text:
A coated stent or intra-luminal prosthesis containing a MAP kinase inhibitor controls, reduces, or prevents restenosis, inflammation, and complications associated with stent or intra-luminal prosthesis implantation and/or cardiovascular disease.
1. A stent or intra-luminal prosthesis comprising a MAP kinase inhibitor of formula (1), (2) or (3), wherein:
formula (1) is:
one Z2 is CA or CR8A and the other is CR1, CR1 2, NR6 or N wherein each R1, R6 and R8 is independently hydrogen or noninterfering substituent;
A is —CO(X)jY wherein Y is COR2 or an isostere thereof and R2 is hydrogen or a noninterfering substituent, X is a spacer preferably of 2–6 Å, and j is 0 or 1;
Z3 is NR7 or O;
each R3 is independently a noninterfering substituent;
n is 0–3;
each of L1 and L2 is a linker;
each R4 is independently a noninterfering substituent;
m is 0–4;
Z1 is CR5 or N wherein R5 is hydrogen or a noninterfering substituent;
each of 1 and k is an integer from 0–2 wherein the sum of 1 and k is 0–3;
Ar is an aryl group substituted with 0–5 noninterfering substituents, wherein two noninterfering substituents can form a fused ring; and the distance between the atom of Ar linked to L2 and the center of the α ring is preferably less than 24 Å;
formula (2)is:
each Z2 is independantly CR1 or CR1 2 wherein R1 is independently hydrogen or noninterfering substituent;
R7 is a non-interferring substituent;
each of Z4 and Z5 is independently N or CR1 is as defined above and wherein at least one of Z4 and Z5 is N;
each R3 is independently a noninterfering substituent;
n is 0–3;
each of L1 and L2 is a linker;
each R4 is independently a noninterfering substituent;
m is 0–4;
Z1 is CR5 or N wherein R5 is hydrogen or a noninterfering substituent;
each of 1 and k is an integer from 0–2 wherein the sum of 1 and k is 0–3;
Ar′ is a cyclic group substituted with 0–5 noninterfering substituents, wherein two said noninterfering substituents can form a fused ring; and
the distance between the atom of Ar′ linked to L2 and the center of the α ring is 4.5–24 Å; 1883
and formula (3) is:
one Z2 is CA and the other is CR1, wherein R1 is hydrogen or a noninterfering substituent;
A is Wi-COXjY wherein Y is COR2 wherein R2 is hydrogen or a noninterfering substituent, each of W and X is a spacer preferably of 26 Å, and each of i and j is independently 0, 1 or 2;
each R6 is independently H, or a noninterfering substituent, wherein two R6 may optionally form a 5–7 membered ring including the nitrogen to which they are bound;
each R3 is independently a noninterfering substituent;
n is 0–3;
each of L1 and L2 is a linker;
each R4 is independently a noninterfering substituent;
m is 0–4;
Z1 is CR5 or N wherein R5 is hydrogen or a noninterfering substituent;
Ar is a phenyl or thienyl group substituted with 0 5 noninterfering substituents, wherein two noninterfering substituents can form a fused ring; and
the distance between the atom of Ar linked to L2 and the center of the α ring is preferably 4.5 to 24 Å;
or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
2. The stent or intra-luminal prosthesis as in
3. The stent or intra-luminal prosthesis as in
4. The stent or intra-luminal prosthesis as in
5. The stent as or intra-luminal prosthesis as in
6. A method of making the stent or intra-luminal prosthesis defined in
combining the MAP kinase with a material to make a stent or intra-luminal prosthesis and forming a stent or intra-luminal prosthesis from the material containing the MAP kinase inhibitor.
7. The method as in
8. The method as defined in
9. A method of treating cardiovascular disease comprising implanting a subject with the stent or intra-luminal prosthesis defined in
10. The method as in
11. The method defined in
12. The method defined in
13. A method of reducing restenosis resulting from vascular stent or intra-luminal prosthesis implantation, comprising:
implanting the stent or intra-luminal prosthesis defined in
14. The stent or intra-luminal prosthesis defined in
15. The stent or intra-luminal prosthesis defined in
16. A method to treat plaque comprising implanting a stent or intra-luminal prosthesis defined in
17. The stent or intra-luminal prosthesis of
19. The stent or intra-luminal prosthesis of
or a pharmaceutically acceptable salt thereof.
This application claims priority to U.S. provisional application 60/506,216 filed Sep. 25, 2003. The contents of this document are incorporated herein by reference.
The disclosed invention relates to stents or intra-luminal prosthesis coated with or otherwise containing a MAP kinase inhibitor such as a p38 MAP kinase inhibitor. MAP kinase inhibitor containing stents or intra-luminal prosthesis control, reduce, or prevent restenosis, inflammation, and complications associated with stent or intra-luminal prosthesis implantation and/or cardiovascular disease.
Coated Stents
The use of stents to hold open the lumens of blood vessels has become quite widespread. Although stents are recognized as being useful for holding open occluded blood vessels, including occluded coronary arteries, the successful use of stents is limited to a certain degree. For example, a significant degree of restenosis, inflammation, and cardiovascular disorders result from stent implantation.
Currently, attempts to improve the clinical performance of stents have involved some variation of either applying a coating to the metal of the stent (as discussed in U.S. Pat. No. 5,356,433, entitled, "Biocompatible metal surfaces" and U.S. Pat. No. 5,336,518, entitled, "Treatment of metallic surfaces using radiofrequency plasma deposition and chemical attachment of bioactive agents", both of which are hereby incorporated by reference), attaching a covering or membrane, embedding material on the surface of the stent via ion bombardment, or including reservoirs in the design of the stent. In addition, certain therapeutic agents such as rapamycin or heparin are coated on stents.
One area in which stents are limited is with respect to inflammation that occurs at the lesion site. It would be useful in the field of stents to provide a stent that contains a therapeutic agent that control, reduce, or prevent restenosis, inflammation, and cardiovascular complications associated with stent implantation and/or cardiovascular disease.
Also encompassed in the invention is a method of treating a subject including providing a stent containing a MAP kinase inhibitor such as p38 kinase inhibitor to a subject.
The disclosed invention is directed to a stent or intra-luminal prosthesis comprising a MAP kinase inhibitor, preferably p38 kinase inhibitor, wherein the inhibitor is adhered thereto or integral therewith, and methods of making and using such a stent or intra-luminal prosthesis. In one preferred embodiment, the stent further comprises a strut containing at least one channel or well therein which contains the MAP kinase inhibitor. In another preferred embodiment, the coating is a dispersion or solution containing the MAP kinase inhibitor. The coating may also contain a polymer, for example, where the MAP kinase is distributed throughout. The stent or intra-luminal prosthesis itself may be bioabsorbable and have MAP kinase inhibitors coated thereon or distributed therethrough. Such stents or intra-luminal prosthesis may also comprise an additional active component such as rapamycin.
Also encompassed in the invention is a method of treating a subject, for example, one having an occluded blood vessel or cardiovascular disease, including implanting a stent or intra-luminal prosthesis containing a MAP kinase inhibitor such as p38 kinase inhibitor to a subject. Further, the invention is directed to a method of reducing restenosis and/or inflammation comprising implanting the stent or intra-luminal prosthesis in a blood vessel such as an artery of a subject, wherein the restenosis of the vessel resulting from implantation of the stent or intra-luminal prosthesis is less than that observed from implantation of a stent or intra-luminal prosthesis not comprising a MAP kinase inhibitor. The methods above are also applicable where the subject has a vulnerable plaque at a site other than the stent or intra-luminal prosthesis implantation. In one embodiment, inflammation at the site of implantation is reduced in comparison to that observed from an implantation of a stent or intra-luminal prosthesis not comprising a MAP kinase inhibitor. The invention also provides a method to treat plaque comprising implanting a stent or intra-luminal prosthesis of the invention in a blood vessel of a subject in need thereof.
This application describes compositions and methods for delivering a therapeutic agent using a stent or intra-luminal prosthesis. Specifically, a stent or intra-luminal prosthesis containing a MAP kinase inhibitor is placed at the diseased site in the vascular system such as within an artery. Stents that can be used in accordance with the invention may be cylindrical and perforated with passages that are slots, ovoid, circular or the like shape. Stents may also be composed of helically wound or serpentine wire structures in which the spaces between the wires form the passages. Stents may be flat perforated structures that are subsequently rolled to form tubular structures or cylindrical structures that are woven, wrapped, drilled, etched or cut to form passages. Examples of stents include but are not limited stents described in the following U.S. Pat. No. 4,733,665 (hereinafter the Palmaz stent); U.S. Pat. No. 4,800,882 (hereinafter the Gianturco stent); U.S. Pat. No. 4,886,062 (hereinafter the Wiktor stent) and U.S. Pat. No. 5,514,154 (hereinafter the Guidant RX Multilink™ stent). These stents can be made of biocompatible materials including biostable and bioabsorbable materials. Suitable biocompatible metals include, but are not limited to, stainless steel, tantalum, titanium alloys (including nitinol), and cobalt alloys (including cobalt-chromium-nickel alloys). Suitable bioabsorbable metallic stents, such as those produced by Biotronik are also contemplated. Suitable nonmetallic biocompatible materials include, but are not limited to, polyamides, polyolefins (i.e., bioabsorbable polymers such as polypropylene, polyethylene etc.), nonabsorbable polyesters (i.e., polyethylene terephthalate), poly (phosphoester) or polyamino carbonate, and bioabsorbable aliphatic polyesters (i.e., omopolymers and copolymers of lactic acid, glycolic acid, lactide, glycolide, para-dioxanone, trimethylene carbonate, ε-caprolactone, etc. and blends thereof), such as poly-L-lactic acid/glycolic acid. In addition, intraluminal prostheses may be used, e.g., those that are tubular in nature and are made from similar materials.
The invention provides for a biodegradable stent MAP kinase inhibitor delivery platform which in one aspect allows for time-dependent delivery of such drug. It also provides a method for delivery of MAP kinase inhibitors to treat multifocal and more diffuse diseases such as vulnerable plaques and peripheral vascular diseases, for example, diseases associated with superficial femoral artery (SFA) and abdominal aortic aneurism (AAA). Subjects with cardiovascular disease generally have vulnerable plaques in multiple locations throughout their coronary arteries and body. Thus, stents according to the invention, in one embodiment, induce MAP kinase mediated responses in subjects with cardiovascular diseases such as those having complex lesions exhibiting features of vulnerable plaques. Thus, the invention is useful for local therapy as well as systemic therapy.
Any MAP kinase, or preferably, p38 kinase, inhibitor may be used to coat or be distributed in a stent or intraluminal prosthesis. Preferred inhibitors of MAP kinase are disclosed in WO 00/12074, WO 99/61426, WO 02/46158, WO 00/71535, WO 0/59904, WO 00/12497, WO 02/042292, WO 2004/032874, and WO 2004/022712, all of which are incorporated herein in their entirety.
MAP Kinase
A large number of chronic and acute conditions have been recognized to be associated with perturbation of the inflammatory response. A large number of cytokines participate in this response, including interleukin 1 (IL-1), interleukin 6 (IL-6), interleukin 8 (IL-8) and tumor necrosis factor (TNF). It appears that the activity of these cytokines in the regulation of inflammation relies at least in part on the activation of an enzyme on the cell signaling pathway, a member of the MAP kinase family generally known as p38 and alternatively known as CSBP and RK. This kinase is activated by dual phosphorylation after stimulation by physiochemical stress, treatment with lipopolysaccharides or with proinflammatory cytokines such as IL-1 and TNF. Therefore, inhibitors of the kinase activity of p38 are useful anti-inflammatory agents.
PCT applications WO 98/06715, WO 98/07425, and WO 96/40143, all of which are incorporated herein by reference, describe the relationship of p38 kinase inhibitors with various disease states, including but not limited to cardiovascular diseases. As mentioned in these applications, inhibitors of p38 kinase are useful in treating a variety of diseases. The compounds disclosed in these applications are either imidazoles or are indoles substituted at the 3- or 4-position with a piperazine ring linked through a carboxamide linkage. Additional compounds which are conjugates of piperazines with indoles are described as insecticides in WO 97/26252, also incorporated herein by reference.
Indolyl substituted piperidines and piperazines which inhibit p38 kinase are described in PCT publication no. WO 99/61426 published 2 Dec. 1999. Certain aroyl/phenyl-substituted piperazines and piperidines which inhibit p38 kinase are described in PCT publication WO 00/12074 published 9 Mar. 2000. Carbolene derivatives of piperidine and piperazine as p38 inhibitors are described in WO 00/59904 published 12 Oct. 2000. Substituted piperidines and piperazines linked to an indole or indole derivative having a glyoxal group at the position corresponding to 2- or 3-position of indole that are used as p38 inhibitors is described in PCT publication WO 00/71535 published 30 Nov. 2000. Substituted piperidines and piperazines which are linked to an aryl group having a glyoxal substituent that are used for p38 inhibition are described in PCT publication WO 02/46158 published 13 Jun. 2002. Azaindole derivatives linked to a piperazine- or piperidine-type moiety used for p38 inhibition are described in WO 2004/032874 published Apr. 26, 2004. Indole derivatives substituted by an amine at position 1, coupled to piperazine- or piperidine-type moieties, are also useful in the apparatuses and methods of the invention as described in WO 2004/022712.
Quinazoline and quinazoline derivatives containing mandatory substituents at positions corresponding to the 2- and 4-positions of quinazoline that are used for p38 inhibitors are described in WO 00/12497 published on 9 Mar. 2000. Substituted piperazines and piperidines linked to an indole or indole derivative having a glyoxal substituent at the position corresponding to the 4-, 5-, 6-, or 7-position of indole which inhibit p38 kinase are described in PCT publication WO 02/042292 published 30 May 2002.
These quinazoline, piperidine and piperazine compounds are particularly useful in the context of the present invention.
It is contemplated that MAP kinase inhibitors include within their scope salts and cosalts, solvates and cosolvates, crystals and cocrystals or combinations thereof, of the components more specifically discussed herein. Examples of such variants may be found in Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000). When the compounds of the invention contain one or more chiral centers, the invention includes optically pure forms as well as mixtures of stereoisomers or enantiomers.
Exemplary Inhibitors
Compounds useful in the practice of the present invention include, but are not limited to, compounds of formula:
Exemplary compounds of this formula include:
Compounds useful in the practice of the present invention also include, but are not limited to, compounds of formula:
Compounds useful in the practice of the present invention also include, but are not limited to, compounds of formula:
Compounds useful in the practice of the present invention also include, but are not limited to, compounds of formulas:
Exemplary compounds of these formulas include:
Compounds useful in the practice of the present invention also include, but are not limited to, compounds of formulas:
Exemplary compounds of these formulas include:
Compounds useful in the practice of the present invention also include, but are not limited to, compounds of formula:
Compounds useful in the practice of the present invention also include, but are not limited to, compounds of formulas:
Compounds useful in the practice of the present invention also include, but are not limited to, compounds of formulas:
Compounds useful in the practice of the present invention also include, but are not limited to, compounds of formulas:
Compounds useful in the practice of the present invention also include, but are not limited to, compounds of formulas:
Compounds useful in the practice of the present invention also include, but are not limited to, compounds of formulas:
Compounds useful in the practice of the present invention also include, but are not limited to, compounds of formula:
Exemplary compounds of these formulas include:
Such compounds are described in published PCT applications WO 96/21452, WO 96/40143, WO 97/25046, WO 97/35856, WO 98/25619, WO 98/56377, WO 98/57966, WO 99/32110, WO 99/32121, WO 99/32463, WO 99/61440, WO 99/64400, WO 00/10563, WO 00/17204, WO 00/19824, WO 00/41698, WO 00/64422, WO 00/71535, WO 01/38324, WO 01/64679, WO 01/66539, and WO 01/66540, each of which is herein incorporated by reference in their entirety.
In all instances herein where there is an alkenyl or alkynyl moiety as a substituent group, the unsaturated linkage, i.e., the vinylene or acetylene linkage, is preferably not directly attached to the nitrogen, oxygen or sulfur moieties, for instance in ORf, or for certain R2 moieties.
As used herein, "optionally substituted" unless specifically defined shall mean such groups as halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; hydroxy-substituted C1-10alkyl; C1-10 alkoxy, such as methoxy or ethoxy; S(O)m alkyl, wherein m is 0, 1 or 2, such as methyl thio, methylsulfinyl or methyl sulfonyl; amino, mono and di-substituted amino, such as in the NR7R17 group; or where the R7R17 can together with the nitrogen to which they are attached cyclize to form a 5- to 7-membered ring which optionally includes an additional heteroatom selected from O, N, and S; C1-10 alkyl, cycloalkyl, or cycloalkyl alkyl group, such as methyl, ethyl, propyl, isopropyl, t-butyl, etc. or cyclopropyl methyl; halo-substituted C1-10 alkyl, such as CF3; an optionally substituted aryl, such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenethyl, wherein these aryl moieties can also be substituted one to two times by halogen; hydroxy; hydroxy-substituted alkyl; C1-10 alkoxy; S(O)m alkyl; amino, mono- and di-substituted amino, such as in the NR7R17 group; alkyl, or CF3.
Inhibitors useful in the present invention can be used with any pharmaceutically acceptable salt. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound utilized by the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Basic salts of inorganic and organic acids also include as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically-acceptable salts of the above-described compounds can also be formed with a pharmaceutically-acceptable cation, for instance, if a substituent group comprises a carboxy moiety. Suitable pharmaceutically-acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations.
Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. Synthesis of the disclosed compounds is discussed in U.S. patent application Ser. No. 09/575,060, which is hereby incorporated by reference in its entirety.
The inhibitors of MAP kinase such as p38 can be used as a single therapeutic agent in a stent or intra-luminal prosthesis of the invention or in combination with other therapeutic agents. Drugs that could be usefully combined with these compounds include monoclonal antibodies targeting cells of the immune system, antibodies or soluble receptors or receptor fusion proteins targeting immune or non-immune cytokines, and small molecule inhibitors of cell division, protein synthesis, or mRNA transcription or translation, or inhibitors of immune cell differentiation, activation, or function (e.g., cytokine secretion). Additionally, compounds that inhibit cell growth or generally inhibit restenosis are contemplated for use with the claimed invention. Examples of such technology include heparin-coated stents, sirolimus-eluting stents, paclitaxol-coated stents, and the like.
The following terms, as used herein, refer to:
For the purposes herein the "core" 4-pyrimidinyl moiety for R1 or R2 is referred to as the formula:
The compounds useful in the practice of the present invention can contain one or more asymmetric carbon atoms and can exist in racemic and optically active forms. The use of all of these compounds are included within the scope of the present invention.
Compounds useful in the practice of the present invention also include, but are not limited to, the compounds shown in Tables A and B, below.
The compounds described above are provided for guidance and exemplary purposes only. It should be understood that any modulator of p38 MAP kinase is useful for the invention provided that it exhibits adequate activity relative to the targeted protein. Alternative modulators of p38 MAP kinase activity, such as antibodies or functional fragments thereof are also contemplated for use in the claimed invention. Preferred modulators useful for the invention should be adequately active against p38 MAP kinase while being compatible with stent coating and applications. Variables to take into consideration should include stent composition, structure, and use, coating methods and techniques, other manufacturing processes including exposure to solvents and relevant chemistries, shelf life, stability, safety, efficacy, pharmokinetics, pharmacodynamics and the like.
Coating Stents or Intra-Luminal Prostheses
One approach to coating stents or intra-luminal prostheses is to incorporate the MAP kinase inhibitor into a polymer material which is then coated on the stent or intra-luminal prosthesis. Such polymer coatings are known in the art such as that discussed in U.S. Pat. Nos. 6,153,252 and 6,364,903. Examples of such polymers include elastomers such as an ε-caprolactone and glycolide copolymer, polytetrafluoroethylene (PTFE), expanded PTFE (ePTFE), polyurethane, fluorinated ethylene propylene (FEP), silicone, polyurethane-acrylate, silicone-acrylate, urethanesilicone, and the like. Combinations of these polymers may also be usefufl. Portions of the stent or intra-luminal prosthesis may also be coated with different polymers.
In addition, film-forming polymers that can be used for coatings in this application can be absorbable or non-absorbable and should be biocompatible to minimize irritation to the vessel wall. The polymer may be either biostable or bioabsorbable depending on the desired rate of release or the desired degree of polymer stability, but a bioabsorbable polymer is preferred since, unlike biostable polymer, it will not be present long after implantation to cause any adverse, chronic local response. Furthermore, bioabsorbable polymers do not present the risk that over extended periods of time there could be an adhesion loss between the stent or intra-luminal prosthesis and coating caused by the stresses of the biological environment that could dislodge the coating and introduce further problems even after the stent is encapsulated in tissue.
Suitable film-forming bioabsorbable polymers that could be used include polymers selected from the group consisting of aliphatic polyesters, poly(amino acids), copoly(ether-esters), polyalkylenes oxalates, polyamides, poly(iminocarbonates), polyorthoesters, polyoxaesters, polyamidoesters, polyoxaesters containing amido groups, poly(anhydrides), polyphosphazenes, biomolecules and blends thereof. For the purpose of this invention aliphatic polyesters include homopolymers and copolymers of lactide (which includes lactic acid d-,1- and meso lactide), ε-caprolactone, glycolide (including glycolic acid), hydroxybutyrate, hydroxyvalerate, para-dioxanone, trimethylene carbonate (and its alkyl derivatives), 1,4-dioxepan-2-one, 1,5-dioxepan-2-one, 6,6-dimethyl-1,4-dioxan-2-one and polymer blends thereof. Poly(iminocarbonate) for the purpose of this invention include as described by Kemnitzer and Kohn, in the Handbook of Biodegradable Polymers, edited by Domb, Kost and Wisemen, Hardwood Academic Press, 1997, pages 251–272. Copoly(ether-esters) for the purpose of this invention include those copolyester-ethers described in Journal of Biomaterials Research, Vol. 22, pages 993–1009, 1988 by Cohn and Younes and Cohn, Polymer Preprints (ACS Division of Polymer Chemistry) Vol. 30(1), page 498, 1989 (e.g., PEO/PLA). Polyalkylene oxalates for the purpose of this invention include U.S. Pat. Nos. 4,208,511; 4,141,087; 4,130,639; 4,140,678; 4,105,034; and 4,205,399 (incorporated by reference herein). Polyphosphazenes, co-, ter- and higher order mixed monomer based polymers made from L-lactide, D, L-lactide, lactic acid, glycolide, glycolic acid, para-dioxanone, trimethylene carbonate and ε-caprolactone such as are described by Allcock in The Encyclopedia of Polymer Science, Vol. 13, pages 31–41, Wiley Intersciences, John Wiley & Sons, 1988 and by Vandorpe, Schacht, Dejardin and Lemmouchi in the Handbook of Biodegradable Polymers, edited by Domb, Kost and Wisemen, Hardwood Academic Press, 1997, pages 161–182 (which are hereby incorporated by reference herein). Polyanhydrides from diacids of the form HOOC—C6H4—O—(CH2)m—O—C6H4—COOH where m is an integer in the range of from 2 to 8 and copolymers thereof with aliphatic alpha-omega diacids of up to 12 carbons. Polyoxaesters polyoxaamides and polyoxaesters containing amines and/or amido groups are described in one or more of the following U.S. Pat. Nos. 5,464,929; 5,595,751; 5,597,579; 5,607,687; 5,618,552; 5,620,698; 5,645,850; 5,648,088; 5,698,213 and 5,700,583; (which are incorporated herein by reference). Polyorthoesters such as those described by Heller in Handbook of Biodegradable Polymers, edited by Domb, Kost and Wisemen, Hardwood Academic Press, 1997, pages 99–118 (hereby incorporated herein by reference). Film-forming polymeric biomolecules for the purpose of this invention include naturally occurring materials that may be enzymatically degraded in the human body or are hydrolytically unstable in the human body such as fibrin, fibrinogen, collagen, elastin, and absorbable biocompatable polysaccharides such as chitosan, starch, fatty acids (and esters thereof), glucoso-glycans and hyaluronic acid.
Suitable film-forming biostable polymers with relatively low chronic tissue response, such as polyurethanes, silicones, poly(meth)acrylates, polyesters, polyalkyl oxides (polyethylene oxide), polyvinyl alcohols, polyethylene glycols and polyvinyl pyrrolidone, as well as, hydrogels such as those formed from crosslinked polyvinyl pyrrolidinone and polyesters could also be used. Other polymers could also be used if they can be dissolved, cured or polymerized on the stent or intra-luminal prosthesis. These include polyolefins, polyisobutylene and ethylene-alphaolefin copolymers; acrylic polymers (including methacrylate) and copolymers, vinyl halide polymers and copolymers, such as polyvinyl chloride; polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene halides such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile, polyvinyl ketones; polyvinyl aromatics such as polystyrene; polyvinyl esters such as polyvinyl acetate; copolymers of vinyl monomers with each other and olefins, such as etheylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins and ethylene-vinyl acetate copolymers; polyamides, such as Nylon 66 and polycaprolactam; alkyd resins; polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxy resins, polyurethanes; rayon; rayon-triacetate, cellulose, cellulose acetate, cellulose acetate butyrate; cellophane; cellulose nitrate; cellulose propionate; cellulose ethers (i.e. carboxymethyl cellulose and hydoxyalkyl celluloses); and combinations thereof. Polyamides for the purpose of this application would also include polyamides of the form —NH—(CH2)n—CO—and NH—(CH2)x—NH—CO—(CH2)y—CO, wherein n is preferably an integer in from 6 to 13; x is an integer in the range of form 6 to 12; and y is an integer in the range of from 4 to 16. The list provided above is illustrative but not limiting.
The polymers used for coatings preferably are film-forming polymers that have molecular weight high enough as to not be waxy or tacky. The polymers also should adhere to the stent and not be so readily deformable after deposition on the stent as to be able to be displaced by hemodynamic stresses. The polymers molecular weight be high enough to provide sufficient toughness so that the polymers will not to be rubbed off during handling or deployment of the stent and should not crack during expansion of the stent. The melting point of the polymer used in the present invention should have a melting temperature above 40� C., preferably above about 45� C., more preferably above 50� C. and most preferably above 55� C.
The preferable embodiment includes bioabsorbable elastomers, more preferably aliphatic polyester elastomers. In the proper proportions aliphatic polyester copolymers are elastomers. Elastomers present the advantage that they tend to adhere well to the metal stents and can withstand significant deformation without cracking. The high elongation and good adhesion provide superior performance to other polymer coatings when the coated stent is expanded. Examples of suitable bioabsorbable elastomers are described in U.S. Pat. No. 5,468,253 hereby incorporated by reference. Preferably the bioabsorbable biocompatible elastomers based on aliphatic polyester, including but not limited to those selected from the group consisting of elastomeric copolymers of ε-caprolactone and glycolide (preferably having a mole ratio of ε-caprolactone to glycolide of from about 35:65 to about 65:35, more preferably 45:55 to 35:65) elastomeric copolymers of ε-caprolactone and lactide, including L-lactide, D-lactide blends thereof or lactic acid copolymers (preferably having a mole ratio of ε-caprolactone to lactide of from about 35:65 to about 90:10 and more preferably from about 35:65 to about 65:35 and most preferably from about 45:55 to 30:70 or from about 90:10 to about 80:20) elastomeric copolymers of p-dioxanone (1,4-dioxan-2-one) and lactide including L-lactide, D-lactide and lactic acid (preferably having a mole ratio of p-dioxanone to lactide of from about 40:60 to about 60:40) elastomeric copolymers of ε-caprolactone and p-dioxanone (preferably having a mole ratio of ε-caprolactone to p-dioxanone of from about 30:70 to about 70:30) elastomeric copolymers of p-dioxanone and trimethylene carbonate (preferably having a mole ratio of p-dioxanone to trimethylene carbonate of from about 30:70 to about 70:30), elastomeric copolymers of trimethylene carbonate and glycolide (preferably having a mole ratio of trimethylene carbonate to glycolide of from about 30:70 to about 70:30), elastomeric copolymer of trimethylene carbonate and lactide including L-lactide, D-lactide, blends thereof or lactic acid copolymers (preferably having a mole ratio of trimethylene carbonate to lactide of from about 30:70 to about 70:30) and blends thereof. As is well known in the art these aliphatic polyester copolymers have different hydrolysis rates, therefore, the choice of elastomer may in part be based on the requirements for the coatings adsorption. For example ε-caprolactone-co-glycolide copolymer (45:55 mole percent, respectively) films lose 90% of their initial strength after 2 weeks in simulated physiological buffer whereas the ε-caprolactone-co-lactide copolymers (40:60 mole percent, respectively) loses all of its strength between 12 and 16 weeks in the same buffer. Mixtures of the fast hydrolyzing and slow hydrolyzing polymers can be used to adjust the time of strength retention.
In one embodiment, the PLGA class of polymers preferably have an inherent viscosity of from about 1.0 dL/g to about 4 dL/g, preferably an inherent viscosity of from about 1.0 dL/g to about 2 dL/g and most preferably an inherent viscosity of from about 1.2 dL/g to about 2 dL/g as determined at 25� C. in a 0.1 gram per deciliter (g/dL) solution of polymer in hexafluoroisopropanol (HFIP).
The solvent is chosen such that there is the proper balance of viscosity, deposition level of the polymer, solubility of the MAP kinase inhibitor, wetting of the stent or intra-luminal prosthesis and evaporation rate of the solvent to properly coat the stent or intra-luminal prosthesis. In the preferred embodiment, the solvent is chosen such the MAP kinase inhibitor and the polymer are both soluble in the solvent. In some cases, the solvent should be chosen such that the coating polymer is soluble in the solvent and such that MAP kinase inhibitor is dispersed in the polymer solution in the solvent. In that case the solvent chosen should be able to suspend small particles of the MAP kinase inhibitor without causing them to aggregate or agglomerate into collections of particles that would clog the slots of the stent when applied. Although the goal is to dry the solvent completely from the coating during processing, it is a great advantage for the solvent to be non-toxic, non-carcinogenic and environmentally benign. Mixed solvent systems can also be used to control viscosity and evaporation rates. In all cases, the solvent should not react with or inactivate the MAP kinase inhibitor or react with the coating polymer. Preferred solvents include by are not limited to: acetone, N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), toluene, methylene chloride, chloroform, 1,1,2-trichloroethane (TCE), various freons, dioxane, ethyl acetate, tetrahydrofuran (THF), dimethylformamide (DMF), and dimethylacetamide (DMAC).
The film-forming biocompatible polymer coatings are generally applied to reduce local turbulence in blood flow through the stent, as well as, adverse tissue reactions. The coating may also be used to administer a pharmaceutically active material to the site of the stents placement. Generally, the amount of polymer coating to be placed on the stent will vary with the polymer and the stent design and the desired effect of the coating. As a guideline the amount of coating may range from about 0.5 to about 20 as a percent of the total weight of the stent or intra-luminal prosthesis after coating and preferably will range from about 1 to about 15 percent. The polymer coatings may be applied in one or more coating steps depending on the amount of polymer to be applied. Different polymers may also be used for different layers in the stent coating. In fact it is highly advantageous to use a dilute first coating solution as primer to promote adhesion of a subsequent coating layers that may contain pharmaceutically active materials.
Additionally, a diffusion barrier can be applied to modulate the release of the MAP kinase inhibitor, or they could be used as the matrix for the delivery of a different pharmaceutically active material. The amount of release regulating layer on the stent or intra-luminal prosthesis may vary, but will generally be less than about 2000 μg preferably the amount of release regulating layer will be in the range of about 10 μg to about 1700 μg and most preferably in the range of from about 100 μg to about 500 μg. Layering of coating of fast and slow hydrolyzing copolymers can be used to stage release of the drug or to control release of different agents placed in different layers. Polymer blends may also be used to control the release rate of different agents or to provide desirable balance of coating (i.e. elasticity, toughness etc.) and drug delivery characteristics (release profile). Polymers with different solubilities in solvents can be used to build up different polymer layers that may be used to deliver different drugs or control the release profile of a drug. For example since ε-caprolactone-co-lactide elastomers are soluble in ethyl acetate and ε-caprolactone-co-glycolide elastomers are not soluble in ethyl acetate. A first layer of ε-caprolactone-co-glycolide elastomer containing a drug can be over coated with ε-caprolactone-co-lactide elastomer using a coating solution made with ethyl acetate as the solvent. Additionally, different monomer ratios within a copolymer, polymer structure or molecular weights may result in different solubilities. For example, 45/55 ε-caprolactone-co-glycolide at room temperature is soluble in acetone whereas a similar molecular weight copolymer of 35/65 ε-caprolactone-co-glycolide is substantially insoluble within a 4 weight percent solution. The second coating (or multiple additional coatings) can be used as a top coating to delay the drug deliver of the drug contained in the first layer. Alternatively, the second layer could contain a different drug to provide for sequential drug delivery. Multiple layers of different drugs could be provided by alternating layers of first one polymer then the other. As will be readily appreciated by those skilled in the art numerous layering approaches can be used to provide the desired drug delivery.
Coating may be formulated by mixing or applying a MAP kinase inhibitor with one or more therapeutic agents with the coating polymers in a coating mixture. The therapeutic agent may be present as a liquid, a finely divided solid, or any other appropriate physical form. Optionally, the mixture may include one or more additives, e.g., nontoxic auxiliary substances such as diluents, carriers, excipients, stabilizers or the like. Other suitable additives may be formulated with the polymer and MAP kinase inhibitor or compound. For example hydrophilic polymers selected from the previously described lists of biocompatible film forming polymers may be added to a biocompatible hydrophobic coating to modify the release profile (or a hydrophobic polymer may be added to a hydrophilic coating to modify the release profile). One example would be adding a hydrophilic polymer selected from the group consisting of polyethylene oxide, polyvinyl pyrrolidone, polyethylene glycol, carboxylmethyl cellulose, hydroxymethyl cellulose and combination thereof to an aliphatic polyester coating to modify the release profile. Appropriate relative amounts can be determined by monitoring the in vitro and/or in vivo release profiles for the therapeutic agents.
In a preferred embodiment, the coating application is performed using a solvent common to the polymer and MAP kinase inhibitor. This provides a wet coating that is a true solution. Less desirable, yet still useable are coatings that contain the MAP kinase inhibitor as a solid dispersion in a solution of the polymer in solvent. Under the dispersion conditions, preferably the particle size of the dispersed MAP kinase inhibitor powder, both the primary powder size and its aggregates and agglomerates, is small enough not to cause an irregular coating surface or to clog the slots of the stent that need to be kept coating-free. In cases where a dispersion is applied to the stent for improved smoothness of the coating surface or to ensure that all particles of the drug are fully encapsulated in the polymer, or in cases where slowing the release rate of the drug is preferable, deposited either from dispersion or solution, a clear (i.e. polymer only) top coat of the same polymer may be used to provide sustained release of the drug or another polymer that further restricts the diffusion of the drug out of the coating. The top coat can be applied by dip coating with mandrel or by spray coating (loss of coating during spray application is preferable for the clear topcoat since the MAP kinase inhibitor is not included). Dip coating of the top coat can be problematic if the MAP kinase inhibitor is more soluble in the coating solvent than the polymer and the clear coating redissolves previously deposited MAP kinase inhibitor. The time spent in the dip bath may need to be limited so that the MAP kinase inhibitor is not extracted out into the MAP kinase inhibitor-free bath. Drying should be rapid so that the previously deposited MAP kinase inhibitor does not completely diffuse into the topcoat.
The amount of MAP kinase inhibitor will be dependent upon the particular MAP kinase inhibitor employed, medical condition being treated and the amount of inflammation present. Typically, the amount of MAP kinase inhibitor represents about 0.001% to about 70%, more typically about 0.001% to about 60%, most typically about 0.001% to about 45% by weight of the coating.
The quantity and type of polymers employed in the coating layer containing the MAP kinase inhibitor in one embodiment of the invention will vary depending on the release profile desired and the amount of MAP kinase employed. The product may contain blends of the same or different polymers having different molecular weights to provide the desired release profile or consistency to a given formulation.
Absorbable polymers upon contact with body fluids including blood or the like, undergoes gradual degradation (mainly through hydrolysis) with concomitant release of the dispersed drug for a sustained or extended period (as compared to the release from an isotonic saline solution). Nonabsorbable and absorbable polymers may release dispersed drug by diffusion. This can result in prolonged delivery (about 1 to 2,000 hours, preferably 2 to 800 hours) of effective amounts (about 0.001 μg/cm2-min to 100 μg/cm2-min) of the drug. The dosage can be tailored to the subject being treated, the severity of the affliction, the judgment of the prescribing physician, and the like.
Individual formulations of drugs and polymers may be tested in appropriate in vitro and in vivo models to achieve the desired drug release profiles. For example, a drug could be formulated with a polymer (or blend) coated on a stent and placed in an agitated or circulating fluid system (such as PBS 4% bovine albumin). Samples of the circulating fluid could be taken to determine the release profile (such as by HPLC). The release of a MAP kinase inhibitor from a stent coating into the interior wall of a lumen could be modeled in appropriate porcine system. The drug release profile could then be monitored by appropriate means such as, by taking samples at specific times and assaying the samples for drug concentration (using HPLC to detect drug concentration). Thrombus formation can be modeled in animal models using the 111In-platelet imaging methods described by Hanson and Harker, Proc. Natl. Acad. Sci. USA 85:3184–3188 (1988). Following this or similar procedures, those skilled in the art will be able to formulate a variety of stent coating formulations.
In a preferred embodiment, the coating material must be able to adhere strongly to the metal stent or intra-luminal prosthesis both before and after expansion, be capable of retaining the drug at a sufficient load level to obtain the required dose, be able to release the drug in a controlled way over a period of several weeks, and be as thin as possible so as to minimize the increase in profile. In addition, the coating material preferably should not contribute to any adverse response by the body (i.e., should non-thrombogenic, non-inflammatory, etc.)
The polymeric coating may be applied to the stent or intra-luminal prosthesis using a number of different techniques. Two preferred examples of application of polymer coating include spraying the stent with a spray of polymer such as PTFE particles or dip coating the stent in a mixture containing PTFE particles. Powder coating generally refers to a variety of methods employing powdered plastics and resins which are used commercially to apply coatings to various articles. These methods include fluidized bed, electrostatic spray, electrostatic fluidized bed, plasma spray, and hot flocking, as well as combinations and variants of these methods.
In the electrostatic spray process, a coating powder is withdrawn from a reservoir in an air stream and electrostatically charged in the high voltage corona field of a spray gun. The charged particles are attracted to the grounded metal object to be coated and adhere to it by electrostatic attraction. The coated substrate is then placed in an oven and the coating is fused to form a substantially continuous film. The discrete polymers such as PTFE particles form a connected path around the stent. The relatively high viscosity of the PTFE melt serves to effectuate a superior coating. If the powder is sprayed on a preheated article, the powder melts and fuses directly on the hot surface; further heating to fuse or cure the coating may be required, depending upon the type of coating powder.
Plasma coating is a method comprising establishing a hot temperature plasma in an inert gas such as nitrogen, and the coating powder is introduced at the periphery of the plasma. The particles melt and are propelled at high velocity to the substrate, where they form a film. In hot flocking techniques, powders are usually dispersed in air and sprayed or blown onto the preheated substrate, where they melt and form a coating. In a variant of this process, small parts are preheated and dropped into a bed of powder kept in a mobile state by vibration. In this method, the parts are completely coated with an unfused layer of powder on the surface.
Another method for coating the stent or intra-luminal prosthesis is to suspend stent in the air, such as, on a hook, and spray the polymeric coating onto the stent according to the electrostatic spray method mentioned above. An advantage of applying the powder coating in this manner, is that it would sufficiently coat the stent in its entirety, and thus provide improved adhesion at its mating surface to the graft.
In another preferred embodiment, the stent can contain reservoirs which could be loaded with the MAP kinase inhibitor. A coating or membrane of biocompatable material could be applied over the reservoirs which would control the diffusion of the MAP kinase inhibitor from the reservoirs to the artery wall. One advantage of this system is that the properties of the coating can be optimized for achieving superior biocompatibility and adhesion properties, without the addition requirement of being able to load and release the drug. The size, shape, position, and number of reservoirs can be used to control the amount of drug, and therefore the dose delivered.
Delivery methods can vary. MAP kinase inhibitors such as a p38 kinase inhibitor can be delivered locally from the struts of a stent, from a stent graft, grafts, stent cover or sheath. In addition, delivery can involve a comixture with polymers (both degradable and nondegrading) to hold the MAP kinase inhibitor to the stent or graft. In addition the drug could be entrapped into the metal of the stent or intra-luminal prosthesis or graft body which has been modified to contain micropores or channels, as discussed in U.S. Pat. No. 6,273,913. In addition, the MAP kinase inhibitor can be covalently bound to the stent or intra-luminal prosthesis via solution chemistry techniques (such as via the Carmeda process) or dry chemistry techniques (e.g., vapor deposition methods such as rf-plasma polymerization) and combinations thereof. In addition, the delivery method could include catheter delivery intravascularly from a tandem balloon or a porous balloon for intramural uptake, extravascular delivery by the pericardial route, extravascular delivery by the advential application of sustained release formulations.
In addition, it is contemplated that another drug may also be coated onto the stent, such as heparin as described in U.S. Pat. No. 5,876,433, or another drug such as rapamycin or other immunosuppressive drug, or another anti-inflammatory drug.
As implied above, although the compounds of the invention may be used in humans, they are also available in treating animal subjects such as mammals. Stents of the invention may be used in a similar fashion as coated or uncoated stents as known in the art.
All of the references listed herein are incorporated herein by reference. The following examples are intended to illustrate but not to limit the invention.
The compounds to be tested are solubilized in DMSO and diluted into water to the desired concentrations. The p38 kinase is diluted to 10 μg/ml into a buffer containing 20 mM MOPS, pH 7.0, 25 mM beta-glycerol phosphate, 2 mg/ml gelatin, 0.5 mM EGTA, and 4 mM DTT.
The reaction is carried out by mixing 20 μl test compound with 10 μl of a substrate cocktail containing 500 μg/ml peptide substrate and 0.2 mM ATP (+200 μCi/ml gamma-32P-ATP) in a 4� assay buffer. The reaction is initiated by the addition of 10 μl of p38 kinase. Final assay conditions are 25 mM MOPS, pH 7.0, 26.25 mM beta-glycerol phosphate, 80 mM KCI, 22 mM MgCl2, 3 mM MgSO4, 1 mg/ml gelatin, 0.625 mM EGTA, 1 mM DTT, 125 μg/ml peptide substrate, 50 μM ATP, and 2.5 μg/ml enzyme. After a 40 minute incubation at room temperature, the reaction is stopped by the addition of 10 μl per reaction of 0.25 M phosphoric acid.
A portion of the reaction is spotted onto a disk of P81 phosphocellulose paper, the filters are dried for 2 minutes and then washed 4� in 75 mM H3PO4. The filters are rinsed briefly in 95% ethanol, dried, then placed in scintillation vials with liquid scintillation cocktail.
Alternatively, the substrate is previously biotinylated and the resulting reactions are spotted on SAM2™ streptavidin filter squares (Promega). The filters are washed 4� in 2M NaCl, 4� in 2M NaCl with 1% phosphoric acid, 2� in water, and briefly in 95% ethanol. The filter squares are dried and placed in scintillation vials with liquid scintillation cocktail.
Counts incorporated are determined on a scintillation counter. Relative enzyme activity is calculated by subtracting background counts (counts measured in the absence of enzyme) from each result, and comparing the resulting counts to those obtained in the absence of inhibitor.
IC50 values are determined with curve-fitting plots available with common software packages. Approximate IC50 values were calculated using formula:
where A=fractional activity and i=total inhibitor concentration.
Venous blood is collected from healthy male volunteers into a heparinized syringe and is used within 2 hours of collection. Test compounds are dissolved in 100% DMSO and 1 μl aliquots of drug concentrations ranging from 0 to 1 mM are dispensed into quadruplicate wells of a 24-well microtiter plate (Nunclon Delta SI, Applied Scientific, So. San Francisco, Calif.). Whole blood is added at a volume of 1 ml/well and the mixture is incubated for 15 minutes with constant shaking (Titer Plate Shaker, Lab-Line Instruments, Inc., Melrose Park, Ill.) at a humidified atmosphere of 5% CO2 at 37� C. Whole blood is cultured either undiluted or at a final dilution of 1:10 with RPMI 1640 (Gibco 31800+NaHCO3, Life Technologies, Rockville, Md. and Scios, Inc., Sunnyvale, Calif.). At the end of the incubation period, 10 μl of LPS (E. coli 0111:B4, Sigma Chemical Co., St. Louis, Mo.) is added to each well to a final concentration of 1 or 0.1 μg/ml for undiluted or 1:10 diluted whole blood, respectively. The incubation is continued for an additional 2 hours. The reaction is stopped by placing the microtiter plates in an ice bath and plasma or cell-free supernates are collected by centrifugation at 3000 rpm for 10 minutes at 4� C. The plasma samples are stored at −80� C. until assayed for TNF-α levels by ELISA, following the directions supplied by Quantikine Human TNF-α assay kit (R&D Systems, Minneapolis, Minn.).
According to the assays in Examples 1 and/or 2, the compounds in Table B exhibit an IC50 relative to p38 kinase of less than 5 μM.
The effect of p38 MAP kinase inhibitor coated stents on restenosis in a porcine model is studied. Eight normolipemic pigs undergo coronary angiography and segments of the left anterior descending and left circumflex arteries are selected as targets for stent implantation. A p38 MAP kinase inhibitor selected from Table B is used to coat 3.5-mm tantalum stents. The p38 MAP kinase inhibitor coated stents are implanted in both arteries of four test pigs. Uncoated stents are implanted into the arteries of four control pigs. Stent-to-artery ratio is similar in the coated stent arteries and the control arteries. Animals are administered 325 mg aspirin daily and are killed at 28 days. The intimal area is significantly reduced in the coated stent arteries as compared with control arteries treated with stent only. This experimental procedure can be used to determine the ability of any p38 MAP kinase to inhibit restenosis.
Modifications of the above-described modes for carrying out the invention that are obvious to persons of skill in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited in this specification are incorporated herein by reference as if each such publication, patent or patent application were specifically and individually indicated to be incorporated herein by reference.
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San Francisco based Kamcord Inc., which focuses exclusively on recording and sharing mobile games, now reaches 175 million devices every month, up from 5 million devices during March last year. Read More »
Mar 11, 2015
San Francisco based Kamcord Inc., which focuses exclusively on recording and sharing mobile games, now reaches 175 million devices every month, up from 5 million devices during March last year. Read More »
Kamcord Inc. co-founder Aditya Rathnam Kamcord Inc. Fast-growing startup Kamcord Inc.–mobile gaming's answer to Twitch–has secured a strategic round led by Japanese gaming giant at a valuation around $100 million. The $15 million infusion comes just a few months after purchased game recording and sharing startup Twitch Interactive Inc. for about $1 billion and underscores [...] Read More »
In this morning's Web roundup, an incubator graduate goes on to big things. Jobs site ZipRecruiter raises $63 million. And burners get drenched. Read More »
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In today's venture roundup, investments soared to dot-com levels in the first quarter, although recent IPO woes could stall that trend. An Australian company gets a massive round from Insight Venture Partners. And a buzzy mobile photo app almost never happened. Read More »
Live video gaming platform Twitch has been on a growth tear this past year and has raised $20 million from investors to rip it up some more.
Unlike competitors Ustream, LiveStream, YouTube and others enabling individuals and companies to broadcast video to the masses, Twitch is focused on just one category: gaming. The company provides an online platform and community for gamers that features live streaming gaming events, personal streams of individual players in action, and talk shows dedicated to gaming.
Individual players who bring in large audiences to watch them play get a portion of revenue generated from advertisements on their stream. The company says some gamers are earning six-figure salaries by gaming full time on the Twitch platform, and it expects the number of gamers to grow when Microsoft's Xbox One and Sony's PlayStation 4 consoles launch this fall and gamers can broadcast and view Twitch content with a single button. Read More »
Produced by the editors of Dow Jones VentureWire, Venture Capital Dispatch tracks the fast-moving developments at the intersection of high-tech innovation and venture capital finance. Featuring the VentureWire reporting team in the Silicon Valley, New York, Boston and Shanghai tech centers, Venture Capital Dispatch provides insight into the newest start-ups and latest trends in venture capital investing. Write us at email@example.com. For more information on Dow Jones products covering venture capital and other financial markets, go to http://pevc.dowjones.com.

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Stephen Colbert Interviews Eminem
Stephen Colbert hosted a 41-minute segment for Monroe Public Access TV show, 'Only In Monroe' where he interviewed music superstar, Eminem.
Stephen Colbert hosted a 41-minute segment for Monroe Public Access TV show, 'Only In Monroe' where he interviewed music superstar, Eminem.
You know you're in trouble when you get a text that starts with "We need to talk!"
, New Orleans Pelicans superstar Anthony Davis signed a 5 year contract extension worth $145 million that begins following next season.
Same-sex marriage has been a hot topic over the last week after the monumental Supreme Court ruling—so Jimmy Kimmel decided to ask kids what they thought.
Looking for family fun this 4th of July? Well you are in luck because we've got your complete rundown of events throughout the Acadiana area so you and family can get out and check out fireworks and more.
Veronica-Pooh Nash Poleate posted a video on the internet in lieu of several shark attacks, and her advice is straight to the point---stay out of the water.
Good news for Diddy. The Bad Boy Records founder will reportedly not be charged with a felony following his arrest for assaulting a UCLA football coach.
Trey Songz performed on the first night of the 2015 Essence Music Festival, which took place at the Mercedes Benz Superdome in New Orleans on Thursday evening (July 2).
Kendrick Lamar is clapping back at criticism – especially coming from Fox News pundit Geraldo Rivera – that his 2015 BET Awards performance of "Alright" sends a bad message to the youth.
Rapper Eminem portrays an action hero in his cinematic video for "Phenomenal," which premiered exclusively on Apple Music.
Happy 4th of July! Celebrate the stars and bars with all-American jams from Katy Perry, Demi Lovato, Taylor Swift and more.
Chef Zack Doise, co-host on "The Lafayette Food Junkie Show" on Sunday nights from 6-7 p.m. on Newstalk 96.5 FM KPEL, has some grilling tips you should follow.
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This is why social media is so dangerous FOR KIDS!


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41 year old man | Aliso Viejo, CA, USA | Seeking women 28-39 within 50 miles of Westminster, CA
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lookin for my best friend...partner in crime
I was never really open to online dating but I figured I would give it a shot. I have a very busy work schedule. So it's difficult to meet a quality woman. I don't really like picking up girls at bars and I'm not into the club scene these days. I'm looking to meet someone who enjoys life and is family oriented. I want someone to laugh with and have a good time with. I want to find someone is willing to put time and effort into a relationship. I want someone who is goal oriented and driven. I want her to inspire me to better and more than I ever thought I could be. I hope I would be able to do the same for her. I'm a fun loving person. I love making my friends and family laugh. I have a sarcastic sense of humor (trust me you'll love it). I can be serious if the moment dictates it. I think you need a balance of being mature but should also be able to let loose and have fun and enjoy life and those around you. Being a former trainer, fitness is important to me. The most important part of fitness is being able to live a good healthy life. With that being said I love food and I do prefer good beer and anything made with Belvedere. I want to wake up thinking about her and go to bed thinking about her and hope that she feels the same about me. I like to cook and would like to be able to cook for someone special. And...I do like kids. In a nutshell I want what my parents have. They still hold hands and go on dates.
Camping , Coffee and conversation , Cooking , Dining out , Movies/Videos , Music and concerts , Exploring new areas , Nightclubs/Dancing , Playing sports , Travel/Sightseeing , Watching sports
Baseball, Basketball, Billiards / Pool, Bowling, Dancing, Football, Golf, Hockey, Other types of exercise, Running, Tennis / Racquet sports, VolleyBall, Weights / Machines
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34 year old man | Florence, AZ, USA | Seeking women 22-40 within 50 miles
I am caring, honest, fun, exiting outgoing looking for someone to get to know better and see where it goes I have a good career.
I am very relaxed an easy going very open to do fun things with some one that desires the same interests as me, looking for some to get to know better and see if more comes of it. Submitted from mobile
Camping , Coffee and conversation , Cooking , Dining out , Fishing/Hunting , Hobbies and crafts , Movies/Videos , Museums and art , Music and concerts , Exploring new areas , Nightclubs/Dancing , Playing cards , Playing sports , Shopping/Antiques , Travel/Sightseeing , Watching sports , Wine tasting
Baseball, Basketball, Billiards / Pool, Bowling, Dancing, Football, Other types of exercise, Running, Swimming, Walking / Hiking, Weights / Machines
I exercise 3-4 times per week.
Rio Salado College, Tempe, AZ
exercising, camping, playing sports, sight seeing, bowling, football, anything sports, dancing/clubs and anything else fun exciting and different.
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|What he is looking for
|5'10" (177cms)
|5'0" (152cms) to 5'7" (170cms)
|Body type:
|Athletic and toned
|Slender, About average, Curvy, Athletic and toned
|Blue, Brown, Green, Hazel
|Dark brown
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|Occasionally, Daily
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|No preference
|$35,001 to $50,000
|$25,001 to $35,000, $35,001 to $50,000, $50,001 to $75,000
|Never Married, Currently Separated, Divorced
|Have kids:
|Yes, and they live away from home
|Yes, and they sometimes live at home
|Wants kids:
|No, but it's OK if my partner has kids
|No, but it's OK if my partner has kids
|Latino / Hispanic, White / Caucasian
|Asian, Latino / Hispanic, Native American, White / Caucasian
|Spiritual but not religious
|No preference
|Some college
|High school, Some college


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» Print Recipe
This is my version or adaption of a wonderful Madhur Jaffrey recipe. Great to share with friends on a cold night. I generally serve with yellow rice, cauliflower with green chillies and ginger, and cumin potatoes. And lots of full-fat yoghurt.
Put the coriander seeds, peppercorns, fennel seeds, fenugreek seeds, chillies and cloves into a small cast-iron frying pan and set over a medium heat.
Stir the spices over the heat until they are a shade darker and give off a roasted aroma. Leave to cool then grind in a spice grinder.
Pour the oil into a wide pan or wok, preferably non–stick, and set it over a medium-high heat.
When it is hot, put in the onions and cook, stirring until they turn brown at the edges.
Add the ginger, garlic, and green chillies and stir for 20 seconds. Add the meat and cook, stirring for 5 minutes.
Stir in the tomatoes, ground roasted spices, salt and coconut milk and bring to the boil.
Cover the pan, turn the heat down to a low simmer and cook gently for 1.5 hours or until the meat is tender.
Before serving, remove the lid and boil away any excess liquid to leave a thick sauce. Serve with yellow rice.
I find that chuck steak is better than blade. If you have the time, prepare the curry earlier and let sit for an hour or two to allow flavours to develop. Then heat up before serving.
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Shiraz, Cabernet Sauvignon and Grenache are the best wines to pair with Beef Madras.
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Beyond Violence
The author shows how figures like Mahatma Ghandi, Martin Luther King, Dorothy Day, and others have taken the example of the Nonviolent Christ as their guide for living and working justly and courageously in the world. He then offers suggestions for incorporating gestures of peace and words of compassion and justice into our daily dealings at home, at work, with difficult people, and as part of the political process. .
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Google + Stop Motion Filmmaker = One of the Coolest Commercials Around
Posted on 02/24/2010 06:47:25 AM
Ever since watching Nick Park's Wallace & Gromit films, I have been fascinated with stop-motion animation. There is something so meticulous and painstaking about this style of film that every time you see one, you are left wondering how on earth they made it (no strings attached Thunderbir..
Belgian Beer Brand's Brilliant Use of Crowdsourcing
Posted on 02/24/2010 06:46:06 AM
Belgian beer brand Vedett has cleverly demonstrated how to interact with its customers. It has asked drinkers to submit a photo of themselves through their website, with a lucky 10,000 becoming "instantly famous" by appearing on the bottle labels. I really like this approach because: ..
Posted on 02/21/2010 09:37:03 AM
My standard response to the often asked question "how do I grow my business" is " learn to harness the power of the brand gossip!" A simple premise is at work here. Your customers are your best sales force so empowering them to start gossipin..
Highly Responsive MLM Leads? In My Dreams!
Posted on 02/19/2010 10:19:38 AM
In days gone by the term 'highly responsive mlm leads' tended to mean leads who responded to our unsolicited pitch by laughing at us. Well, that is highly responsive after all. What I never realised in the bad old pre-web days is that if people aren't at the point of looking for a ..
Network Marketing Tip: Don't get caught between 'Cold Call Mountain' and 'Flyers Gulch'
Posted on 02/19/2010 10:15:25 AM
The sort of network marketing tip I could have expected years ago would be 'don't pre-judge', 'you don't know who's looking' and my favourite – 'sponsor up (peer group and above'. That last tip did have some merit. It gave me the chance to ..
6 Free Search engine optimization Tutorials
Posted on 02/16/2010 11:41:48 AM
6 Free Search engine optimization Tutorials Posted on February 16, 2010, 6:50 am, by Madviral, under SEO. ♻ Retweet 1. SEO Tutorial – The Fundamentals I hope this free tutorial series will give you a clear idea how to get your website rank top in Goog..


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Alans Get Off/Progress Report
View Single Post
Beastly Adventurer
Joined: Apr 2007
Location: Payette ID
Oddometer: 1,173
The Story in my Own Words Part I
Decided to write down the story of my little incident last week in my own words while I can still remember it. Thought some on here might enjoy reading it. If some of the small details are mixed up, it is because i was in a lot of pain during much of the time and may not of been thinking and remembering straight.
I will do a Part II and Part III if there is any interest.
Warning: It is very long.
Alan Smutzs Motorcycle Incident August 2013 Part I
I am writing this to let our friends and family know what happened to me this last week concerning my motorcycle incident and weeklong stay in the hospital. Much of the info given here has already been given out in bits and pieces during our other emails, posts and private messages on ADV Rider. Just trying to put the details on one spot and get them written down before I begin to forget them. This first part will cover my time until I reach the hospital in Weiser.
A few weeks ago, Katy (aka Rocky) and I decided to do a little riding in the area north/west of Weiser ID. Part of that ride consisted of riding up Jenkins Creek road as far as we could go. We ended up getting into some fairly steep and rocky (fun) areas and ended coming out onto Dennett Creek road a couple of miles above the Snake River. We rode down to the Snake River and back along the river and back to Weiser via Rock Creek Road.
Fast-forward to Thursday, August 1. Katy and I decided to go back to the same area to do a little more exploring. Our goal was to ride up Dennett Creek road and see where it went and then go on from there. I had several possible routes programmed into my GPS including the actual tracks from the earlier ride that showed exactly where we rode a couple weeks earlier.
Rode through Weiser and then to the bottom of Dennett Creek road without incident. Rode up past where we had come out onto the road a couple of weeks earlier. Rode the rest of the way up to the top of the mountain and came out at the Gypsum mine. The top part of the road was very steep and rocky, but still very ride-able.
The GPS showed that we were very close (within a mile or so) from where we had been a couple of weeks earlier. Wanting to get a better idea of how all the roads in the area connected and being on a exploring ride, decided to find a route back to Jenkins Creek road near where it enters the National Forest where we had been a couple weeks earlier.
The first route we tried ended at a dead end. Tried a second route and were getting closer. The road we were on soon narrowed down to a single track trail. At this point the GPS showed we were just a little over a half mile away from the road we were on a couple weeks earlier. Despite trail being very rocky and fairly narrow, since we were so close, decided to press on.
The trail we were on was about 18 to 24 inches wide. To the right side there was a nearly straight down drop off several feet high and then the steep side of the hill continues on past the drop off for several hundred feet. There are several trees of various sizes growing on the side of the steep slope. The tread (face of the trail) is mostly dirt with a lot of rocks of various sizes, many of them loose. To the left of the trail is steep uphill.
This next part happened fairly quickly and I could not actually see what happened, however Katy saw it. I am basing this next part on what she told me. My bike flipped up a rock as I rode over it. The rock was large enough that it hit the bottom of my bike and as I moved forward, lifted the rear wheel of my bike off the ground and pushed it off the right side of the trail.
Even though I was moving fairly slowly at the time, once the rear of my bike was flipped off the trail there was nothing I could do to prevent it from tipping over. There was nothing but air for my right foot to try to press on. I was already leaning too far to the right to lean back to the left and successfully stop my fall. Within a split second of my bikes rear end being flipped off the trail, I was free falling off the right side of the trail. About 15 to 20 feet below the level of the trail, but before I had even touched the ground, I grabbed a small tree in attempt to stop my fall. I successfully grabbed the tree and at first it appeared I was stopped from falling further. A second or two later, I was hit by my bike as it was tumbling down the steep slope. It pushed my right leg under the bike and slammed me to the ground so my head was downhill and the bike was on top of me. We slid together down the hill for a short distance further.
Once we stopped sliding, I attempted to push the bike off of me. I was only able to get the bike part way off of myself. By then, Katy was stopped and attempting to make her way down to assist me. It took her several moments as the ground was very steep and she didnt want to fall herself and either injure herself or fall on top of me and my bike and injure me further. Once she got down to me, she was able to lift the bike enough for me to crawl (slide) out from under the bike. I knew my right leg was broken as it was bending nearly 90 degrees at a spot between my hip and my knee. Legs are not meant to bend in that manner. I am positive my leg was broken when the bike hit me and pinned me under it.
I knew I needed to get my leg straightened out, but was unable to on my own. My lower leg simply would not move on its own below the break. I had Katy grab my boot and straighten my leg the best she could. She also twisted my foot so the toes were pointing up. At this point the pain was bad, but I knew it would soon get much worse as the shock of the break wore off.
Katy found a sturdy branch about 2 to 3 inches in diameter. I had her break if off to about 3 feet long to use as a splint. We used some sturdy zip ties I had to attach the stick to the side of my right boot. Used some nylon straps I had to attach the splint to the leg just below the knee and then to the leg as high as I could get it against my hip. The splint helped with the pain and it kept my leg from moving around so much as every time my leg moved in the smallest amount, severe pain would shoot up and down my leg. With Katys assistance, I tried to crawl up the hill to the trail. I tried to crawl with my back facing the ground and my feet pointing downhill. After much effort and pain on my part, I was only able to get approximately 1/3 of the way up to the trail. The ground was too steep and the pain was getting way too much for me to continue further. However, I was now above the bike and could use the bike to press my left foot against to keep me from sliding down the hill every time I moved even just a little.
By now, the pain was very severe and I was not sure how long I could/would remain conscious. By now, I knew we would not be able to get off the mountain without outside assistance. I had Katy get my GPS and I put in a way point so Katy could show someone else exactly where I was at. I directed her to ride the trail back the way we had come to the main road we had just been on. (Turns out that road was Adams Creek road.) Told her to follow it down until she came to another main road or the highway and then on into Weiser where she could get help. We had never been on these roads, but from looking at my maps earlier in the day, I was sure she could get to Weiser without too much trouble.
Katy didnt really want to leave me up there alone, but also knew we needed assistance and the only way to get it was for her to leave me and go get it. Katy gathered up the water we had left between us and left it with me along with a couple of bottles of pop and two salted nut roll candy bars. She also got out some of the OTC pain pills she had in her first aid kit and gave them to me. Katy then left to go get help. It took her a long time to turn around on the narrow trail and ride out on the single track. I knew she made it out past the difficult part as there was one spot of the road I could see from my position and I saw her riding out.
I had no way of knowing what time it was or how long I had been sitting alone. My watch had come off during my fall and the only other clock was on my GPS which Katy was using. Later, Katy told me it as 2:30 when she first left me to go get help. We estimate my fall happened at approximately 2 pm. I was very uncomfortable and even if I didnt move my leg, my leg was getting very painful. It was difficult not to move my leg as I kept sliding down hill even while trying to hold my body still. I forced myself (despite the intense pain) to slide up the hill a little more. At this point, I could get a good foot hold for my left leg against the bike to keep me from sliding and was also able to get the heel of my right foot onto the handle bars in a position where my right foot was held fairly steady. By then I was in a fairly stable position and was not moving that much. I had also learned how to use my hand on the top of the stick/splint to reposition my foot as needed to find that magic spot where the pain let up a little. Somewhere along the line, I had to remove the top strap securing my splint as the pain from that strap was too much to bear. As I said, I had no real sense of time and how much time had passed. At times it seemed like Katy had been gone for hours and at other times, I was sure she had only been gone 10 minutes. However, I knew some time was passing as I could see the sun move across the sky and could see a thunder storm approaching.
As I was sitting/laying as still as possible and with my eyes closed I thought I heard a bike in the distance. I was not sure if it was real or wishful thinking on my part. I found that while I was sitting alone, hurt and in pain that I began to imagine all sorts of things. As the sound became more pronounced, I forced myself up into a sitting position so I could watch that portion of the road visible to me. Not sure if it was due to the pain from moving, but I could suddenly no longer hear the bike. I felt very dejected at this point. Just as I was about to slump back in despair, I saw Katy riding back towards me and also could see a maroon colored pickup following her. A minute or so later I saw two more pickups with flashing red and blue lights heading in the same direction. I knew that help was close and thought that I would soon be surrounded by my rescuers. The sight of help nearby was the mental lift I really by then.
Since I figured that my rescuers were only minutes away, I sat up as much as possible and got ready to be moved. After sitting for several more minutes and not hearing or seeing anyone approach me, I then again began to wonder if I had actually saw and heard them on the portion of road visible to me. I was sure I had seen them and not imagined all of it. I had moved around quite a little during this time and was in extreme pain. I really wanted to believe they were just very short distance (1/2 mile or so) away and would soon be by my side. However, if they were actually that close, what were they waiting for? Was I imagining all of this or was help really nearby? I was no longer sure if I was conscious or if I was dreaming all of what I had thought I had seen and heard. Time stood still for me and for the first time since getting hurt, I was afraid I may not survive. I kept asking myself over and over, if they were actually that close to me, what were they waiting for?
In my deep and darkest moments of despair, I thought I heard Katys bike coming down the trail towards me. I kept telling myself that it has to be real. It has to be real. I then heard Katys voice above me on the trail. She was saying that there were several people nearby wanting to help us. Katy then came down the steep bank and sat down beside me. I felt that this had to be real.
As we talked, I asked what everyone was waiting for? She explained that they were not sure how they were going to able to reach me as the trail was far too narrow for a quad or Gator. I told Katy that if I could just get back up onto the trail, I would walk myself out as it could not be that far. She told me to just relax and that they were in charge of my rescue and they would figure it out. I dont think Katy or anyone else involved knew how difficult it was for me both mentally and physically to just be sitting there. Katy told me some rescue personal with dirt bikes were suppose on be the way and hopefully would soon be there.
After what seemed like forever, I heard and then saw a couple of bikes approaching in the distance. About this time, the thunder storm I had seen approaching hit in full force and it began to rain really hard. I was concerned that with the heavy rain, the trail would get very slick and Katy may find it really difficult to ride her bike back out. By this time, I was sure this was all real and I was not imagining it and that help was really close by. I told Katy I wanted her to ride back out to where everyone else was before the trail got too slick for her to ride out. Katy agreed to leave ride back out.
Soon after I heard Katy ride away, I heard two strokes headed my way. Two rescuers on bikes soon arrived and begin to try to make me comfortable. They told me their names and I believe one was named Jerry and cant recall the others name but believe it also begins with a J. (I had a hard time remembering any names given to me) A third rescuer on a bike soon arrived. They told me they had plenty of help nearby, but no one could figure out how to actually get to me. I told them that with three of them, if they could help me up to the trail and help me find a good stick I could use for a crutch, that I would try walking out as I was sure it was not that far. One of the guys checked his GPS and told the other two guy that it was only 4 tenths of a mile and that the rest of the rescuers needed to just walk in. I heard one of them talking on the radio saying that to just walk in as it would only take them a few minutes.
Within a few minutes, there was a group of approximately 10 people around me. One EMT told me his name was Matt. During the rescue, Matt went way out of his way to make me as comfortable as possible. Anyway, I was soon loaded onto a gurney and pulled back up to the trail. Due to the efforts of all concerned, this was not near as painful as I figured it would be. Could also be the morphine they gave me was taking effect. I was hand carried out the approximately 4 tenths of a mile out to the waiting Gator. I was loaded onto the Gator. Matt was right there beside me during the whole ride out. The Gator ride was fairly rough but it felt good to finally be moving off of the mountain. After a few miles of riding the Gator, we reached the Weiser Ambulance waiting back on the main road. Matt was my EMT in the back of the ambulance on our way to the Weiser Hospital.
During my Gator ride, a few of the guys including Jerry and the other bike riders returned to where my bike was and got my bike back onto the trail and rode it out to where their bike trailer was waiting. They ultimately hauled my bike down to the Washington County Sherriffs office where it could be safely stored. A special thank-you goes out for that extra special effort.
During the ambulance ride, Matt mentioned that protocol called for him to fully check out the rest of my body to check for other injuries and that would likely require cutting off my riding gear. However, he didnt want to cut off my gear and he said it looked fairly new and expensive. I assured him that I only hurt on the upper half of my right leg. He agreed to wait until we got to the hospital before attempting to remove any more of my clothing. I still had on the stick that Katy and I tied to my leg as a splint. Everyone that looked at our stick/splint set up felt it was doing its job as well as anything they could apply in the field to replace it so decided it was better to leave it in place. After arriving at the hospital in Weiser, I was taken into an exam room and there Matt helped me to carefully remove my boots and the rest of my riding gear and my stick/splint. The only article of clothing that was ultimately cut off was my underwear bottoms. I soon begin to miss my stick/splint as I no longer had a way to move my foot by myself and keep it in a semi comfortable position.
I sent Katy home on her bike so she could change and then bring the car back to Weiser and pickup my clothing and riding gear. She had time to return to the Weiser hospital before I was transferred to a different hospital.
A very big thank you goes out to all those that were involved in my rescue. I dont know for sure who all was involved, but believe I had people from the Washington County Sherriffs Office, County Search and Recuse, Volunteer Fire Department and Weiser Hospital EMTs. If I missed someone, I am sorry. I am sure many of the people assisting me were volunteers. I felt that everyone involved was really concerned about my well-being and getting me safely off the mountain. Again thank you very much.
This is the end of Part I.
DISCLAIMER: Suitability of any roads or trails mentioned in my ride reports are given from the view point of me and my wife (two old grandparents of moderate riding ability) and may or may not be applicable to your personal situation. Be mature, ride within your own abilities.
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Chicken Breasts All' Alba
28 Jan 2011
Do not fear when you have to impress a crowd. This Chicken Breasts All' Alba recipe is a lifesaver. If you have a lot of chicken on hand then you know its time to make some Chicken Breasts All' Alba. This Chicken Breasts All' Alba is a High Protein recipe. Stop thinking! Try this Chicken Breasts All' Alba recipe immediately.
|Whole chicken breasts
|2 , boned and halved
|1⁄2 Cup (8 tbs) (For Dredging)
|2 Tablespoon
|Freshly ground black pepper
|To Taste
|Sliced mushrooms/Slices of white / black truffles
|4 , sauteed in butter
|Mozzarella cheese slice/Fontina
|To Taste
1. Remove and discard skin from chicken breasts. Place the chicken breasts between pieces of waxed paper and pound until thin.
2. Dredge the chicken with flour. In a skillet heat the butter, add the chicken and cook until tender, five to six minutes on each side. Remove to a shallow pan and sprinkle with salt and pepper. Arrange on each breast half a dozen small slices of truffles or mushrooms and cover with a slice of cheese.
3. Place the chicken breasts under a hot broiler just long enough to melt the cheese. once.
Recipe Summary
Difficulty Level:Easy
Course:Side Dish
Dish:Dry Curry
Preparation Time:10 Minutes
Cook Time:10 Minutes
Ready In:20 Minutes
Rate It
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Chicken Breasts All' Alba Recipe


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On September 30, 2011, the U.S. District Court for the Western District of Louisiana ordered the United States to pay $1.7 million in a malicious prosecution lawsuit to Hubert Vidrine, based on findings that the U.S. government had maliciously prosecuted Vidrine for alleged environmental crimes. This is a rare ruling by a federal court requiring the government to pay money damages for the overzealous actions of its agents.
In September 1996, agents from multiple law enforcement agencies and the Environmental Protection Agency (EPA) executed a search warrant on Canal Refining Company, where Vidrine worked as a manager. The search was based on the assertion that hazardous materials may have been improperly stored at the facility in violation of the Resource Conservation and Recovery Act. However, the search did not uncover evidence of any violations.
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