WO2003049593A2 - Prevention of flap necrosis in plastic surgery - Google Patents

Prevention of flap necrosis in plastic surgery Download PDF

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Publication number
WO2003049593A2
WO2003049593A2 PCT/US2002/036138 US0236138W WO03049593A2 WO 2003049593 A2 WO2003049593 A2 WO 2003049593A2 US 0236138 W US0236138 W US 0236138W WO 03049593 A2 WO03049593 A2 WO 03049593A2
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Prior art keywords
cyclodextrin
topicauy
drag
pedicle
nitrosothiol
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PCT/US2002/036138
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French (fr)
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WO2003049593A3 (en
Inventor
Jonathan S. Stamler
Michael R. Zenn
Eric J. Toone
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Duke University
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Publication date
Application filed by Duke University filed Critical Duke University
Priority to JP2003550646A priority Critical patent/JP4563679B2/en
Priority to EP02804687A priority patent/EP1463440B1/en
Priority to CA002467245A priority patent/CA2467245A1/en
Priority to DE60234642T priority patent/DE60234642D1/en
Priority to AT02804687T priority patent/ATE450187T1/en
Priority to AU2002365036A priority patent/AU2002365036B2/en
Priority to US10/521,394 priority patent/US20060153931A1/en
Publication of WO2003049593A2 publication Critical patent/WO2003049593A2/en
Publication of WO2003049593A3 publication Critical patent/WO2003049593A3/en

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • 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
    • A61K31/04—Nitro compounds
    • 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
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • This invention is directed to a method for resolving or preventing vasoconstriction and preventing depletion of or restoring blood flow in a pedicle flap or any other microsurgery.
  • a flap may be used for reconstruction.
  • a flap is a block of tissue isolated on its nutrient blood supply. Any time tissue is transferred on its pedicle (artery and vein), it is subject to vasospasm and thrombosis which may lead to necrosis of the tissue, if uncorrected.
  • vasodilator such as Kdocaine or paparavine to pedicle which attaches the pedicle flap to its source of blood supply.
  • This resolves or prevents vasoconstriction intraoperatively but that effect is not always effective for preventing depletion of or restoiing blood flow.
  • this effect is short-lived, decreasing to about 50% of less of baseline 30 minutes after Kdocaine appKcation.
  • the invention herein in a first embodiment is directed to a method for preventing necrosis in a pedicle flap or in any microvascular surgery comprising topicaUy applying to pedicle or other source of blood supply a therapeuticaUy effective amount of vasodilator composition containing NO or NO donor or prodrug that causes formation of nitrosothiol in tissue optionaUy in combination with Kdocaine.
  • therapeutically effective amount is used herein, in respect to the first embodiment, to mean a vasoconstriction resolving or preventing amount and blood flow depletion preventing or restoring amount.
  • the invention herein in a second embodiment is directed to a method for deKveruig a drug comprising incorporating the drug in a therapeuticaUy effective amount in a gel or solution or in a pharmaceutical base containing from 1 ⁇ M to 100 mM nitrosylated polythiolated cyclodextrin or other nitrosylated polymer or long Kved gel coating equivalent exemplified by cyclodextrin or coating the drug in piU form with coating that deKvers nitric oxide and adrninistering the resulting combination topicaUy to the skin or topicaUy to the gastrointestinal tract, thereby to improve the deKvery of the drug by increasing absorption of the drug and/or to negate side effects of the drug and/or to obtain the combined effect of the drug and nitric oxide deKvery.
  • FIG. 1 is a graph of time in minutes versus % baseline and sets for the results of Background Example 2.
  • the first embodiment of the invention that is to the method for preventing necrosis in a pedicle flap or in any microvascular surgery comprising topicaUy applying to the pedicle or other source of blood supply a therapeuticaUy effective amount of vasodUation composition containing NO or NO donor or prodrug that causes formation of mtrosothiol in tissue optionaUy in combination with Kdocaine.
  • a therapeuticaUy effective amount of vasodUation composition containing NO or NO donor or prodrug that causes formation of mtrosothiol in tissue optionaUy in combination with Kdocaine.
  • NO, NO donors, and pro drugs that cause formation of nitrosothiol in tissue that are topicaUy appKed in compositions i ⁇ the first embodiment of the invention herein.
  • Nitric oxide is readUy appKed as a water solution.
  • NO donor donates nitric oxide or a related redox species and more generaUy provides nitric oxide bioactivity, that is activity which is identified with nitric oxide, e.g., vasorelaxation or stimulation or inhibition of a receptor protein, e.g., ras protein, adrenergic receptor, NFKB.
  • NO donors including S-nitroso, O-nitroso, C-nitroso and N-nitroso compounds and nitro derivatives thereof and metal NO complexes, but not excluding other NO bioactivity generating compounds, useful herein, are described in "Methods in Nitric Oxide Research," edited by FeeKsch, M., and Starnler, J.
  • NO donors which are C-nitroso compounds where nitroso is attached to a tertiary carbon which are useful herein include those described in U.S. Patent AppKcation No. 09/695,934 which has matured into U.S. Patent No. 6,359,182 and those described in WO 02/34705.
  • S-nitroso compounds including S-nitrosothiols useful herein include, for example, S-nitrosoglutathione, S-r ⁇ troso-N-acetylpem ⁇ iUarr ⁇ ie, S-nitroso-cysteine and ethyl ester thereof, S-nitroso cysteinyl glycine, S-nitiOso-gamma-methyl-L- homocysteine, S-nitroso-L-homocysteine, S-nitroso-garnma-thio-L-leucine, S-nitroso- delta-thio-L-leucine, and S-nitrosoalbumin.
  • an S-nitrosylated or an O- and S-nitrosylated compound is nitrosylated polythiolated cyclodextrin (hereinafter cyclodextrin NO or CX-NO) as described in Starnler, et al U.S. Patent No. 6,403,759 which can be, for example O- and S- nitrosylated ⁇ -cyclodextrin as described in Example 14 of U.S. Patent No. 6,403,759 or rdtrosylated perthiolated- ⁇ -cyclodext ⁇ n as described in Examples 3-6 of U.S. Patent No. 6,403,759.
  • cyclodextrin NO or CX-NO nitrosylated polythiolated cyclodextrin
  • NO donors useful herein are metal nitrosyls such as sodium nitroprusside (nipride), alkyl nitrites of molecular weight up to 10,000 such as ethyl nitrite, nitroglycerin, SINl which is molsidomine, furoxamines, N-hydroxy (N-m ⁇ rosamine), perfluorocarbons that have been saturated with NO or a hydrophobic NO donor, and NO entrained in carbon monotubules.
  • metal nitrosyls such as sodium nitroprusside (nipride), alkyl nitrites of molecular weight up to 10,000 such as ethyl nitrite, nitroglycerin, SINl which is molsidomine, furoxamines, N-hydroxy (N-m ⁇ rosamine), perfluorocarbons that have been saturated with NO or a hydrophobic NO donor, and NO entrained in carbon monotubules.
  • NO donors or NO prodnigs that causes foimation of nitrosothiol in tissue that are used in working examples are ethyl nitrite or nitrosylated polythiolated cyclodextrin.
  • the NO, NO donor and/or prodrug is administered in a therapeuticaUy effective amount.
  • these are appKed at a concentration ranging from 1 ⁇ M to 100 rnM, with variation within the range depending on the agent administered.
  • Ethyl nitrite is avaUable as 90-95% ethyl rritrite in ethanol and can be appKed as an ethanol solution at a concentration, e.g., of 5X10 "3 - 5X10 ⁇ 4 M.
  • Cyclodextrin NO can be appKed as a solution or gel or as fine particles in a pharmaceutical base at a concentration of 1 ⁇ M to 100 mM.
  • the Kdocaine can be appKed in solution or in a cream or as viscous Kdocaine present in the appKed composition, e.g., at 2 to 20%.
  • the NO, NO donor or prodrug that causes formation of nitrosothiol in tissue, and Kdocaine, if used, can be topicaUy appKed in a Kquid or viscous composition, e.g., as a solution, cream, ointment or gel.
  • a drag (which is not nitrosylated) comprising incorporating the drug in a therapeuticaUy effective amount in a gel or solution or in a pharmaceutical base containing from 1 ⁇ M to 100 mM nitrosylated polythiolated cyclodextrin (sometimes denoted CX-NO) or any nitrosylated polymer or long Kved gel coating equivalent exemplified by cyclodextrin or coating the drug in pitt fo ⁇ n with a coating that deKvers nitric oxide, e.g., a coating comprising CX-NO or other nitrosylated polymer or of nitric oxide entrained in carbon nanotubules and administeiing the resulting combination topicaUy to the skin or topicaUy to the gastrointestinal tract, thereby to improve the deKvery of the drug and/or to negate side effects of the drug and/or to
  • nitrosylated polythiolated cyclodextrin is that described for the first embodiment.
  • the drags can be, for example, aspirin or nonsteroidal anti-inflammatory drags (NSATDs) or selective inhibitors of cyclooxygenase-2, for treatment of pain or inflammation, e.g. for headache or osteoarthritis, or an antiproliferative agent, e.g. rapamycin or taxol, for the treatment of the kinds of cancer that the antiproliferative agent is therapy for, or proteins including hemoglobin as a blood substitute, factor VTA inhibitor for sepsis or insulin for the treatment of Type I diabetes.
  • CX-NO can be formulated with hemoglobin based blood substitutes at a ratio of hemoglobin to NO ranging from 25: 1 to 1,000: 1 to improve peripheral blood flow and mitigate hypertension.
  • the CX-NO can be formulated in a gel or solution or as fine particles in a pharmaceutical base and the drug later admixed or the drug and CX-NO can be formulated together in a gel or solution or pharmaceutical base or the drag can be incorporated before the CX-NO.
  • Composition containing the drug and CX-NO can be administered by appKcation topicaUy to the skin where it acts locaUy or can be incorporated in a capsule or other oral dosage form for appKcation topicaUy to the gastrointestinal tract or can be administered via inhalation for appKcation to the gastrointestinal tract.
  • Composition constituted of component(s) comprising drag, in piU form, and coating on the pUl that deKvers NO, can be administered orally for appKcation topicaUy to the gastrointestinal tract.
  • the nitric oxide from the CX-NO increases absorption of the drag by causing vasodUation and/or increasing peimeabiKty and in such case is administered in a vaso dilating and/or permeabiKty increasing amount.
  • the method of the second embodiment can also aUeviate side effects of a drag, e.g., the nitric oxide of the CX-NO wiU arneKorate or prevent gastrointestinal bleeding that can be caused by aspirin and NSAIDs.
  • a drag e.g., the nitric oxide of the CX-NO wiU arneKorate or prevent gastrointestinal bleeding that can be caused by aspirin and NSAIDs.
  • the method of the second embodiment also can be an alternative to NO or SNO substitution of the drug as described in U.S. Patent No. 6,057,367 and U.S. Patent No. 6,359,182 to obtain the combined effect of drags and NO or NO donor administration.
  • ENO means ethyl nitrite.
  • CX-NO means nitrosylated polythiolated cyclodextrin.
  • ENO slowly dilated the artery to 83+5% of baseline after 1 rnin and 98+5% of baseline after 30 min and dilated the vein to 75+5% of baseline after 30 mi ⁇ .
  • ENO restored blood flow to 62+6% of baseline after 2 rnin and 86+10% of baseline after 30 rnin.
  • ENO caused a greater restoration of blood flow and arterial diameter (p ⁇ 05) compared to Kdocaine beginrring 13 rnin (for blood flow) or 10 min (for diameter) after appKcation of each dUator. Lidocaine was shown to have a faster effect, but ENO had a longer lasting and greater effect on arterial dUation and blood flow.
  • Rats Male male rats (six) weighing 250-250 gm were anesthetized with intraperitoneal sodium pentobartital at initial doses of 50 mg/kg after being induced with isofluorane as an inhalational anesthetic. Supplemental pentobarbital was a ⁇ miirdstered as needed. The rats' core temperature was measured via rectal probe and maintained at 36-38° C with a heating pad. The groin and abdomen were shaved.
  • a tracheotomy was performed, and the rats intubated directly to help eliminate motion associated with respiratory movements.
  • BUateral 3x3 cm island skin flaps based upon the epigastic artery and vein were raised.
  • the epigastic artery and vein were carefuUy isolated from each other and from sunounding soft tissue. Dissection was performed with the aid of a surgical microscope. After elevation of the flap, it was positioned on a clear acryKc sheet and maintained at its original dimensions with 4-0 nylon sutures.
  • a laser Doppler flow probe was placed on the center of the flap.
  • a video camera was connected to the camera port opening of the microscope. Camera output was connected to a video timer, a 13 -inch video monitor, and a videotape recorder.
  • Diameter measurements were made using a digital caKper with 100- rnicrometer resolution. After dissection, the rats were aUowed to stabilize for 60 minutes before baseline measurements were recorded and the experirnent begun i ⁇ order to better help control any vascular changes associated with the preparation of the model.
  • vascular endothelin-1 (ET-1) at 10 "5 M concentration directly to the exposed vascular pedicle using a 27 gauge needle on a mberculin syringe.
  • ET-1 was dissolved in 0.1% acetic acid and stored at 20° C. Data coUected each subsequent minute included the arterial diameter, vein diameter, and laser Doppler flow. Fifteen (15) minutes foUowing the administration of ET-1, 0.25ml of 3.17mM CX-NO in ⁇ nnethylsulfoxide (DMSO) was appKed. Data were gathered for an additional thirty (30) minutes. The rats were then sacrificed with an overdose of pentobarbital.
  • DMSO ⁇ nnethylsulfoxide
  • results are shown in FIG. 1 where the upper curve is for arterial diameter as a percentage of baseline, the lowest curve is for vein diameter as a percentage of baseline and the dashed curve shows measurement of blood flow with a laser Doppler flowmeter and shows blood flow in smaU vessels as a percentage of baseline flow.
  • the results show that the CX-NO caused increase in arterial and vein diameter and increase in blood flow in smaU vessels.
  • the invention is iUustrated in the following working examples.
  • CX-NO of Example 14 of U.S. Patent No. 6,403,759 is formulated in a gel at 50 mM and is appKed topicaUy to skin to reKeve pain of osteoarthritis.
  • CX-NO of Example 14 of U.S. Patent No. 6,403,759 is formulated in a gel at 50 mM and is admixed with aspirin and the combination used to fill capsules each containing 100 mg aspirin and 200 mg of CX-NO. Adrninistration of capsules oraUy reKeved headache without any gastrointestinal bleeding.
  • the CX-NO is used as or included in a coating for aspirin tablets (100 mg aspirin in a tablet), and administration orally of the coated aspirin provides the same result.
  • Example 14 of U.S. Patent No. 6,403,759 is formulated in a gel at 50 mM together with a therapeutic amount of insulin.
  • AppKcation to skin is a treatment for Type I diabetes.
  • Example 14 of U.S. Patent No. 6,403,759 is foimulated with hemoglobin based blood substitute in a ratio of hemoglobin to NO of 500: 1.
  • the formulation is administered to a patient to improve peripheral blood flow and mitigate hypertension.

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Abstract

NO, NO donor or prodrug that causes formation of nitrosothiol in tissue optionally in combination with lidocaine is topically applied to pedicle of a pedicle flap or other source of blood supply to prevent necrosis in pedicle flap or in any microvascular surgery. Composition containing drug is formulated with nitrosylated polythiolated cyclodextrin to improve drug delivery.

Description

PREVENTION OF FLAP NECROSIS IN PLASTIC SURGERY
Cross-Reference to Related Applications
This application claims the benefit of U.S. Application No. 60/336,175, filed on December 6, 2001, the whole of which is incorporated herein by reference.
Technical Field
This invention is directed to a method for resolving or preventing vasoconstriction and preventing depletion of or restoring blood flow in a pedicle flap or any other microsurgery.
Background of the Invention
In plastic/microvascular surgery for providing new tissue where such is necessary because of traumatic or other injury or for reconstruction after surgery to remove cancerous and surrounding tissue, a flap may be used for reconstruction. Specifically, a flap is a block of tissue isolated on its nutrient blood supply. Any time tissue is transferred on its pedicle (artery and vein), it is subject to vasospasm and thrombosis which may lead to necrosis of the tissue, if uncorrected.
In an attempt to prevent flap necrosis, it is standard procedure to topically apply a vasodilator such as Kdocaine or paparavine to pedicle which attaches the pedicle flap to its source of blood supply. This resolves or prevents vasoconstriction intraoperatively but that effect is not always effective for preventing depletion of or restoiing blood flow. Moreover, this effect is short-lived, decreasing to about 50% of less of baseline 30 minutes after Kdocaine appKcation.
Summary of the Invention
It has been found herein that the effect of Kdocaine in resolving or preventing vasoconstriction and preventing depletion of or restoring blood flow in a pedicle flap in plastic surgery or other microsurgery can be improved and lengthened by use of nitric oxide (NO) and/or NO donor and/or prodrag that causes formation of nitrosothiol in tissue as the only vasodilator or in combination with Kdocaine compared to conventional use of Kdocaine alone.
The invention herein in a first embodiment is directed to a method for preventing necrosis in a pedicle flap or in any microvascular surgery comprising topicaUy applying to pedicle or other source of blood supply a therapeuticaUy effective amount of vasodilator composition containing NO or NO donor or prodrug that causes formation of nitrosothiol in tissue optionaUy in combination with Kdocaine.
The term "therapeuticaUy effective amount" is used herein, in respect to the first embodiment, to mean a vasoconstriction resolving or preventing amount and blood flow depletion preventing or restoring amount.
The invention herein in a second embodiment is directed to a method for deKveruig a drug comprising incorporating the drug in a therapeuticaUy effective amount in a gel or solution or in a pharmaceutical base containing from 1 μM to 100 mM nitrosylated polythiolated cyclodextrin or other nitrosylated polymer or long Kved gel coating equivalent exemplified by cyclodextrin or coating the drug in piU form with coating that deKvers nitric oxide and adrninistering the resulting combination topicaUy to the skin or topicaUy to the gastrointestinal tract, thereby to improve the deKvery of the drug by increasing absorption of the drug and/or to negate side effects of the drug and/or to obtain the combined effect of the drug and nitric oxide deKvery.
Brief Description of the Drawing
FIG. 1 is a graph of time in minutes versus % baseline and sets for the results of Background Example 2.
DetaUed Description
We turn now to the first embodiment of the invention, that is to the method for preventing necrosis in a pedicle flap or in any microvascular surgery comprising topicaUy applying to the pedicle or other source of blood supply a therapeuticaUy effective amount of vasodUation composition containing NO or NO donor or prodrug that causes formation of mtrosothiol in tissue optionaUy in combination with Kdocaine. We turn now to the NO, NO donors, and pro drugs that cause formation of nitrosothiol in tissue, that are topicaUy appKed in compositions iα the first embodiment of the invention herein.
Nitric oxide is readUy appKed as a water solution.
We turn now to the NO donor which is administered. An NO donor donates nitric oxide or a related redox species and more generaUy provides nitric oxide bioactivity, that is activity which is identified with nitric oxide, e.g., vasorelaxation or stimulation or inhibition of a receptor protein, e.g., ras protein, adrenergic receptor, NFKB. NO donors including S-nitroso, O-nitroso, C-nitroso and N-nitroso compounds and nitro derivatives thereof and metal NO complexes, but not excluding other NO bioactivity generating compounds, useful herein, are described in "Methods in Nitric Oxide Research," edited by FeeKsch, M., and Starnler, J. S., John WUey & Sons, New York, 1996, pages 71-115 which is incorporated herein by reference. NO donors which are C-nitroso compounds where nitroso is attached to a tertiary carbon which are useful herein include those described in U.S. Patent AppKcation No. 09/695,934 which has matured into U.S. Patent No. 6,359,182 and those described in WO 02/34705. Examples of S-nitroso compounds including S-nitrosothiols useful herein include, for example, S-nitrosoglutathione, S-rήtroso-N-acetylpem^iUarrώie, S-nitroso-cysteine and ethyl ester thereof, S-nitroso cysteinyl glycine, S-nitiOso-gamma-methyl-L- homocysteine, S-nitroso-L-homocysteine, S-nitroso-garnma-thio-L-leucine, S-nitroso- delta-thio-L-leucine, and S-nitrosoalbumin. An example of an S-nitrosylated or an O- and S-nitrosylated compound is nitrosylated polythiolated cyclodextrin (hereinafter cyclodextrin NO or CX-NO) as described in Starnler, et al U.S. Patent No. 6,403,759 which can be, for example O- and S- nitrosylated β-cyclodextrin as described in Example 14 of U.S. Patent No. 6,403,759 or rdtrosylated perthiolated-β-cyclodextιτn as described in Examples 3-6 of U.S. Patent No. 6,403,759. Examples of other NO donors useful herein are metal nitrosyls such as sodium nitroprusside (nipride), alkyl nitrites of molecular weight up to 10,000 such as ethyl nitrite, nitroglycerin, SINl which is molsidomine, furoxamines, N-hydroxy (N-m^rosamine), perfluorocarbons that have been saturated with NO or a hydrophobic NO donor, and NO entrained in carbon monotubules. Examples of C-nitroso compounds that are NO donors include:
(1), NO
Figure imgf000006_0001
Figure imgf000006_0002
Figure imgf000006_0003
NO donors or NO prodnigs that causes foimation of nitrosothiol in tissue, that are used in working examples are ethyl nitrite or nitrosylated polythiolated cyclodextrin.
As indicated above, the NO, NO donor and/or prodrug is administered in a therapeuticaUy effective amount. In general, these are appKed at a concentration ranging from 1 μM to 100 rnM, with variation within the range depending on the agent administered. Ethyl nitrite is avaUable as 90-95% ethyl rritrite in ethanol and can be appKed as an ethanol solution at a concentration, e.g., of 5X10"3- 5X10~4M. Cyclodextrin NO can be appKed as a solution or gel or as fine particles in a pharmaceutical base at a concentration of 1 μM to 100 mM.
We turn now to where the NO, NO donor or prodrug that causes formation of nitrosothiol in tissue is used iα combination with Kdocaine. The Kdocaine can be appKed in solution or in a cream or as viscous Kdocaine present in the appKed composition, e.g., at 2 to 20%.
The NO, NO donor or prodrug that causes formation of nitrosothiol in tissue, and Kdocaine, if used, can be topicaUy appKed in a Kquid or viscous composition, e.g., as a solution, cream, ointment or gel.
We turn now to the method of the second embodiment herein which is directed to a method for deKvering a drag (which is not nitrosylated) comprising incorporating the drug in a therapeuticaUy effective amount in a gel or solution or in a pharmaceutical base containing from 1 μM to 100 mM nitrosylated polythiolated cyclodextrin (sometimes denoted CX-NO) or any nitrosylated polymer or long Kved gel coating equivalent exemplified by cyclodextrin or coating the drug in pitt foπn with a coating that deKvers nitric oxide, e.g., a coating comprising CX-NO or other nitrosylated polymer or of nitric oxide entrained in carbon nanotubules and administeiing the resulting combination topicaUy to the skin or topicaUy to the gastrointestinal tract, thereby to improve the deKvery of the drug and/or to negate side effects of the drug and/or to obtain the combined effect of the drug and nitric oxide deKvery.
The nitrosylated polythiolated cyclodextrin is that described for the first embodiment.
The drags can be, for example, aspirin or nonsteroidal anti-inflammatory drags (NSATDs) or selective inhibitors of cyclooxygenase-2, for treatment of pain or inflammation, e.g. for headache or osteoarthritis, or an antiproliferative agent, e.g. rapamycin or taxol, for the treatment of the kinds of cancer that the antiproliferative agent is therapy for, or proteins including hemoglobin as a blood substitute, factor VTA inhibitor for sepsis or insulin for the treatment of Type I diabetes. For example, CX-NO can be formulated with hemoglobin based blood substitutes at a ratio of hemoglobin to NO ranging from 25: 1 to 1,000: 1 to improve peripheral blood flow and mitigate hypertension.
The CX-NO can be formulated in a gel or solution or as fine particles in a pharmaceutical base and the drug later admixed or the drug and CX-NO can be formulated together in a gel or solution or pharmaceutical base or the drag can be incorporated before the CX-NO.
Composition containing the drug and CX-NO can be administered by appKcation topicaUy to the skin where it acts locaUy or can be incorporated in a capsule or other oral dosage form for appKcation topicaUy to the gastrointestinal tract or can be administered via inhalation for appKcation to the gastrointestinal tract.
Composition constituted of component(s) comprising drag, in piU form, and coating on the pUl that deKvers NO, can be administered orally for appKcation topicaUy to the gastrointestinal tract.
The nitric oxide from the CX-NO increases absorption of the drag by causing vasodUation and/or increasing peimeabiKty and in such case is administered in a vaso dilating and/or permeabiKty increasing amount.
The method of the second embodiment can also aUeviate side effects of a drag, e.g., the nitric oxide of the CX-NO wiU arneKorate or prevent gastrointestinal bleeding that can be caused by aspirin and NSAIDs.
The method of the second embodiment also can be an alternative to NO or SNO substitution of the drug as described in U.S. Patent No. 6,057,367 and U.S. Patent No. 6,359,182 to obtain the combined effect of drags and NO or NO donor administration.
The invention is supported by the foUowing background examples, which uses a standard model for deteimirώig flap blood flow. In the Background Example 1, ENO means ethyl nitrite. In the Background Example 2, CX-NO means nitrosylated polythiolated cyclodextrin.
Background Example 1
Male rats (N=9) were anesthetized and skin flaps (3 x 3 cm) were raised bUateraUy based on the epigastric arteiy and vein. Pedicle vasoconstriction was induced by topicaUy applying 10"5 M endothenin-1 (ET-1). Fifteen minutes after ET-1 appKcation, either 2% Kdocaine or 10"4 M ENO, dissolved iα saline, was appKed. Over the subsequent 30 rnin, flap blood flow was measured with a laser Doppler flowmeter and the diameter of pedicle vessels was measured using videomicroscopy. Data are expressed as % of baseline (mean+SEM). Pairwise comparisons were perfoimed using a Student's t-test. ET-1 caused a 69-76% vasoconstriction of the epigastric artery, 43- 72% vasoconstriction of the epigastric vein, and a reduction of flap blood flow to 35- 45% of baseline. AppKcation of Kdocaine caused a rapid arterial vasodUation to 101+6% of baseline within 1 min, but after 30 iα the effect decreased to 82+6% of baseline. The vein dUated to 68+7% of baseline 30 rnin after Kdocaine appKcation. Lidocaine also caused an increase of blood flow to 87+13% of baseline in 2 min, but only 55+7% of baseline after 30 min. ENO slowly dilated the artery to 83+5% of baseline after 1 rnin and 98+5% of baseline after 30 min and dilated the vein to 75+5% of baseline after 30 miα. ENO restored blood flow to 62+6% of baseline after 2 rnin and 86+10% of baseline after 30 rnin. ENO caused a greater restoration of blood flow and arterial diameter (p< 05) compared to Kdocaine beginrring 13 rnin (for blood flow) or 10 min (for diameter) after appKcation of each dUator. Lidocaine was shown to have a faster effect, but ENO had a longer lasting and greater effect on arterial dUation and blood flow.
Background Example 2
Adult male rats (six) weighing 250-250 gm were anesthetized with intraperitoneal sodium pentobartital at initial doses of 50 mg/kg after being induced with isofluorane as an inhalational anesthetic. Supplemental pentobarbital was aαmiirdstered as needed. The rats' core temperature was measured via rectal probe and maintained at 36-38° C with a heating pad. The groin and abdomen were shaved.
A tracheotomy was performed, and the rats intubated directly to help eliminate motion associated with respiratory movements. BUateral 3x3 cm island skin flaps based upon the epigastic artery and vein were raised. The epigastic artery and vein were carefuUy isolated from each other and from sunounding soft tissue. Dissection was performed with the aid of a surgical microscope. After elevation of the flap, it was positioned on a clear acryKc sheet and maintained at its original dimensions with 4-0 nylon sutures. A laser Doppler flow probe was placed on the center of the flap. A video camera was connected to the camera port opening of the microscope. Camera output was connected to a video timer, a 13 -inch video monitor, and a videotape recorder. Diameter measurements were made using a digital caKper with 100- rnicrometer resolution. After dissection, the rats were aUowed to stabilize for 60 minutes before baseline measurements were recorded and the experirnent begun iα order to better help control any vascular changes associated with the preparation of the model.
Vasoconstriction was induced by adding a drop of Endothelin-1 (ET-1) at 10"5 M concentration directly to the exposed vascular pedicle using a 27 gauge needle on a mberculin syringe. ET-1 was dissolved in 0.1% acetic acid and stored at 20° C. Data coUected each subsequent minute included the arterial diameter, vein diameter, and laser Doppler flow. Fifteen (15) minutes foUowing the administration of ET-1, 0.25ml of 3.17mM CX-NO in άnnethylsulfoxide (DMSO) was appKed. Data were gathered for an additional thirty (30) minutes. The rats were then sacrificed with an overdose of pentobarbital.
The results are shown in FIG. 1 where the upper curve is for arterial diameter as a percentage of baseline, the lowest curve is for vein diameter as a percentage of baseline and the dashed curve shows measurement of blood flow with a laser Doppler flowmeter and shows blood flow in smaU vessels as a percentage of baseline flow. The results show that the CX-NO caused increase in arterial and vein diameter and increase in blood flow in smaU vessels.
The invention is iUustrated in the following working examples.
Example I
A 40-year-old white male with a head and neck tumor resected and reconstructed with a free tissue transfer of forearm tissues to the face develops vasospasm after reattachement and no blood flow is seen. Topical appKcation of ethyl nitrite (100 μM) results in vasodUation and flow is restored. The same result is obtained when compound (1) described above is appKed at a concentration of 50mM instead of the ethyl nitrite. The same result is obtained when sodium nitroprusside is appKed at a concentration of 50 mM instead of the ethyl nitrite.
Example II
A 60-year-old undergoing emergent CABF (coronary arteiy bypass) develops cardiac ischemia after grafting, from vasospasm of the grafts. Topical appKcation of Kdocaine (2%) resulted in temporaiy but marginal blood flow. Addition of 100 μM ethyl nitrite restored flow and normalized EKG (ischemia).
Example III
CX-NO of Example 14 of U.S. Patent No. 6,403,759 is formulated in a gel at 50 mM and is appKed topicaUy to skin to reKeve pain of osteoarthritis.
Example IV
CX-NO of Example 14 of U.S. Patent No. 6,403,759 is formulated in a gel at 50 mM and is admixed with aspirin and the combination used to fill capsules each containing 100 mg aspirin and 200 mg of CX-NO. Adrninistration of capsules oraUy reKeved headache without any gastrointestinal bleeding. Alternatively, the CX-NO is used as or included in a coating for aspirin tablets (100 mg aspirin in a tablet), and administration orally of the coated aspirin provides the same result.
Example V
The CX-NO of Example 14 of U.S. Patent No. 6,403,759 is formulated in a gel at 50 mM together with a therapeutic amount of insulin. AppKcation to skin is a treatment for Type I diabetes.
Example VI
The CX-NO of Example 14 of U.S. Patent No. 6,403,759 is foimulated with hemoglobin based blood substitute in a ratio of hemoglobin to NO of 500: 1. The formulation is administered to a patient to improve peripheral blood flow and mitigate hypertension.
Variations
Variations wiU be obvious to those skiUed in the art. Thus, the scope of the invention is defined by the claims.

Claims

WHAT IS CLAIMED IS:
1. A method for preventing necrosis in a pedicle flap or in any microvascular surgery comprising topicaUy applying to pedicle or other source of blood supply, a therapeuticaUy effective amount of vasodUator composition containing NO or NO donor or prodrug that causes formation of nitrosothiol in tissue, optionaUy in combination with Kdocaine.
2. The method of Claim 1 where the vasodilator composition contains alkyl nitrite of molecular weight up to 10,000.
3. The method of Claim 2 where the alkyl nitrite is ethyl nitrite.
4. The method of Claim 1 where the vasodilator composition contains an S- nitrosothiol.
5. The method of Claim 4 where the S-nitrosothiol is cyclodextrin NO.
6. The method of Claim 1 where the vasodUator composition contains a metal nitrosyl.
7. A method for deKveriαg a drag comprising incorp orating the drag in a gel or in a solution or in a pharmaceutical base, containing from 1 μM to 100 μM nitrosylated polythiolated cyclodextrin or other nitrosylated polymer or long Kved gel coating equivalent exemplified by cyclodextrin or coating the drag in piU form with a coating that deKvers nitric oxide, and adinimstering the resulting drag containing com osition topicaUy to the skin or topicaUy to the gastrointestinal tract.
8. The method of Claim 7 where the drug is incorporated in a therapeuticaUy effective amount in a gel containing from 1 μM to 100 mM nitrosylated polythiolated cyclodextrin.
PCT/US2002/036138 2001-12-06 2002-12-02 Prevention of flap necrosis in plastic surgery WO2003049593A2 (en)

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JP2003550646A JP4563679B2 (en) 2001-12-06 2002-12-02 Prevention of tissue valve necrosis in plastic surgery
EP02804687A EP1463440B1 (en) 2001-12-06 2002-12-02 Prevention of flap necrosis in plastic surgery
CA002467245A CA2467245A1 (en) 2001-12-06 2002-12-02 Prevention of flap necrosis in plastic surgery
DE60234642T DE60234642D1 (en) 2001-12-06 2002-12-02 PREVENTION OF SKIN LAPSE NECROSIS IN PLASTIC SURGERY
AT02804687T ATE450187T1 (en) 2001-12-06 2002-12-02 PREVENTION OF SKIN FLAPE NECROSIS IN PLASTIC SURGERY
AU2002365036A AU2002365036B2 (en) 2001-12-06 2002-12-02 Prevention of flap necrosis in plastic surgery
US10/521,394 US20060153931A1 (en) 2001-12-06 2002-12-02 Prevention of flap necrosis in plastic surgery

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AU2002365036B2 (en) 2006-09-21
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EP1463440B1 (en) 2009-12-02
EP1463440A2 (en) 2004-10-06
JP2005511708A (en) 2005-04-28
JP5266191B2 (en) 2013-08-21
JP4563679B2 (en) 2010-10-13
DE60234642D1 (en) 2010-01-14
WO2003049593A3 (en) 2004-02-19
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CA2467245A1 (en) 2003-06-19
US20060153931A1 (en) 2006-07-13

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