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Methods for reducing or preventing transplant rejection in the eye of an individual are described, comprising: a) performing an ocular transplant procedure; and b) implanting in the eye a bioerodible drug delivery system comprising an immunosuppressive agent and a bioerodible polymer.
1. A method for treating edema in an eye of an individual, comprising: placing a bioerodible drug delivery system comprising dexamethasone and a bioerodible polymer in an eye of an individual, thereby treating edema of the eye of the individual.
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This application is a Divisional of co-pending application Ser. No. 11/738,409, filed on Apr. 20, 2007, which is a Divisional of co-pending application Ser. No. 11/180,079 filed on Jul. 11, 2005, which is a continuation application of U.S. application Ser. No. 09/997,094, filed Nov. 28, 2001, now U.S. Pat. No. 6,699,493, which claims the benefit of U.S. Provisional Application No. 60/250,023, filed Nov. 29, 2000 and U.S. Provisional Application No. 30/298,253, filed Jun. 12, 2001, the entire contents of all are hereby incorporated by reference.
This invention relates to the field of transplantation, in particular transplantation of components of the eye, and methods for preventing transplant rejection.
Certain conditions and diseases of the eye, such as corneal failure, keratoconus, corneal dystrophies, scarring, age related macular degeneration (AMD) and retinitis pigmentosa, have been treated using ocular transplant procedures such as corneal and retinal pigment epithelial (RPE) transplants. Transplant rejection is one of the problems which may arise from transplant procedures (Enzmann V et al. (1998). "Immunological problems of transplantation into the subretinal space." Acta Anal (Basel). 162(2-3): 178-83). In spite of the overall success with corneal transplants, a substantial percentage of corneal grafts experience at least one rejection episode (PCT/US97/21393).
One of the problems with present immunosuppressive drug therapy is the inability to achieve adequate intraocular drug concentrations. Systemic immunosuppression may require prolonged exposure to high plasma concentrations so that therapeutic levels can be achieved in the eye. Overall drug delivery to the eye may be poor due to the short drug plasma half-life limiting exposure into intraocular tissues. In addition, this may turn lead to numerous negative side effects.
There is a continued need for improved intraocular sustained release drug therapies for patients following ocular transplant procedures.
All references cited in this patent are incorporated herein by reference in their entirety.
One embodiment of the present invention provides a method for reducing or preventing transplant rejection in the eye of an individual, where the method comprises: a) performing an ocular transplant procedure; and b) implanting in the eye a bioerodible drug delivery system comprising an immunosuppressive agent and a bioerodible polymer.
Another embodiment of the invention provides a method for reducing or preventing transplant rejection in the eye of an individual, where the method comprises: a) performing an ocular transplant procedure; and b) implanting a solid body into the eye, said body comprising particles of an immunosuppressive agent entrapped within a bioerodible polymer, whereby said agent is released from the body by erosion of the polymer.
Another embodiment of the invention provides a method which includes placing in an eye of an individual a bioerodible drug delivery system, where the bioerodible drug delivery system includes an immunosuppressive agent and a bioerodible polymer; and where the eye of the individual has undergone or is undergoing an ocular transplant procedure. This method may be used to reduce or prevent transplant rejection.
Another embodiment of the invention provides a kit comprising: a) a bioerodible drug delivery system comprising an immunosuppressive agent and a bioerodible polymer, wherein the drug delivery system is designed to be implanted in the eye; and b) instructions for use. This kit may be used to reduce or prevent transplant rejection.
An "ocular transplant procedure," as used herein, refers to any transplant procedure performed in the eye. Non-limiting examples of ocular transplant procedures include, but are not limited to, retinal pigment epithelium (RPE) transplant and cornea transplant. It includes autograft, allograft and xenograft transplant procedures.
"Immunosuppressive agent," "agent," "immunosuppressive drug," and "drug," are used interchangeably herein, and refer to any agent which inhibits or prevents an immune response against the transplanted tissue following a transplant procedure. Exemplary agents include, but are not limited to, dexamethasone, cyclosporin A, azathioprine, brequinar, gusperimus, 6-mercaptopurine, mizoribine, rapamycin, tacrolimus (FK-506), folic acid analogs (e.g., denopterin, edatrexate, methotrexate, piritrexim, pteropterin, Tomudex�, trimetrexate), purine analogs (e.g., cladribine, fludarabine, 6-mercaptopurine, thiamiprine, thiaguanine), pyrimidine analogs (e.g., ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, doxifluridine, emitefur, enocitabine, floxuridine, fluorouracil, gemcitabine, tegafur), fluocinolone, triaminolone, anecortave acetate, flurometholone, medrysone, and prednislone.
An "implant" and a "drug delivery system," are used interchangeably herein, and include any bioerodible device for implantation in the eye which is capable of delivering a therapeutic level of drug to the eye.
To "implant" to "place" and to "insert" are equivalent as used in this patent and mean to place an object in the desired site by any means capable of placing the object at that site.
By "therapeutic level" is meant a level of drug sufficient to prevent, inhibit, or reduce the level of transplant rejection in the eye.
The term "bioerodible polymer" refers to polymers which degrade in vivo, and wherein erosion of the polymer over time is required to achieve the agent release kinetics according to the invention. Specifically, hydrogels such as methylcellulose which act to release drug through polymer swelling are specifically excluded from the term "bioerodible polymer", The terms "bioerodible" and "biodegradable" are equivalent and are used interchangeably in this patent.
An "individual" is a vertebrate, preferably mammal, more preferably a human, Mammals include, but are not limited to, humans, rodents, sport animals and pets, such as rats, dogs, and horses.
Methods for Reducing or Preventing Transplant Rejection
Intraocular immunosuppressive drug delivery systems made of a biodegradable polymer matrix are provided which can release drug loads over various programmed time periods. When inserted into the eye these drug delivery systems provide therapeutic levels of immunosuppressive agent for reducing or preventing transplant rejection.
Accordingly, one embodiment of the present invention provides a method for reducing or preventing transplant rejection in the eye of an individual, comprising: performing an ocular transplant procedure; and implanting in the eye a bioerodible drug delivery system comprising an immunosuppressive agent and a bioerodible polymer.
In another embodiment of the invention, a method for reducing or preventing transplant rejection in the eye of an individual is provided, comprising: performing an ocular transplant procedure; and implanting a solid body into the eye, said body comprising particles of an immunosuppressive agent entrapped within a bioerodible polymer, whereby said agent is released from the body by erosion of the polymer.
Ocular transplant procedures which may be used with the methods of the invention include, but are not limited to, cornea transplant and RPE transplant. Methods for performing these transplant procedures are well known in the art. Methods for performing RPE transplants are described in, for example, U.S. Pat. Nos. 5,962,027, 6,045,791, and 5,941,250 and in Eye Graefes Arch Clin Exp Opthalmol 1997 March; 235(3):149-58; Biochem Biophys Res Commun 2000 Feb. 24; 268(3): 842-6; Opthalmic Surg 1991 February; 22(2): 102-8. Methods for performing corneal transplants are described in, for example, U.S. Pat. No. 5,755,785, and in Eye 1995; 9 (Pt 6 Su):6-12; Curr Opin Opthalmol 1992 August; 3 (4): 473-81; Ophthalmic Surg Lasers 1998 April; 29 (4): 305-8; Ophthalmology 2000 April; 107 (4): 719-24; and Jpn J Ophthalmol 1999 November-December; 43(6): 502-8. Exemplary methods for corneal and RPE transplantation in animal models are described in Examples 1, 4 and 5 below. In a preferred embodiment, the ocular transplant procedure is a cornea transplant. In another preferred embodiment, the ocular transplant procedure is an RPE procedure.
The drug delivery system may be implanted at various sites in the eye, depending on the size, shape and formulation of the implant, the type of transplant procedure, etc. Suitable sites include but are not limited to the anterior chamber, anterior segment, posterior chamber, posterior segment, vitreous cavity, suprachoroidal space, subconjunctiva, episcleral, intracorneal, epicorneal and sclera. In a preferred embodiment, the drug delivery system is placed in the anterior chamber of the eye. In another preferred embodiment, the drug delivery system is placed in the vitreous cavity.
The implants may be inserted into the eye by a variety of methods, including placement by forceps or by trocar following making an incision in the sclera (for example, a 2-3 mm incision) or other suitable site. In some cases, the implant may be able to be placed by trocar without making a separate incision, but instead by punching a hole directly into the eye with the trocar. The method of placement may influence the drug release kinetics. For example, implanting the device into the vitreous with a trocar may result in placement of the device deeper within the vitreous than placement by forceps, which may result in the implant being closer to the edge of the vitreous. The location of the implanted device may influence the concentration gradients of drug surrounding the device, and thus influence the release rates (e.g., a device placed closer to the edge of the vitreous may result in a slower release rate).
U.S. Pat. No. 5,869,079 farther describes locations for intraocular implants and methods for insertion (see in particular col. 6-7).
In one embodiment, the implant delivers the immunosuppressive agent for at least about 5 days. In other embodiments, the implant delivers the immunosuppressive agent for at least about one week, at least about 2 weeks, at least about 3 weeks, at least about four weeks, at least about five weeks, at least about six weeks, at least about seven weeks, at least about eight weeks, at least about nine weeks, at least about 10 weeks, and at least about 12 weeks. The preferred duration of drug release may be determined by the type of transplant, the medical history of the patient, etc. In one embodiment, drug release may occur for up to 6 months, or one year, or longer. In one embodiment, more than one implant may be sequentially implanted into the vitreous in order to maintain drug concentrations for even longer periods. In one embodiment, more than one implant may be sequentially implanted into the eye in order to maintain therapeutic drug concentrations for longer periods. Co-owned U.S. patent application Ser. No. 09/693,008, titled "Methods For Treating Inflammation-Mediated Conditions of the Eye," to Wong et al. filed Oct. 20, 2000, which is expressly incorporated herein by reference in its entirety, further describes implants and methods for making the implants which can achieve and maintain particular drug concentrations for programmed extended periods of time.
The methods of the invention are preferably performed on vertebrates, preferably mammal, more preferably a human. Mammals include, but are not limited to, humans, rodents, sport animals and pets, such as rats, dogs and horses.
The formulation of the implants for use in the invention may vary according to the preferred drug release profile, the particular immunosuppressive agent used, the transplant procedure, the medical history of the patient and other factors affecting the formulation.
The implants of the invention are formulated with particles of the immunosuppressive agent associated with the bioerodible polymer matrix. In a preferred embodiment the immunosuppressive agent is entrapped within the bioerodible polymer matrix. Without being bound by theory, we hypothesize that release of the agent is achieved by erosion of the polymer followed by exposure of previously entrapped agent particles to the eye, and subsequent dissolution and release of agent. The release kinetics achieved by this form of drug release are different than that achieved through formulations which release drug through polymer swelling, such as with hydrogels such as methylcellulose. In that case, the drug is not released through polymer erosion, but through polymer swelling, which release drug as liquid diffuses through the pathways exposed. The parameters which may determine the release kinetics include the size of the drug particles, the water solubility of the drug, the ratio of drug to polymer, the method of manufacture, the surface area exposed, and the erosion rate of the polymer.
In a preferred embodiment the immunosuppressive agent is selected from the group consisting of dexamethasone, cyclosporin A, azathioprine, brequinar, gusperimus, 6-mercaptopurine, mizoribine, rapamycin, tacrolimus (FK-506), folic acid analogs (e.g., denopterin, edatrexate, methotrexate, piritrexim, pteropterin, Tomudex�, trimetrexate), purine analogs (e.g., cladribine, fludarabine, 6-mercaptopurine, thiamiprine, thiaguanine), pyrimidine analogs (e.g., ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, doxifluridine, emitefur, enocitabine, floxuridine, fluorouracil, gemcitabine, tegafur) fluocinolone, triaminolone, anecortave acetate, fluorometholone, medrysone, and prednislone. In a preferred embodiment, the immunosuppressive agent is dexamethasone. In another preferred embodiment, the immunosuppressive agent is cyclosporin A. In another embodiment, the bioerodible implant comprises more than one immunosuppressive agent.
The implants may further comprise one or more additional therapeutic agents, such as antibiotics or antiinflammatory agents. Specific antibiotics include, but are not limited to:
Antibacterial Antibiotics:
Aminoglycosides (e.g., amikacin, apramycin, arbekacin, bambermycins, butirosin, dibekacin, dihydrostreptomycin, fortimicin(s), gentamicin, isepamicin, kanamycin, micronomicin, neomycin, neomycin undecylenate, netilmicin, paromomycin, ribostamycin, sisomicin, spectinomycin, streptomycin, tobramycin, trospectomycin), amphenicols (e.g., azidamfenicol, chloramphenicol, florfenicol, thiamphenicol), ansamycins (e.g., rifamide, rifampin, rifamycin sv, rifapentine, rifaximin), β-lactams (e.g., carbacephems (e.g., loracarbef), carbapenems (e.g., biapenem, imipenem, meropenem, panipenem), cephalosporins (e.g., cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, cefazolin, cefcapene pivoxil, cefclidin, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefmenoxime, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotiam, cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime proxetil, cefprozil, ceftoxadine, cefsulodin, cefltazidime, cefteram, ceftezole, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, cefuizonam, cephacetrile sodium, cephalexin, cephaloglycin, cephaloridine, cephalosporin, cephalothin, cephapirin sodium, cephradine, pivcefalexin), cephamycins (e.g., cefbuperazone, cefmetazole, cefminox, cefotetan, cefoxitin), monobactams (e.g., aztreonam, carumonam, tigemonam), oxacephems, flomoxef, moxalactam), penicillins (e.g., amdinocillin, amdinocillin pivoxil, amoxicillin, ampicillin, apalcillin, aspoxicillin, azidocillin, azlocillin, bacampicillin, benzylpenicillinic acid, benzylpenicillin sodium, carbenicillin, carindacillin, clometocillin, cloxacillin, cyclacillin, dicloxacillin, epicillin, fenbenicillin, floxacillin, hetacillin, lenampicillin, metampicillin, methicillin sodium, mezlocillin, nafcillin sodium, oxacillin, penamecillin, penethamate hydriodide, penicillin g benethanine, penicillin g benzathine, penicillin g benzhydrylamine, penicillin g calcium, penicillin g hydrabamine, penicillin g potassium, penicillin g procaine, penicillin n, penicillin o, penicillin v, penicillin v benzathine, penicillin v hydrabamine, penimepicycline, phenethicillin potassium, piperacillin, pivampicillin, propicillin, quinacillin, sulbenicillin, sultamicillin, talampicillin, temocillin, ticarcillin), other (e.g., ritipenem), lincosamides (e.g., clindamycin, lincomycin), macrolides (e.g., azithromycin, carbomycin, clarithromycin, dirithromycin, erythromycin, erythromycin acistrate, erythromycin estolate, erythromycin glucoheptonate, erythromycin lactobionate, erythromycin propionate, erythromycin stearate, josamycin, leucomycins, midecamycins, miokamycin, oleandomycin, primycin, rokitamycin, rosaramicin, roxithromycin, spiramycin, troleandomycin), polypeptides (e.g., amphomycin, bacitracin, capreomycin, colistin, enduracidin, enviomycin, fusafungine, gramicidin s, gramicidin(s), mikamycin, polymyxin, pristinamycin, ristocetin, teicoplanin, thiostrepton, tuberactinomycin, tyrocidine, tyrothricin, vancomycin, viomycin, virginiamycin, zinc bacitracin), tetracyclines (e.g., apicycline, chlortetracycline, clomocycline, demeclocycline, doxycycline, guamecycline, lymecycline, meclocycline, methacycline, minocycline, oxytetracycline, penimepicycline, pipacycline, rolitetracycline, sancycline, tetracycline), and others (e.g., cycloserine, mupirocin, tuberin).
Synthetic Antibacterials:
2,4-Diaminopyrimidines (e.g., brodimoprim, tetroxoprim, trimethoprim), nitrofurans (e.g., furaltadone, furazolium chloride, nifuradene, nifuratel, nifurfoline, nifurpirinol, nifurprazine, nifurtoinol, nitrofurantoin), quinolones and analogs (e.g., cinoxacin, ciprofloxacin, clinafloxacin, difloxacin, enoxacin, fleroxacin, flumequine, grepafloxacin, lomefloxacin, miloxacin, nadifloxacin, nalidixic acid, norfloxacin, ofloxacin, oxolinic acid, pazufloxacin, pefloxacin, pipemidic acid, piromidic acid, rosoxacin, rufloxacin, sparfloxacin, temafloxacin, tosufloxacin, trovafloxacin), sulfonamides (e.g., acetyl sulfamethoxypyrazine, benzylsulfamide, chloramine-b, chloramine-t, dichloramine t, n2-formylsulfisomidine, n4-β-d-glucosylsulfanilamide, mafenide, 4′-(methylsulfamoyl)sulfanilanilide, noprylsulfamide, phthalylsulfacetamide, phthalylsulfathiazole, salazosulfadimidine, succinylsulfathiazole, sulfabenzamide, sulfacetamide, sulfachlorpyridazine, sulfachrysoidine, sulfacytine, sulfadiazine, sulfadicramide, sulfadimethoxine, sulfadoxine, sulfaethidole, sulfaguanidine, sulfaguanol, sulfalene, sulfaloxic acid, sulfamerazine, sulfameter, sulfamethazine, sulfamethizole, sulfamethomidine, sulfamethoxazole, sulfamethoxypyridazine, sulfametrole, sulfamidochrysoidine, sulfamoxole, sulfanilamide, 4-sulfanilamidosalicylic acid, n4-sulfanilylsulfanilamide, sulfanilylurea, n-sulfanilyl-3,4-xylamide, sulfanitran, sulfaperine, sulfaphenazole, sulfaproxyline, sulfapyrazine, sulfapyridine, sulfasomizole, sulfasymazine, sulfathiazole, sulfathiourea, sulfatolamide, sulfisomidine, sulfisoxazole) sulfones (e.g., acedapsone, acediasulfone, acetosulfone sodium, dapsone, diathymosulfone, glucosulfone sodium, solasulfone, succisulfone, sulfanilic acid, p-sulfanilylbenzylamine, sulfoxone sodium, thiazolsulfone), and others (e.g., clofoctol, hexedine, methenamine, methenamine anhydromethylene-citrate, methenamine hippurate, methenamine mandelate, methenamine sulfosalicylate, nitroxoline, taurolidine, xibornol).
Antifungal Antibiotics:
Polyenes (e.g., amphotericin b, candicidin, dermostatin, filipin, fungichromin, hachimycin, hamycin, lucensomycin, mepartricin, natamycin, nystatin, pecilocin, perimycin), others (e.g., azaserine, griseofulvin, oligomycins, neomycin undecylenate, pyrrolnitrin, siccanin, tubercidin, viridin).
Synthetic Antifungals:
Allylamines (e.g., butenafine, naftifine, terbinafine), imidazoles (e.g., bifonazole, butoconazole, chlordantoin, chlormidazole, cloconazole, clotrimazole, econazole, enilconazole, fenticonazole, flutrimazole, isoconazole, ketoconazole, lanoconazole, miconazole, omoconazole, oxiconazole nitrate, sertaconazole, sulconazole, tioconazole), thiocarbamates (e.g., tolciclate, tolindate, tolnaftate), triazoles (e.g., fluconazole, itraconazole, saperconazole, terconazole) others (e.g., acrisorcin, amorolfine, biphenamine, bromosalicylchloranilide, buclosamide, calcium propionate, chlorphenesin, ciclopirox, cloxyquin, coparaffinate, diamthazole dihydrochloride, exalamide, flucytosine, halethazole, hexetidine, loflucarban, nifuratel, potassium iodide, propionic acid, pyrithione, salicylanilide, sodium propionate, sulbentine, tenonitrozole, triacetin, ujothion, undecylenic acid, zinc propionate).
Antibiotics and analogs (e.g., aclacinomycins, actinomycin f1, anthramycin, azaserine, bleomycins, cactinomycin, carubicin, carzinophilin, chromomycins, dactinomycin, daunorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, idarubicin, menogaril, mitomycins, mycophenolic acid, nogalamycin, olivomycines, peplomycin, pirarubicin, plicamycin, porfiromycin, puromycin, streptonigrin, streptozocin, tubercidin, zinostatin, zorubicin), antimetabolites (e.g. folic acid analogs (e.g., denopterin, edatrexate, methotrexate, piritrexim, pteropterin, Tomudex�, trimetrexate), purine analogs (e.g., cladribine, fludarabine, 6-mercaptopurine, thiamiprine, thioguanine), pyrimidine analogs (e.g., ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, doxifluridine, emitefur, enocitabine, floxuridine, fluorouracil, gemcitabine, tagafur).
Specific Antiinflammatory Agents Include, but are Not Limited to:
Steroidal Antiinflammatory Agents:
21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, halopredone acetate, hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, and triamcinolone hexacetonide.
Non-Steroidal Antiinflammatory Agents:
Aminoarylcarboxylic acid derivatives (e.g., enfenamic acid, etofenamate, flufenamic acid, isonixin, meclofenamic acid, mefenamic acid, niflumic acid, talniflumate, terofenamate, tolfenamic acid), arylacetic acid derivatives (e.g., aceclofenac, acemetacin, alclofenac, amfenac, amtolmetin guacil, bromfenac, bufexamac, cinmetacin, clopirac, diclofenac sodium, etodolac, felbinac, fenclozic acid, fentiazac, glucametacin, ibufenac, indomethacin, isofezolac, isoxepac, lonazolac, metiazinic acid, mofezolac, oxametacine, pirazolac, proglumetacin, sulindac, tiaramide, tolmetin, tropesin, zomepirac), arylbutyric acid derivatives (e.g., bumadizon, butibufen, fenbufen, xenbucin), arylcarboxylic acids (e.g., clidanac, ketorolac, tinoridine), arylpropionic acid derivatives (e.g., alminoprofen, benoxaprofen, bermoprofen, bucloxic acid, carprofen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, piketoprolen, pirprofen, pranoprofen, protizinic acid, suprofen, tiaprofenic acid, ximoprofen, zaltoprofen), pyrazoles (e.g., difenamizole, epirizole), pyrazolones (e.g., apazone, benzpiperylon, feprazone, mofebutazone, morazone, oxyphenbutazone, phenylbutazone, pipebuzone, propyphenazone, ramifenazone, suxibuzone, thiazolinobutazone), salicylic acid derivatives (e.g., acetaminosalol, aspirin, benorylate, bromosaligenin, calcium acetylsalicylate, diflunisal, etersalate, fendosal, gentisic acid, glycol salicylate, imidazole salicylate, lysine acetylsalicylate, mesalamine, morpholine salicylate, 1-naphthyl salicylate, olsalazine, parsalmide, phenyl acetylsalicylate, phenyl salicylate, salacetamide, salicylamide o-acetic acid, salicylsulfuric acid, salsalate, sulfasalazine), thiazinecarboxamides (e.g., ampiroxicam, droxicam, isoxicam, lornoxicam, piroxicam, tenoxicam), ε-acetamidocaproic acid, s-adenosylmethionine, 3-amino-4-hydroxybutyric acid, amixetrine, bendazac, benzydamine, α-bisabolol, bucolome, difenpiramide, ditazol, emorfazone, fepradinol, guaiazulene, nabumetone, nimesulide, oxaceprol, paranyline, perisoxal, proquazone, superoxide dismutase, tenidap, and zileuton.
The immunosuppressive agent is preferably from about 10 to 90% by weight of the implant. More preferably, the agent is from about 50 to about 80% by weight of the implant. In a preferred embodiment, the agent comprises about 50% by weight of the implant. In a preferred embodiment, the agent comprises about 70% by weight of the implant.
The implants are preferably monolithic, i.e. having the immunosuppressive agent homogeneously distributed through the polymeric matrix. In this patent, by homogeneously distributed we mean that the immunosuppressive agent is distributed evenly enough that no detrimental fluctuations in rate of immunosuppressive agent release occur because of uneven distribution of the immunosuppressive agent in the polymer matrix. The selection of the polymeric composition to be employed will vary with the desired release kinetics, the location of the implant, patient tolerance, the nature of the transplant procedure and the like. Characteristics of the polymers will include biodegradability at the site of implantation, compatibility with the agent of interest, ease of encapsulation, water insolubility, and the like. Preferably, the polymeric matrix will not be fully degraded until the drug load has been released, The polymer will usually comprise at least about 10, more usually at least about 20 weight percent of the implant. In one embodiment, the implant comprises more than one polymer.
Biodegradable polymeric compositions which may be employed may be organic esters or ethers, which when degraded result in physiologically acceptable degradation products, including the monomers. Anhydrides, amides, orthoesters or the like, by themselves or in combination with other monomers, may find use. The polymers may be condensation polymers. The polymers may be cross-linked or non-cross-linked, usually not more than lightly cross-linked, generally less than 5%, usually less than 1% cross-linked. For the most part, besides carbon and hydrogen, the polymers will include oxygen and nitrogen, particularly oxygen. The oxygen may be present as oxy, e.g., hydroxy or ether, carbonyl, e.g., non-oxo-carbonyl, such as carboxylic acid ester, and the like. The nitrogen may be present as amide, cyano and amino. The biodegradable polymers set forth in Heller, Biodegradable Polymers in Controlled Drug Delivery, in: CRC Critical Reviews in Therapeutic Drug Carrier Systems, Vol. 1. CRC Press, Boca Raton, Fla. (1987), may be used.
Of particular interest are polymers of hydroxyaliphatic carboxylic acids, either homo- or copolymers, and polysaccharides. Included among the polyesters of interest are polymers of D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid, polycaprolactone, and combinations thereof. By employing the L-lactate or D-lactate, a slowly biodegrading polymer is achieved, while degradation is substantially enhanced with the racemate. Copolymers of glycolic and lactic acid are of particular interest, where the rate of biodegradation is controlled by the ratio of glycolic to lactic acid. The % of polylactic acid in the polylactic acid polyglycolic acid (PLGA) copolymer can be 0-100%, preferably about 15-85%, more preferably about 35-65%. In a particularly preferred embodiment, a 50/50 PLGA copolymer is used. The most rapidly degraded copolymer has roughly equal amounts of glycolic and lactic acid, where either homopolymer is more resistant to degradation. The ratio of glycolic acid to lactic acid will also affect the brittleness of in the implant, where a more flexible implant is desirable for larger geometries. The size of the polymer particles is preferably about 1-100 μm in diameter, more preferably about 5-50 μm in diameter, more preferably about 9-12 μm in diameter, still more preferably about 10 μm in diameter.
Among the polysaccharides of interest are calcium alginate, and functionalized celluloses, particularly carboxymethylcellulose esters characterized by being biodegradable, water insoluble, a molecular weight of about 5 kD) to 500 kD, etc. In one embodiment, the implant comprises hydroxypropyl methylcellulose (HPMC).
Additionally, release modulators such as those described in U.S. Pat. No. 5,869,079 may be included in the implants. The amount of release modulator employed will be dependent on the desired release profile, the activity of the modulator, and on the release profile of the immunosuppressive agent in the absence of modulator.
Other agents may be employed in the formulation for a variety of purposes. For example, buffering agents and preservatives may be employed. Water soluble preservatives which may be employed include sodium bisulfite, sodium bisulfate, sodium thiosulfate, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, methylparaben, polyvinyl alcohol and phenylethyl alcohol. These agents may be present in individual amounts of from about 0.001 to about 5% by weight and preferably about 0.01 to about 2%. Suitable water soluble buffering agents that may be employed are sodium carbonate, sodium borate, sodium phosphate, sodium acetate, sodium bicarbonate, etc., as approved by the FDA for the desired route of administration. These agents may be present in amounts sufficient to maintain a pH of the system of between 2 to 9 and preferably 4 to 8. As such the buffering agent may be as much as 5% on a weight to weight basis of the total composition. Electrolytes such as sodium chloride and potassium chloride may also be included in the formulation. Where the buffering agent or enhancer is hydrophilic, it may also act as a release accelerator. Hydrophilic additives act to increase the release rates through faster dissolution of the material surrounding the drug particles, which increases the surface area of the drug exposed, thereby increasing the rate of drug bioerosion. Similarly, a hydrophobic buffering agent or enhancer dissolve more slowly, slowing the exposure of drug particles, and thereby slowing the rate of drug bioerosion.
The proportions of immunosuppressive agent, polymer, and any other modifiers may be empirically determined by formulating several implants with varying proportions. A USP approved method for dissolution or release test can be used to measure the rate of release (USP 23; NF 18 (1995) pp. 1790-1798). For example, using the infinite sink method, a weighed sample of the drug delivery system is added to a measured volume of a solution containing 0.9% NaCl in water, where the solution volume will be such that the drug concentration is after release is less than 5% of saturation. The mixture is maintained at 37� C. and stirred slowly to maintain the implants in suspension. The appearance of the dissolved drug as a function of time may be followed by various methods known in the art, such as spectrophotometrically, HPLC, mass spectroscopy, etc. until the absorbance becomes constant or until greater than 90% of the drug has been released.
The release kinetics of the drug delivery systems of the invention are dependent in part on the surface area of the implants. Larger surface area exposes more polymer to the eye, causing faster erosion and dissolution of the drug particles entrapped by the polymer. The size and form of the implant can be used to control the rate of release, period of treatment, and drug concentration at the site of implantation. Larger implants will deliver a proportionately larger dose, but depending on the surface to mass ratio, may have a slower release rate. The implants may be particles, sheets, patches, plaques, films, discs, fibers, microcapsules and the like and may be of any size or shape compatible with the selected site of insertion, as long as the implants have the desired release kinetics. Preferably, the implant to be inserted is formulated as a single particle. Preferably, the implant will not migrate from the insertion site following implantation. The upper limit for the implant size will be determined by factors such as the desired release kinetics, location of the implant in the eye, toleration for the implant, size limitations on insertion, ease of handling, etc. For example, the vitreous chamber is able to accommodate relatively large implants of varying geometries, having diameters of 1 to 3 mm. In a preferred embodiment, the implant is a cylindrical pellet (e.g., rod) with dimensions of about 2 mm�0.75 mm diameter. In another preferred embodiment, the implant is a cylindrical pellet (e.g., rod) with dimensions of about 1 mm�380 μm diameter. The implants will also preferably be at least somewhat flexible so as to facilitate both insertion of the implant in the eye and accommodation of the implant. The total weight of the implant is preferably about 50-5000 μg, more preferably about 100-1000 μg. In one embodiment, the implant is about 500 μg. In a particularly preferred embodiment, the implant is about 1000 μg. In another particularly preferred embodiment, the implant is about 120 μg. U.S. Pat. No. 5,869,079 further describes preferred implant sizes for particular regions of the eye, as well as preferred sizes for particular implant shapes.
In a preferred embodiment, a solid bioerodible implant for reducing or preventing transplant rejection in the eye is provided, comprising about 50% by weight of dexamethasone, about 15% by weight of hydroxypropyl methylcellulose (HPMC) and about 35% by weight of polylactic polyglycolic acid (PLGA).
In another preferred embodiment, a solid bioerodible implant for reducing or preventing transplant rejection in the eye is provided, comprising about 70% by weight of dexamethasone and about 30% by weight of polylactic polyglycolic acid (PLGA).
In another preferred embodiment, a solid bioerodible implant for reducing or preventing transplant rejection in the eye is provided, comprising about 50% by weight of dexamethasone and about 50% by weight of polylactic polyglycolic acid (PLGA).
The preferred supplier of PLGA is Boehringer Ingelheim and the preferred PLGA products are Resomer RG 502 and Resomer RG 502H.
In a preferred embodiment, the solid bioerodible implant includes about 50% by weight of dexamethasone, about 15% by weight of hydroxypropyl methylcellulose (HPMC) and about 35% by weight of Resomer RG 502H PLGA.
In a preferred embodiment, the solid bioerodible implant includes about 60% by weight of dexamethasone, about 30% by weight of Resomer RG 502H PLGA, and about 10% by weight of Resomer RG 502 PLGA.
Methods for Making the Implants
Various techniques may be employed to produce the implants. Useful techniques include phase separation methods, interfacial methods, extrusion methods, compression methods, molding methods, injection molding methods, heat press methods and the like.
Choice of the technique and manipulation of the technique parameters employed to produce the implants can influence the release rates of the drug. Room temperature compression methods result in an implant with discrete microparticles of drug and polymer interspersed. Extrusion methods result in implants with a progressively more homogenous dispersion of the drug within the polymer, as the production temperature is increased. When using extrusion methods, the polymer and drug are chosen to as to be stable at the temperatures required for manufacturing, usually at least about 85� C. Extrusion methods use temperatures of about 25� C. to about 150� C., more preferably about 65� C. to about 130� C. Generally, compression methods yield implants with faster release rates than extrusion methods, and higher temperatures yield implants with slower release rates.
In a preferred embodiment, compression methods are used to produce the implants of the invention. Preferably, compression methods use pressures of 50-150 psi, more preferably about 70-80 psi, even more preferably about 76 psi, and use temperatures of about 0� C. to about 115� C., more preferably about 25� C. In another preferred embodiment, extrusion methods are used. Preferably, implants produced by extrusion methods are heated to a temperature range of about 60� C. to about 150� C. for drug/polymer mixing, preferably about 85� C., preferably about 130� C., for a time period of about 0 to 1 hour, 0 to 30 minutes, 5-15 minutes, preferably about 10 minutes, preferably about 0 to 5 min, preferably about 1 hour. Preferably, the implants are then extruded at a temperature of about 60� C. to about 130� C., preferably about 95� C., preferably about 85� C., preferably about 75� C.
U.S. Pat. No. 4,997,652 further describes suitable methods for making the implants of the invention, and is herein incorporated by reference in its entirety.
Kit for the Administration of the Implants
In another aspect of the invention, a kit for treating or preventing transplant rejection in the eye is provided, comprising a bioerodible drug delivery system comprising an immunosuppressive agent and a bioerodible polymer, wherein the drug delivery system is designed to be implanted in the eye. The kit may also include instructions for use.
The bioerodible drug delivery systems as described herein are suitable for use in the kits of the invention. In a preferred embodiment, the immunosuppressive agent is dexamethasone.
The invention is further described by the following nonlimiting examples.
The objective of this study was to determine the efficacy of sustained release intraocular dexamethasone implanted in the anterior chamber of the rat eye at the end of cornea transplant surgery and compare it with local eye drop therapy. The approximately 120 μg dexamethasone implant contained about 15% HPMC, 35% PLGA and 50% dexamethasone, and was prepared and tested in vitro as described in U.S. Pat. No. 5,869,079 (See Example 1), which is specifically incorporated herein by reference in its entirety.
In order to create a very high risk of cornea rejection, a xenograft model was chosen. Mouse cornea from 12 mice of either sex were used as donor tissues for rat.
Eighteen rats of either sex were used in the study They were divided into 3 groups. Group #1-6 animals received treatment with the dexamethasone implant, Group #2—received treatment with topical steroid and Group #3—control group (without any treatment). Animals were followed up to 8 weeks. After euthanasia eyes were sent for histopathology examination.
Supplies: 0.5% Ophthaine Solution, euthasol solution, ketamine HCl, xylazine.
Obtaining donor corneas: Each mouse was weighed and anesthetized. While under anesthesia, the ophthalmologist collected all donor cornea buttons from mice using trephine. After the procedure mice were euthanized by a lethal dose of Euthasol.
Penetrating keratoplasty (PKP): Each rat was weighed and anesthetized. Using 2.5 mm trephine an initial incision was made in the middle of cornea. The incision was finished using corneal scissors. The anterior chamber (AC) was held using balanced salt solution (BSS). The donor cornea button was attached to the host cornea with 8 interrupted sutures with 11-0 nylon. Before closing the anterior chamber, the dexamethasone implant was implanted into the AC of the first 6 animals.
All eighteen rats survived the procedure. All eyes were examined by an ophthalmologist by slit lamp and all signs of cornea rejection (neovascularization, edema, etc.) were recorded.
In group #2, all animals received 2 drops of Dexamethasone eye drops every day, until the rejection occurred.
Based on clinical observation, rejection of cornea in Group #3 (control) occurred in the first few days after surgery, and by week one 80% of donors' cornea were rejected, by week two 100%. Corneas were showing heavy neovascularization in the first few days followed by corneal edema and total rejection. Group #2 (topical Dexamethasone eye drops) had similar signs observed in this group with some delay. 20% of cornea rejection occurred by week two, 50% by week three, and 80% by week six. At the time of euthanasia (week 8) only 20% were not completely rejected.
However, in group #1, treated with the dexamethasone implant, the corneas did not show any signs of rejection (neovascularization, edema). In all eyes the corneas stayed clear. By the end of the study (week eight) the graft survival was 100%.
Histopathology examination confirmed the clinical observations. In Group #3 heavy inflammation was observed in AC, cornea endothelium, also in the stroma, and some in the epithelium. Corneas also showed edema due to destroyed endothelial cells.
In Group #2 similar findings were observed.
In Group #1, inflammation was totally suppressed by the dexamethasone implant.
The entire clinical and histological finding in this study clearly demonstrated that intraocular sustained release Dexamethasone can prevent corneal rejection in a high-risk xenograft model.
2100 mg of dexamethasone powder (Upjohn) (particle sizes less than 10 μm in diameter) were mixed with 900 mg of 50/50 polylactic acid polyglycolic acid (PLGA) (particle sizes approximately 9-12 μm in diameter) at ambient temperature. A small Teflon� tube was filled with 900-1100 μg of the above mixture, and placed directly on the die cavity. The powder was pushed out of the tubing into the die cavity with a stainless steel wire and the tube and wire were removed from the die. The powder was pressed using a tablet press (approximately 76 psi), ejected with the ejector switch, and removed with tweezers. The resulting pellet was approximately 2 mm�0.75 mm.
Release of dexamethasone from the DEX PS DDS� system was measured. One DDS was placed in a glass vial filled with receptor medium (0.9% NaCl in water). To allow for "infinite sink" conditions, the receptor medium volume was chosen so that the concentration would never exceed 5% of saturation. To minimize secondary transport phenomena, e.g. concentration polarization in the stagnant boundary layer, the glass vial was placed into a shaking water bath at 37� C. Samples were taken for HPLC analysis from the vial at defined time points. The HPLC method was as described in USP 23(1995) pp. 1791-1798. The concentration values were used to calculate the cumulative release data, as shown in Table 2.
Table 2 shows an almost linear in vitro release of dexamethasone over a one month period of time.
One DEX PS DDS� per eye was implanted into the vitreous of four rabbits with forceps. The in vivo vitreous concentrations of dexamethasone in each of the four eyes were monitored by vitreous sampling. For example, at day 2 the concentrations measured were 0.03 μg/ml, 0.1 μg/ml, 0.33 μg/ml and 0.19 μg/ml. The concentrations in each of the four eyes were measured on days 2, 7, 21, 28 and 35; the average results are summarized in Table 3. The volume of rabbit eyes is approximately 60-70% percent that of human eyes.
The same DDS was tested in vivo in rabbits, wherein the DDS was placed to a depth of about 5-10 mm in the vitreous with trocar. The levels of dexamethasone in the vitreous are shown in Table 4.
The data indicate that the DEX PS DDS� releases dexamethasone to the vitreous in concentrations above 0.01 μg/ml for an extended period of time. Further, the data indicate that placement of the device with trocar results in much higher levels of drug release than with placement with forceps, most likely due to placement of the device deeper within the vitreous. The data at two, four, six, and 24 hours in Table 4 shows an initial spike of drug release.
2.5 g of PLGA (particle sizes approximately 9-12 μm in diameter) were placed in a mixing vessel. The vessel was placed in the oven (130� C.) for ten minutes. 2.5 g of dexamethasone (particle sizes less than approximately 10 μm in diameter) were added to the vessel, and the vessel was returned to the oven for 10 minutes. The PLGA/dexamethasone mixture was mixed well, the blend loaded into a barrel, and 650-790 μm diameter filaments extruded. The resulting filaments were cut into lengths of approximately 0.94 and 1.87 mm for the 500 μg and 1000 μg formulations, respectively.
Release of dexamethasone from the 50/50 dexamethasone/PLGA DDS formulations were measured. One DDS was placed in a glass vial filled with receptor medium (0.9% NaCl in water). To allow for "infinite sink" conditions, the receptor medium volume was chosen so that the concentration would never exceed 5% of saturation. To minimize secondary transport phenomena, e.g. concentration polarization in the stagnant boundary layer, the glass vial was placed into a shaking water bath at 37� C. Samples were taken for HPLC analysis from the vial at defined time points. The HPLC method was as described in USP 23(1995) pp. 1791-1798. The concentration values were used to calculate the cumulative release data, as shown in Tables 5 and 6.
One 50/50 dexamethasone/PLGA 1 mg formulation DDS per eye was implanted into the vitreous of 6 rabbits using a trocar. The DDS was loaded into the trocar, a hole was punched through the sclera, the trocar inserted through the hole, and the trocar plunger depressed to insert the DDS into the vitreous. In vivo vitreous concentrations of dexamethasone were monitored, as shown in Table 7.
The data indicate that the 50/50 dexamethasone/PLGA DDS releases dexamethasone to the vitreous in concentrations above 0.01 μg/ml for an extended period of time. The data at two, four, six, and 24 hours in Table 7 shows an initial spike of drug release, due to drug which is unencapsulated by the delivery system.
Modifications of the above described modes for carrying out the invention that are obvious to those of ordinary skill in the surgical, pharmaceutical, or related arts are intended to be within the scope of the following claims.
Patent Citations
Non-Patent Citations
Referenced by
Legal Events
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Grassroots: Legislation & Leadership
AIA Nevada leaders travel to Washington, DC each February. The purpose of our annual trip is twofold - First, to speak directly with our congressional representatives about the current legislative issues that are most important to architects and the practice of architecture; Second, to meet with the leadership from other chapters from across the country and explore ways in which we can work more closely together to become "one AIA". The effort to unify our organization and organize our resources to benefit all members is essential to building the future of the profession. While in DC, our chapter leaders confer with others from across the country and share their knowledge and experiences as well.
Our positions are as follows:
The AIA's Plans for Economic Recovery
Pass a Transportation Bill to Get our Communities Moving Again
AIA Position: The AIA supports reforming federal transportation policy to help the country develop and improve transportation systems that promote economic vitality and create vibrant, prosperous communities.
click here to read the entire position statement
Remove Barriers to Private Sector Lending
AIA Position: The AIA supports policies that will ensure credit is available for worthy commercial and residential development projects that create jobs and rebuild our communities.
click here to read the entire position statement
Help Small Architecture Firms Thrive
AIA Position: The AIA supports government policies that open doors for small design firms to create jobs and economic opportunity in every community in the country. The AIA strongly opposes policy proposals that discriminate against small design firms and place barriers in the way of their survival.
Save Energy, Create Jobs
AIA Position: The AIA believes that governmental policies, programs, and incentives should encourage energy efficiency, especially as it relates to the built environment.

subset: commoncrawl


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Written by Administrator Wednesday, 05 March 2014 22:21
In preparation for the summer camp season, we are rolling out a new, simplified annual health and medical record effective March 1, 2014. Thanks to you, your volunteers, your parents, and your unit leaders for providing constructive feedback on how we could make the record easier to use while still collecting the information needed to make sure our Scouts are ready for their experience.
Some of the key updates include:
The primary version will be English. The existing bilingual version will remain available.
Part A (Informed Consent, Release Agreement, and Authorization) will contain no medical information and will be shorter by one page.
Part B (General Information/Health History) will include only the most important information needed.
Part C (Pre-Participation Physical) will be reduced to one page with expanded sections for allergy explanation.
Supplemental Risk Advisory (former Part D) will be shortened and be location specific. This is designed to take to physicians so they will better understand what activities their patients will participate in.
A redesign of the landing page for the annual health and medical record website so participants and parents will be able to download only what they need.Last Updated on Thursday, 06 March 2014 15:45


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A machine is only good as its parts, that's why Ditch Witch Northwest stocks the largest parts inventory in the West for modular attachments and replacement parts for your Ditch Witch® equipment.
As a core facet of both repair and reconfiguration, we recognize the importance of identifying which parts our customers will need. From our knowledgeable staff and technicians to our comprehensive inventory management system, Ditch Witch Northwest ensures that we can always provide the parts for your equipment.
Having the right parts is important, but so is making sure those parts are properly fitted and stable. At Ditch Witch Northwest, our technicians are happy to outfit your rigs per your instructions.
Machine maintenance is a matter of caring for each and every individual component. At Ditch Witch Northwest, we believe that carrying a diverse selection of parts is the best way to ensure that your machinery is properly maintained and serviced. Trust Ditch Witch Northwest to deliver premium, on-demand parts for all your Ditch Witch® products.
Let the expert parts team at Ditch Witch Northwest help you get moving forward today!


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More New and Used
from Private Sellers
Theories of International Politics and Zombiesby Drezner, Daniel W.
Princeton Univ Pr
Questions About This Book?
Why should I rent this book?
Renting is easy, fast, and cheap! Renting from eCampus.com can save you hundreds of dollars compared to the cost of new or used books each semester. At the end of the semester, simply ship the book back to us with a free UPS shipping label! No need to worry about selling it back.
How do rental returns work?
Returning books is as easy as possible. As your rental due date approaches, we will email you several courtesy reminders. When you are ready to return, you can print a free UPS shipping label from our website at any time. Then, just return the book to your UPS driver or any staffed UPS location. You can even use the same box we shipped it in!
What version or edition is this?
This is the edition with a publication date of 1/3/2011.
What is included with this book?
- The Used copy of this book is not guaranteed to include any supplemental materials. Typically, only the book itself is included.
- The Rental copy of this book is not guaranteed to include any supplemental materials. You may receive a brand new copy, but typically, only the book itself.
- The eBook copy of this book is not guaranteed to include any supplemental materials. Typically only the book itself is included.
What would happen to international politics if the dead rose from the grave and started to eat the living? Daniel Drezner's groundbreaking book answers the question that other international relations scholars have been too scared to ask. Addressing timely issues with analytical bite, Drezner looks at how well-known theories from international relations might be applied to a war with zombies. Exploring the plots of popular zombie films, songs, and books,Theories of International Relations and Zombiespredicts realistic scenarios for the political stage in the face of a zombie threat and considers how valid--or how rotten--such scenarios might be.Drezner boldly lurches into the breach and "stress tests" the ways that different approaches to world politics would explain policy responses to the living dead. He examines the most prominent international relations theories--including realism, liberalism, constructivism, neoconservatism, and bureaucratic politics--and decomposes their predictions. He digs into prominent zombie films and novels, such asNight of the Living DeadandWorld War Z, to see where essential theories hold up and where they would stumble and fall. Drezner argues that by thinking about outside-of-the-box threats we get a cognitive grip on what former U.S. Secretary of Defense Donald Rumsfeld famously referred to as the "unknown unknowns" in international security.Correcting the zombie gap in international relations thinking and addressing the genuine but publicly unacknowledged fear of the dead rising from the grave,Theories of International Relations and Zombiespresents political tactics and strategies accessible enough for any zombie to digest.


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"You know, it's not a sin to make mistakes, fail to
succeed on the first (or 45th) try, or generally show that we're imperfect. The
unspoken strictures that some businesses, churches, schools, other establishments
place upon their members or employees make following the 10 Commandments look
pretty darn easy." --From
Start Your Week with Steve, the free weekly e-mail newsletter of Steve Henderson Fine Art.
Painting materials
aren't free and time is precious -- that being said, if more artists would
worry less about creating the perfect painting and more about experimenting as
a painting artist and getting better at what they do and the painting
techniques they employ, then they would sooner reach a consistency of quality as
a painting artist and create artworks with which they are delighted, time after
It's a great
big world out there, and we're a part of it. Dream big and work hard in your
painting art. The rewards will follow. Diaphanous by Steve Henderson of Steve Henderson Fine Art.
There are
enough people in our lives expecting unrealistic things of us that we don't
have to be one of them. Falling down isn't failure. Trying and not getting it
quite right isn't tragedy. Doing something completely different, just because,
isn't a waste of time.
Go for it.
Grab a different painting brush. Use a color you usually avoid. Shake around
your subject matter. Play with your paint and see where it takes you on the
next step of your journey.
Thanks Carolyn. That's inspirational. Along these lines, I had a teacher say to me, "you're so cheap with your self, put more paint out. This isn't the last tube of paint you intend to buy, is it?" It's true. If you can clear away the concerns of money and time, and just focus on your work, you can make great strides.
In my mind I know this, Carolyn... It's the application of the concept that always gets me... But I constantly work on it!! Always love your posts!!
I did a "guest post" on my blog of this post with all links intact and attribution back here. But being somewhat new to blogging I wanted to make sure I didn't do anything wrong as far as blog etiquette or copyright. Please let me know if I need to do anything else.
The guest post is here: TabascoCatArt.com
I had/have a painting where it began as one concept, kept it for a while, then changed it. Kept it for a while then changed it again; now I have something. "Hidden Faces" stems for a chemical reaction of three or mixed mediums. The last concept was going to be titled "Health Conscious, Three Eggs Two Yokes" when I started seeing faces in the mix. Next!
© 2015 F+W All rights reserved.Use of this site signifies your agreement to the Terms and Privacy Policy, updated March 2007


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Gear Review
Sweet bike rack
This thing is pretty sweet. Not much to say about it. It simply does exactly what its supposed to do. If you want to crry your bike uprightin your truck bed without mounting anything to the truck itself, this is your rack, plain and simple. Easy to use, holds even my heavy downhill bikes solidly in place.
View More Details on Thule Insta-Gator Truck Mount


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Many thanks
The Volunteer Way Hunger Relief charity had a lot to be thankful about this Thanksgiving. We live in the greatest country in the world, and God has blessed the United States.
We have been going through a very difficult time, with our economy being in a recession. More people are using our food bank, food pantry and soup kitchen to feed their families.
What I like about our country is when everything gets tough, people stick together and help each other. This year we had a few of our resources close down, which made it very difficult to be able to give out the amount of turkeys that we had requests for. Then we started to get phone calls from many of the community's churches, businesses and residents that wanted to help us assist the many hungry people of our community.
American Legion Auxiliary Unit 79 and Sons of the American Legion Squadron 79 donated 18 boxes of food.
Where else but America do people, regardless of their beliefs, come together in one common cause to help less fortunate people? We can all learn from this example. Thanks to all who came forward to help Pasco people in need. We are truly a community of "People Helping People."
Lester Cypher
New Port Richey
The writer is founder and CEO of The Volunteer Way, a food charity.


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We hope you like the new look, and keep checking back for new features - we are adding new content every day.
Coming Events
Get the latest information on where to take one of Chef Bon's classes, attend one of her lectures, or see her in action on one of her projects.
Our Autism Support Programs
At Bonita Woods Wellness Institute, we transform therapy for special needs children into fun, family friendly activities and entertaining educational programs. We present creative solutions and provide tools to both achieve your developmental goals and continue with the learned techniques at home.
Join us for our next MeetUp!
Where can you find the BWWI team? Check out our schedule of on- and off-site events here.
Kids Help Kids
Zander and his friends came up with the idea - every kid should be able to have an after school snack; even when their parents need our help to nurture and nourish their family.
The Muffintop Project
The Muffintop Project is a multimedia program and interactive website currently being designed to help kids understand how their lifestyle choices effect their bodies.
Marine Corps Youth Fitness Challenge
The Bonita Woods Wellness Institute is honored to coordinate programs with Marine Corps Youth Foundation. Work out with real Marines! You only compete against yourself! Learn how to exercise safely & effectively as you increase your strength and stamina!
For Your Health!
Get tips on how to get and keep yourself healthy - what foods to include and what foods to avoid, behaviors that help and behaviors that don't, activities that lead to better health, and more!
Community & Family Health
Exercising isn't just performing a workout routine. You can add exercise to your daily life while also helping your community or having fun with your family & friends.
Food & Recipes
Check out Chef Bon's favorite recipes - they're easy to prepare and good for you!
Food Politics
How do other people's decisions - the government, businesses, etc - affect you, your food, and your health? How can you make a difference? Find out here!
Fun, Funny and Nice Stories to Share
These articles may not be specifically about your health, nutrition, or well-being, but Chef Bon thought you might enjoy reading them anyway :)
Everyone has the right to eat healthfully!
Do you know what is missing from your life? Pictures of animals eating healthfully! Browse through them here, and get tips on how to help the wildlife in your area.
About Us & What We Do
Learn about the Wellness Institute's leader, Bonita Woods, and check out some of the great things she's accomplished, including projects and articles.
Meet Our Team
Under Construction
BWWI in the Press
What do Bonita and her colleagues have to say? Browse through press releases, magazine and newspaper articles, TV appearances, event write-ups, and more!
Friends of BWWI
The Bonita Woods Wellness Institute has relationships with various local and national organizations. Find out who they are, what they do, and what they have to offer you...
So many of you have asked me where you can take my cooking classes. Happily, my wellness center is across the street from the Falls Church Community Center and the has a wonderful kitchen classroom. This makes me happy on so many levels, including the fact that I get to work with my favorite community center! Zander and I have benefited so much from the wonderful and affordable programs they offer, I am thrilled that I get actually to work with this wonderful organization. You can see the actual class brochure here. I also present classes, lectures, workshops and CEC programs for healthcare professionals. Mostly, I present at local senior care & healthcare facilities, government centers, schools, public libraries and community centers. The easiest way to learn about them is on our MeetUp page. Please also feel welcome to contact me if you are interested in my presenting to your organization!
If your school is in the Greater Washington, DC metropolitan area, you can invite Chef Bon to visit your school! The Bonita Woods Wellness Institute offers a variety of culinary, nutrition and wellness programs for students. Our programs are fun, educational and memorable.
No matter where you are in the USA, you can also get Food Health type programs through Chefs Move to Schools & Prevent Obesity. Both programs are part of Mrs Obama's Let's Move! campaign, and Chef Bon is active with all of them.
Why do we do this? Because our children have the right to grow up healthfully and age as gracefully as Master Tao... and Chef Bon's mom, Ursy Potter. Ursy just returned from horseback riding & hiking very steep mountains of San Miguel, Mexico, where she took pictures of monarch butterflies (at the final stop of their southern migration). As soon as she was back home, Ursy and her husband Carter Hearn went kayaking at the Needles section of the Shenandoah River.
All 3 of these amazing adults are an inspiration to us all!
Every child also has the right to also be an inspiration of fun & healthful living!
Health and wellness education is important for our kids. Equally important is making sure that all children have access to healthful food. Please visit No Kid Hungry to give your voice in asking Congress to protect SNAP (formerly food stamps) and other federal nutrition programs in the Farm Bill. Also, you can add your email to the pledge. Your support will be very helpful!
Want to learn more? Check out these sites: Food Research and Action Center (FRAC), USDA Food and Nutrition Service, and SNAP to Health!.
Thank you Cecilia for pointing this article out to me. You can read about Marshall's innovative program here in this New York Times article from 4/25/2012.
What a wonderful program this young man has started! Look further on their Facebook page.
No one noticed the added health value to my desserts but they did notice how good they felt after eating them!
In this photo, you see:
Chef Bonita and her favorite nutrition partner Laurie Young are having fun making cooking videos. To answer the questions running through your head: No, we have no idea what we are doing. Yes, they will get better over time as we figure out how to do this right (ish). Yes, we are so happy & having a blast! Have any recipe requests? Please let us know! We would love to hear from you. Currently, we have 5 recipes on YouTube. We will get a bunch more starting in a couple of weeks. Check them out here :)


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The English High Court in Beijing Jianlong Heavy Industry Group v Golden Ocean Group Limited & Ors1 recently addressed the issue of the separability of arbitration agreements and the circumstances in which public policy factors invalidating the underlying contract may also impeach an arbitration clause.
In its pro-arbitration conclusion, the court reinforced the strength of "powerful commercial factors" which weigh in favour of upholding an agreement to arbitrate.
The doctrine of separability
Separability is a legal doctrine that allows an arbitration agreement to be considered entirely separately from the underlying contract in which it is contained. This is important where there are questions about the enforceability of the underlying agreement.
The rule stems from the case of Harbour Assurance2 and was subsequently enshrined in section 7 of the Arbitration Act 1996. The practical effect of the rule is that unenforceability of the underlying agreement does not automatically render an arbitration agreement contained within it unenforceable. Without the rule, an arbitral tribunal would always be precluded from hearing any dispute which raised a question about the validity or existence of the contract containing the arbitration agreement.
It follows that, in order to render an agreement to arbitrate unenforceable, the arbitration agreement itself must be directly impeached. In other words, there must be independent factors that specifically invalidate or render void the arbitration clause3.
Under English law, an arbitration agreement may be directly impeached on public policy grounds. The question which arises is whether or not the arbitration agreement can stand independently of the void contract4 or whether enforcement of the arbitration agreement assists in the furtherance or concealment of an illegal scheme, or the evasion of a foreign law which it causes to be broken5.
Beijing Jianlong illustrates the principle that whether or not the agreement will be struck down depends on the nature of the public policy rule that invalidates the underlying contract.
Background to Beijing Jianlong
Beijing Jianlong concerned various letters of guarantee that had been entered into by the claimant in relation to the performance of certain charterparties by a third party (HXS). The claim arose because the defendant alleged that HXS had repudiated its obligations under the charterparties, thereby rendering Beijing Jianlong liable under the guarantees.
The defendants commenced arbitration proceedings. The claimant's principal defence was that the parties knew that the giving of such guarantees is illegal in China without prior state authorisation. This rendered the guarantees unenforceable as a matter of English public policy. However, the tribunal held that the arbitration agreements would not be void or unenforceable. It was this finding that the claimant sought to challenge.
For the purposes of the court proceedings, it was assumed that the claimant's allegations were correct and that the underlying guarantees were illegal under Chinese law and therefore unenforceable. The question then became whether the arbitration agreements within the guarantees were also unenforceable.
Basis of unenforceability
The claimants relied on the public policy rule in Foster v Driscoll6 that in English law a contract will not be enforceable if the common intention of the parties was to perform, in a foreign country, an act that is illegal under the law of that country. The claimants argued that since the arbitration agreements formed part of the overall transaction to provide and conceal unlawful guarantees they were tainted by this illegality and should similarly be deemed unenforceable, as various ancillary contracts were in Foster v Driscoll.
The defendants submitted that this was going too far, and that Foster v Driscoll did not lay down a general rule to this effect. Instead they argued the court should apply the separability principle established in Harbour Assurance and ask whether the policy of the rule invalidating the main contract also invalidated the arbitration agreement.
Thus, the question for the court in Beijing Jianlong was whether the arbitration agreements were directly and distinctly impeached by the illegality of the underlying guarantees, such that by allowing the parties to arbitrate the policy of the rule rendering the contract unenforceable would be defeated.
The decision - arbitration agreement upheld
The court held that the arbitration agreements were enforceable and that the rule in Foster v Driscoll did not apply for the following reasons:
The court also emphasised that the "powerful commercial factors in favour of upholding arbitration provisions", as well as a desire to respect the parties' choice and provide a one-stop process for resolving disputes, applied to this case as they would any other arbitration dispute. The court went so far as to say that even if a public policy rule might be liable to be defeated by allowing the parties to arbitrate, this must be balanced against the powerful commercial reasons for upholding arbitration clauses, unless it is clear that this would defeat the policy of the specific illegality rule.
The English court will look at each case on its facts
Beijing Jianlong illustrates that the English court will not only enforce an arbitration agreement where the underlying contract is found to be unenforceable, but that it may also be prepared to do so even where there is a public policy rule rendering the underlying contract void for illegality.
The court will look at each case on its facts to determine if the specific public policy rule would be defeated by allowing the parties to arbitrate, but this appears to be a high test, and the courts will bear in mind the factors weighing in favour of upholding arbitration agreements.
The decision reinforces the pro-arbitration stance of the English courts, who will not lightly allow parties to avoid an agreement to arbitrate their disputes.
1 [2013] EWHC 1063 (Comm)
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I'd say that what looks to have been a weird, unfunny attempt at a Sokal-like hoax has lowered my opinion of Taleb, but that's not really possible. Not that I've ever read Taleb or have substantial basis for a negative opinion of him per se, but as best as I've been able to gather, his entire claim to fame and genius consists of continually yelling at the world that Not All Distributions Are Gaussian, thereby bravely correcting the erroneous belief to the contrary that had been held by, approximately, none people.
Feel free to correct me if I'm wrong there, but assuming I'm not, doesn't that entire schtick pretty much have to be a hoax? Because if not, that's sad.
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@Sonic Charmer- Taleb's assertion wasn't that people weren't aware of non-Gaussian distributions. For fuck's sake, his book The Black Swan was partially addressed to quants who probably knew far more math than he did. His complaint was that quants were making category errors in their analysis, which was why the market kept blowing up in their face and they kept being surprised. Their risk analysis simply did not match reality.
Now, he's a bit of a blowhard about this, and appears to think that he's discovered this wonderful theory of everything, but his book was well-timed and made some quite valid points, his personal douchiness aside.
Additionally, you'd probably agree with a good number of the criticisms he makes of quants and of scientists, who have apparently been educated beyond their intelligence, for blindly trusting their analytical models without giving much thought to the assumptions governing them. It's basically the inverse of your recent tirade against neo-cons bitching about Nate Silver's stats. They didn't like the outcome so they criticized Silver while never bothering to understand his model and what made it tick. Likewise, a lot of quants and even scientists will implicitly trust their statistical analysis because they like the results, and never bother to question the assumptions upon which their analysis is predicated. Basically, Taleb was criticizing data guys (and especially economists) for being to trusting of their implicit assumptions and the theories predicated thereupon.
The bubble pop of '08 really had less to do with models than simple greed. Ratings agencies, banks, and hedge funds effectively conspired (although mostly not intentionally) to create a serious of investments that looked too good to be true to the investors backed by mortgages that were too good to be true for the home buyers.
Thus, in a very simple, very human way, the sins of greed and pride combined to create massive failure. Most of those responsibile still retain positions of power in banks, corporations, and the government. Almost none have been held responsible for the fraud that was perpetuated.


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Metabolic Diet Review
What You Should Know
Click Here To See Our Highest Rated Review
The Metabolic Diet was created by Dr. Mauro G. Di Pasquale. He is a licensed physician in Ontario, Canada. Dr. Pasquale has been involved in the sports world for over 20 years, even competing as a power lifter in the 1976 world championships, winning the event. He used to be the former medical director for the WWF (World Wide Wrestling Federation) and is currently the president of the United World Powerlifting Federation.
Product Features
The diet itself has a two phase approach. There is the low carb Assessment Phase and the Moderate Carb Assessment Phase. The low carb Assessment Phase is more of the jump in feet-first kind of approach to see if you can handle the low carb lifestyle. The Moderate Carb Assessment Phase isn't so restrictive. The idea of the diet is to eat a low-carb lifestyle 5 days a week and then 2 days a week, however you want.
There are no ingredients in this aside from foods you would normally consider proteins and not carbohydrates. A lot of what this diet is about seems to be very similar to the Atkins Diet.
Sensible eating, exercise, and proper hydration all are part of a good diet. While there is the support of a doctor backing up the whole plan, it seems so similar to the Atkins diet that we have to take note. We've seen the low-carb craze come and go and we have to pay attention to the amount of saturated fat in our diets. This diet seems to encourage full fat versions of dairy products and makes no real mention of lean proteins over any ordinary protein. We also think it's a problem that there are 2 days during the week where you can eat anything. While we do advocate being able to treat yourself once in awhile, taking 2 whole days each week to gorge yourself on this diet isn't exactly responsible.


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Comment Suspicious article (Score 1) 200 200
Comment low tech solution (Score 1) 359 359
Don't switch banks... get a calendar
Apple Patches Massive Holes In OS X 246 246
Comment Advertizing (Score 2, Funny) 454 454
I think that will boost Nokia sales in the UK!
Comment Simple! (Score 1) 1146 1146
You don't need books to read about how a marriage works.
Believe me, all you need is love for your spouse and respect for each other. If you both have that, any problems (yep, don't believe anyone telling you that a marriage doesnt have its rainy days!), can and will be solved.
Don't look into books, look into yourself, and your partner as the most cherished person in the world. That's all.
Hey, worked for my 20 years of marriage, lol!
Comment "Coming from Netscape"... not that good PR (Score 3, Funny) 62 62
Might work unless they keep the Netscape logo
A green monster eating a planet would do them pretty poor PR
Comment bad move (Score 1) 208 208
Isn't the goal of a space agency to promote scientific advance for space travel? If they are tryng to get additional funding, they'd better team up with someone serious, like Blizzard, who knows the market, player's expectations and... how to make a successful game.
If the goal is to increase common Joe's awareness that you need to recycle etc, a boring game won't do this either.
Waste of taxpayer's money in a field where NASA has no history, no experience and
Comment Innovative methods? Old ones work best (Score 1) 504 504
A data transfer protocol described numerous times...
send messages in a bottle! Seems to work, search Slashdot for rubberduck stories!


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ABCbodybuilding - View Single Post - My summary of latest on Protein Metabolism
My summary of latest on Protein Metabolism
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Ordo Ab Chao
Ordo Ab Chao
is SHEIKO
Join Date: Oct 2008
Location: East Bay, CA
Posts: 400
Originally Posted by
President Wilson
Great points. Basically what we know from studies on concurrent training is that the effects appear to be specific to the muscle groups trained. So if you were to do say cardio for the lower body it may not effect the upper body. Probably because negative regulators of protein synthesis are generally upregulated in the trained muscle groups.
thats good news. I typically do my cardio sessions on mon and fri, which are both upper body days, and do my legs on wednesday. If I read what you said right, there should be minimal/no interference, right?
Originally Posted by
President Wilson
Now if we are dealing with legs then yes, seperating the sessions would be ideal. For strength purposes there appears to be little interference when cardio is performed the next day, but if you are doing legs at night, while protein synthesis may be back up, it is possible that the residual fatigue such as glycogen depletion from the morning session could impair performance at night. So if cardio is done on the same day, the reccomendation would be to do lower intensity, less glycogen depleting training.
The glycogen depletion is what makes me a bit hesitant to do pm lifting following am cardio. Correct me if I'm wrong, but it typically takes only 6 hours to renew glycogen stores (using proper pwo nutrition). Also, I believe a good shot of caffeine pwo will help glycogen uptake allowing this am/pm session split to work my feasibly.
I forge myself in the fire of my own will
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Starting April 24th, we are open everyday!
We are also open all holidays, usually from 10 - 5. The exact times, including sales will be listed on the Calendar of Events on the homepage.
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Learn to create a native iPad app using existing HTML, CSS, and JavaScript files. This course will show you how to take any web project and convert it into an app that is ready to earn you money, or bragging rights, in the App Store. Find out how Adobe PhoneGap Build can make this a possibility for you.
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Join us for Ignite Kids on Wednesday evenings from 6-7:30 pm! This is a new and exciting ministry for pre-K through 5th grade is a combination of music and missions. Children will get to use their musical abilities to worship God and also learn about serving in their community and world. We also provide loving child-care for our little ones, birth-3 years. Extended child-care is available for all ages until 8:15 pm for parents who are involved in the Worship Choir and Orchestra rehearsals. Stop by our Welcome Center and let one of our volunteers get you to the right class.
For more information about Ignite Kids, please contact our Children's & Preschool Office or call 972-512-3850.


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Millikin University will welcome Grammy-nominated platinum recording artist Sara Bareilles for the annual University Center Board (UCB) Big Event on April 5 at 8 p.m. in the Kirkland Fine Arts Center.
Sara Bareilles gained mainstream success with her 2007 hit, "Love Song," which brought her into the number one spot on the Billboard Pop 100 chart. She has sold over 1 million records worldwide and has been nominated for three Grammy awards. Bareilles' second album, "Little Voice" was certified as platinum by Recording Industry Association of America in 2010.
Bareilles' most recent album, "Kaleidoscope Heart," was released Sept. 7, 2010 and debuted at #1 in the United States. It features the hit song, "King of Anything," which reached #1 on the Hot AC and AAA charts and VH1. For more information on Bareilles, visit www.sarabmusic.com
Bareilles will be joined by opening acts Elizabeth and the Catapult, a pop-rock trio from Brooklyn, N.Y. and Ximena Sarinana, a Grammy and Latino Grammy-nominated singer-songwriter from Guadalajara, Mexico. For more information, visit www.Elizabethandthecatapult.com and www.Ximenamusic.com.
The UCB is Millikin University's student-run programming board, comprised of 11 student executive board members and staff advisors with the responsibility to plan, promote, execute, and evaluate student events and activities. UCB plans a variety of annual events for students to enjoy, including Fall Family Weekend, the Pancake Breakfast, Millipalooza, and Springfest. In addition, the UCB brings a nationally recognized band to campus each spring to entertain the community. Millikin students voted for Sara Bareilles as their #1 choice to perform this year. Past artists have included OneRepublic, Gavin DeGraw, The Roots, O.A.R., Ben Folds, Jason Mraz, Train, 3 Doors Down, Sugar Ray, Vertical Horizon, and Sister Hazel.
In order to maintain appropriate decorum and an atmosphere that encourages respect, Kirkland Fine Arts Center asks patrons to honor the following requests:
• All bags are subject to search
• No photography, audio taping, or videography
• No alcohol, drugs, tobacco products, or smoking of any kind
• No re-admittance once inside the theater
Patrons who do not follow the above requests or those who display inappropriate or illegal behavior will be ejected from the facility.
Tickets for the event are $20 for the general public and may be purchased at the Kirkland Fine Arts Center Box Office, by phone at 217.424.6318 or online at www.kirklandfinearts.com. A $2.50 fee will be charged for credit card purchases. This is a per transaction fee, not per ticket, and applies to online and Box Office orders. Kirkland Box Office hours are Monday-Tuesday and Thursday-Friday from 10 a.m. to 5 p.m.