Astaxanmin ⁇ u.- ⁇ rans 35,3 'S; chiral purity > 97%) was synthesized by Synchem, Inc. (Des Plaines, IL; patents pending) and supplied by Hawaii Biotech, Inc. (HBI).
  • Other chemical reagents and all drugs were purchased from independent commercial sources, including Sigma (St. Louis, MO), Acros Organics (Morris Plains, NJ), and Calbiochem (San Diego, CA).
  • drugs and sulfone compounds methyl phenyl sulfone, dimethyl sulfone
  • Lipids were stored at -8O 0 C in HPLC-grade chloroform.
  • thiobarbituric-acid- reactive-substances Purified LDL (100 ⁇ g protein/ml) was incubated for 30 minutes with either vehicle or an NSAID at various concentrations followed by addition of 50 ⁇ M CuSO 4 at 37 0 C.
  • Conjugated diene formation was measured by continuously monitoring the change in absorbance at 234 nm on a Beckman DU 640 spectrophotometer, as described by Esterbauer et al., 1985. Stock solutions were tested for iron contamination, which can contribute independently to lipid peroxidation and assay artifacts.
  • the lipid vesicles also contained cholesterol at a level that reproduced physiologic conditions (0.2 cholesterol to phospholipid mole ratio).
  • the drug effects were tested in the vesicles following addition of astaxanthin, rofecoxib or the combination of these two agents at an identical concentration (250 nM).
  • LOOH lipid peroxide
  • This reaction takes place in the presence of LOOH in a manner that can be measured photometrically at 365 nm, El-Saadani, 1989.
  • This assay is sensitive to peroxide concentrations as low as 10 ⁇ M and has the further advantage in that it does not require the use of exogenous peroxide radical initiators.
  • the lipid peroxidation reaction occurs gradually under normal atmospheric oxygen conditions in a shaking water bath (37 0 C).
  • F 2 -Isoprostanes are derived principally from the formation of positioned peroxyl radical isomers of arachidonic acid, endocyclization to protaglandin G 2 -like structures, and reduction to PGF 2 -like compounds.
  • F 2 -Isoprostane formation was also measured independently using mass spectroscopy in a blinded study at the Antioxidant Research Laboratory, Tufts University, Boston, MA.
  • the comparative effect of COX-2 selective agents on the antioxidant capacity of human plasma was assessed using the Oxygen Radical Absorption Capacity (ORAC) assay.
  • ORAC Oxygen Radical Absorption Capacity
  • MLVs multilamellar lipid vesicles
  • POPC phospholipid
  • Small-angle x-ray diffraction approaches were used to examine the effects of COX-2 inhibitors on the time- averaged molecular structure of lipids in vascular cell-like membranes.
  • X-ray diffraction experiments were conducted by aligning the samples at grazing incidence with respect to a collimated x-ray source. Corrected diffraction orders obtained from samples in this study were analyzed using Fourier summation to yield one- dimensional electron density profiles (A versus electrons/A 3 ) of the membrane lipid bilayer.
  • Rofecoxib Increases the Susceptibility of Human LDL to Oxidative Modification: Comparison to other COX- 2 Inhibitors and NSADDs Minimally modified or oxidized LDL has an essential role in atherosclerotic plaque instability by contributing to mechanisms of endothelial dysfunction and inflammation. We evaluated the effects of rofecoxib on rates of lipid peroxidation in isolated human LDL and lipid vesicles enriched with polyunsaturated fatty acids (e.g., arachidonic acid).
  • polyunsaturated fatty acids e.g., arachidonic acid
  • Lipid peroxidation in these various biological preparations was monitored and compared to other selective (rofecoxib, etoricoxib, celecoxib, valdecoxib), preferential (meloxicam) and non-selective (ibuprofen, naproxen, diclofenac) COX inhibitors under identical conditions.
  • the activity of rofecoxib was also compared to sulfone analogs, including methyl phenyl sulfone and dimethyl sulfone.
  • rofecoxib significantly (p ⁇ 0.001) decreased the lag time for human LDL conjugated diene formation by 42.8 ⁇ 1.5% at 100 nM (FIG. 10A). This pronounced effect on the rate of conjugated diene formation indicates that rofecoxib has potent pro-oxidant activity, as evidenced by depleted LDL antioxidant capacity.
  • conjugated diene formation we also measured the formation of reactive aldehydes, especially maion ⁇ iaiueuyde (MDA). Consistent with its effect on conjugated diene formation, rofecoxib and etoricoxib also caused marked increases in MDA levels.
  • Isoprostanes are prostaglandin isomers that can be generated non-enzymatically by free radical modification of arachidonic acid associated with phospholipid in LDL and cellular membranes.
  • F 2 -isoprostanes have been specifically identified in atherosclerotic plaques and oxidized LDL levels have been correlated with severity of acute coronary syndromes and plaque instability.
  • DAPC arachidonic acid
  • C max the maximum plasma concentration for celecoxib at an approved 200 mg dose is 1.85 ⁇ M (705 ng/ml).
  • rofecoxib an approved dose of 25 mg results in a plasma concentration of 658 nM (207 ng/ml).
  • astaxanthin a 100 mg oral 'racemic' dose results in a maximum plasma concentration of 2.18 ⁇ M (1.3 mg/L; ⁇ sterlie et al. 2000).
  • Astaxanthin (3,3'-dihydroxy- ⁇ , ⁇ '-carotene-4,4'-dione) is a carotenoid with significant antioxidant activity, even as compared to other compounds in this class.
  • This highly lipophilic molecule reduces oxidative damage to biological lipids by quencning singiet oxygen ana scavenging free radicals.
  • the chemical basis for its activity is a 40-carbon polyene chromophore terminated by cyclic end groups with oxygen-containing polar substituents.
  • the polar terminal groups allow for a preferred membrane orientation that facilitates its scavenging properties. It has no pro-vitamin A activity in mammals (Jyonouchi et al. 2000).
  • astaxanthin was able to completely inhibit the adverse effects of rofecoxib on lipid peroxidation when added together with rofecoxib at an equimolar concentration (decrease in lipid peroxidation of 6.5 %; p ⁇ 0.01 vs control).
  • the presence of rofecoxib produced a decrease in electron density in the hydrocarbon core, 0-10 A from the membrane center, a change similar to that associated with thermal heating or oxidative damage to the membrane.
  • the pro-oxidant activity of rofecoxib may be related, in part, to physico-chemical changes in lipid structure, as opposed to electron transfer mechanisms associated with the sulfone group.
  • celecoxib to the phospholipid bilayer produced an increase in electron density associated with the upper hydrocarbon core of the membrane, 5-20 A from the center of the membrane.
  • a portion of the lipophilic celecoxib molecule being associated with the phospholipid acyl chains, adjacent to the headgroup region.
  • the location of rofecoxib in the phospholipid headgroup region caused disordering of the phospholipid acyl chain.
  • the alteration in the intermolecular packing of the lipid molecules may facilitate the propagation of free radicals.
  • celecoxib had a well-defined location in the membrane hydrocarbon core; a position consistent with its highly lipophilic properties. The equilibrium position of the celecoxib molecule did not cause a disordering in the lipid molecules.
  • the covalent structure of celecoxib includes a trifluoromethly group, a substituent associated with hydrophobic properties that may underlie the membrane location and high volume of distribution for celecoxib (400 L). These differences in the molecular membrane interactions of the COX-2 inhibitors may contribute to their distinct physico-chemical effects on lipid peroxidation (FIG. 13).
  • a mechanistic basis for cardiotoxicity with rofecoxib can be attributed to its distinct chemical properties and pro-oxidant activity (FIG. 14).
  • Rofecoxib readily forms a highly reactive maleic anhydride derivative capable of reacting with, various biological targets, including PUFAs, to form atherogenic reactive aldehydes and isoprostanes. This has been experimentally demonstrated with rofecoxib at low concentrations in isolated samples of human LDL and biological lipids.
  • This method has several advantages over the conventional assays, and makes the present model study more valid from the physiological point of view.
  • POPC l-Palmitoyl ⁇ -Oleoyl-sn-Glycero-S-Phosphocholine
  • Astaxanthin (a31-trans-3S,3'S): Albany Molecular Research, Inc., Lot # MY966-Z, FW 596.84, concentration 500 ⁇ M in chloroform. Drug was stored at -20 0 C.
  • This assay is based on the principle of the oxidative capacity of lipid peroxides to convert I 2 to I 3 " (triiodide), which can be measured photometrically at 365 nm (El-Saadani et al., 1989). This assay is sensitive to peroxide concentration as low as 10 ⁇ M.
  • test samples were incubated about 6 hours in darkness at ambient temperature.
  • the absorbance (A 365 nm) of the samples was measured using a spectrophotometer.
  • Table V Effects of Carotenoids at Two Different Concentrations on Lipid Peroxidation (24 Hour)
  • Multi-lamellar vesicles were prepared by the method developed by Bangham and Standish (1965). After samples were removed from the vacuum desiccator, they were immediately resuspended in 400 ⁇ l of diffraction buffer warmed to room temperature and vortexed for 3 minutes to form MLVs.
  • Each sedimentation cell consists of a solid base and a hollow cylindrical top between which is fastened a thin aluminum foil substrate, positioned to collect the membrane sample pellet upon centrifugation.
  • Membrane samples were centrifuged in a Sorvall AH-629 swinging bucket ultracentrifuge rotor (Dupont Corp., Wilmington, DE) at 35,000 x g for 1 hour at 5 0 C.
  • sample supernatants were aspirated followed by disassembly of the sedimentation cells; aluminum foil substrates, supporting the membrane pellets, were removed and mounted onto curved glass supports.
  • the fixed geometry beamline utilized a single Franks mirror providing nickel-filtered radiation (K ⁇ i and Ka 2 unresolved) at the detection plane.
  • Diffraction data were collected on a one-dimensional, position-sensitive electronic detector (Innovative Technologies, Newburyport, MA), calibrated using cholesterol monohydrate crystals.
  • the sample-to-detector distance for this experiment was set to 150 mm.
  • the unit cell periodicity, or d space, of the membrane lipid bilayer is the measured distance from the center of one lipid bilayer to the next, including surface hydration.
  • the d spaces for the membrane multibilayer samples were calculated using Bragg' s Law.
  • h is the diffraction order number
  • ⁇ is the wavelength of the x-ray radiation (1.54 A)
  • d is the membrane lipid bilayer unit cell periodicity
  • ⁇ is the Bragg angle equal to one-half the angle between the incident beam and scattered beam.
  • Multi-lamellar vesicles were prepared by the method developed by Bangham and Standish (1965). 5 After samples were removed from the vacuum desiccator, they were immediately resuspended in 1 ml of diffraction buffer warmed to room temperature and vortexed for 3 minutes to form MLVs.
  • This assay is based on the principle of the oxidative capacity of lipid peroxides to convert I 2 to I 3 " (triiodide), 0 which can be measured photometrically at 365 nm (el-Saadani et al., 1989). This assay is sensitive to peroxide concentrations as low as 10 ⁇ M.
  • test samples were incubated for about 6 hours in darkness at ambient temperature.
  • FIG. 15 shows representative membrane electron density profiles that were generated from the small angle x-ray diffraction data. To understand the effects of the carotenoids on membrane structure, the electron density profiles were superimposed on the same scale. With the exception of astaxanthin, all of the carotenoids alter membrane structure, but to different extents at a C/P of 0.2 (FIG. 15A).
  • the carotenoids altered the electron density associated with the membrane hydrocarbon core over a broad range ( ⁇ 10 A from the center of the membrane).
  • the changes indicate that the compounds are disrupting the intermolecular packing of the phospholipids acyl chains near the membrane center.
  • the greatest disordering effect was observed with lycopene, followed by ⁇ -carotene, lutein, and zeaxanthin (FIG. 15A).
  • lycopene followed by ⁇ -carotene, lutein, and zeaxanthin (FIG. 15A).
  • ⁇ -carotene, lutein, and zeaxanthin FIG. 15A
  • cholesterol In addition to its ability to increase membrane order, cholesterol is also known to promote peroxidation and change the drug partition coefficients in membranes. These factors might contribute to the lack of correlation between membrane disordering and antioxidant properties of the carotenoids observed in the more ordered membrane system.

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Abstract

L'administration de caroténoïdes, et notamment de caroténoïdes de xanthophylle, ou d'analogues ou de dérivés de l'astaxanthine, lutéine, zéaxanthine, lycoxanthine, lycophylle ou lycopène à un sujet subissant un traitement avec des médicaments inhibiteurs de COX-2 permet de réduire au moins une partie des effets secondaires associés à l'administration des médicaments inhibiteurs sélectifs de COX-2. Les caroténoïdes, ou des analogues ou des dérivés de ceux-ci, peuvent être administrés à un sujet avant, simultanément ou après le début de la thérapie utilisant des médicaments inhibiteurs sélectifs de COX-2. Les caroténoïdes, ou des analogues ou des dérivés de ceux-ci, peuvent être administrés à un sujet simultanément avec la thérapie utilisant des médicaments inhibiteurs sélectifs de COX-2. Les caroténoïdes, ou des analogues ou des dérivés de ceux-ci, peuvent être incorporés à une préparation pharmaceutique en combinaison avec les médicaments inhibiteurs sélectifs de COX-2 ou séparément. L'administration des analogues ou des dérivés précités peut réduire la peroxydation du LDL et d'autres lipides dans les membranes cellulaires du sérum et du plasma des sujets soumis à une thérapie utilisant des médicaments inhibiteurs sélectifs de COX-2. L'administration des analogues ou des dérivés précités peut réduire l'incidence d'événements cardio-vasculaires cliniques préjudiciables dans le cas d'une thérapie utilisant des médicaments inhibiteurs sélectifs de COX-2.
EP06758837A 2005-05-02 2006-05-02 Utilisation de carotenoides et/ou de derives/analogues de carotenoides dans la reduction/inhibition de certains effets negatifs des inhibiteurs de cox Withdrawn EP1890729A2 (fr)

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