text:
|Publication number
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|PCT number
|Publication date
|Dec 22, 1998
|Filing date
|Mar 29, 1995
|Priority date
|Mar 30, 1994
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|Denis Barritault, Jean-Pierre Caruelle, Anne Meddahi
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|Societe Valbiofrance
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|Patent Citations (1), Non-Patent Citations (1), Referenced by (18), Classifications (23), Legal Events (4)
|External Links: USPTO, USPTO Assignment, Espacenet
This invention relates to the use of polymers or biopolymers for the preparation of a drug for the treatment of lesions of all origins affecting the digestive tract from the buccal cavity to the anal extremity in human or veterinary medicine.
It also relates to a composition containing these polymers and intended for such a treatment.
The synthesis of CMDBS polymers (dextrans substituted by carboxymethyl, benzylamine and sulfonate) has been described in French Patent 2 461 724 and U.S. Pat. No. 4,740,594. Some of these polymers mimic heparin and may be used as plasma heparin replacement products, thanks to their anticoagulant and anticomplement properties.
Some of these CMDBS polymers mimic another property of heparin consisting of a stabilization, protection and potentialization of the in vitro biological activity of the growth factors of the FGF family (Tardieu and coll., Journal of Cellular Physiology, 1992, 150 pp. 194 to 203).
French Patent 2 644.066 describes the use of certain CMDBSs associated with FGFs for healing the skin and the cornea. Experiments have been conducted by provoking a cutaneous wound with the help of a hollow punch 6 mm in diameter in the rat. In this example, the CMDBS associated with the FGF 2 makes it possible to obtain a definite effect on the speed and the quality of skin repair.
Another biopolymer, dextran sulfate, has also been advanced in association with FGFS, as a stabilizer and protector, in Japanese Patent No. 13890. Dextran sulfate, moreover, is widely used in skin healing ointments and creams as well as in collyrium compositions, but, to the knowledge of the applicant, has no reported effect on the healing and regeneration of muscular lesions.
Another agent, sucrose sulfate ester and its aluminum salt, sucralfate, are products described and used, on their own or associated with FGFs, as agents in the treatment of ulcers and lesions of the digestive tract (U.S. Pat. No. 3.432.489 ) and in different pharmaceutical associations and compositions described in a series of patents (U.S. Pat. Nos. 4,975,281, 4,885,281, 5,013,557, 5,164,379, 5,196,405, 5,240,710 and Danish Patents 102488 and 505588).
The tissues of the digestive tract are particularly rich in growth factors and several authors have described the presence and/or action of FGFs and beta TGFs in/on enterocyte cells or the healing action of these factors in lesions of tissues of the digestive tract as well as the presence or the action of growth factors presenting an affinity for heparin or heparan such as AB or BB PDGFs or Hepatocyte Growth Factor (Lemoine N R; Leung H Y; Gullick W J; Growth Factors in the Gastrointestinal tract ; Gut 1992, 33, pp. 1297 to 1300; Di Gulietta A, Hervada T; Nardy R V; LESH C A: Effect of platelet derived growth factor BB on indomethacin-induced gastric lesions in rats; Scand. J. Gastroenterol. 1992, 27, pp. 673 to 676; Tajagascu M and coll. Hepatocyte growth factor induces mitogenic reaction to the rabbit gastric epithelial cells in primary culture; Biochem. and Biophys. Res. Comm. 1993, 191; 528-534; Mustoe and Coll. Differential acceleration of healing of surgical incisions in the rabbit gastrointestinal tract by platelet derived growth factor and transforming growth factor beta; Surgery 1990, 108, pp. 324 to 330; Katayama M; Kan M: Heparin-binding (fibroblast) growth factors are potential autocrine regulators of oesophageal epithelial cell proliferation, In Vitro Cell. Dev. Biol. 1991, 27, pp.533 to 541).
It thus emerges from an analysis of the state of the prior art that polymers have already been used in association with growth factors on certain lesions of a very particular type of tissue, namely cutaneous tissue.
In view of the unpredictable nature of the therapeutic effects of a given molecule, it was not clear wether these polymers could have an effect on tissues other than those of the skin.
It is, in fact, well known that the different tissues of the human or animal body present structural and functional specific features making it impossible to predict the effect of a molecule, known for its effect on the cutaneous tissue, and on tissues of the digestive tract.
This is particularly true in view of the fact that the tissues of the digestive tract and those of cutaneous tissues, for example, have different embryonic origins.
Similarly, it is well known that it is impossible to predict the in vivo activity of a molecule on a particular tissue from results obtained in vitro on a specific experimental model.
All the other known drugs in this field, such as anti ulcerous drugs, act by protecting the mucosa by antacid gels, by inhibition of gastric acid secretions or by H2 anti-receptor action.
The activity of a mixture of glycosaminoglycans, mesoglycan, on hemorrhoids has been tested by Saggioro et al., (1985, Min. Diet. e. Gastr, 31, pp. 311-315). This publication shows that mesoglycan is very effective against hemorrhoids, eliminating the symptoms while improving the endoscopic aspect.
However this publication teaches only its inquiry polymers of a very particular type which, moreover, present a composition of poorly defined animal origin and subject to variations.
Surprisingly, it has been found, according to the invention, that certain polymers have a very marked effect on the speed of healing and regeneration of lesions of digestive tract tissues as well as on the quality and solidity of these scars.
It has also been shown that very low doses of these polymers provide therapeutic effects.
This invention relates to the use of at least one polymer or one biopolymer, called HBGFPP, with the exception of mesoglycan, specifically protecting the growth factors of the FGF and beta TGF families from tryptic degradation and not significantly inhibiting coagulation, in the manufacture of a drug for the treatment of lesions of the digestive tract, and of secondary and primary derived tissues of the endoderm and the mesoderm.
In particular, such a polymer displays an anticoagulant activity of less than 50 international units per mg of polymer, measured according to Maillet et al. (Mol. Immunol, 1988, 25, 915-923). Advantageously, the polymer potentializes the FGFs in vitro.
Preferably, it does not substantially activate the complement system, that is to say, it possesses an anti-complement system of above 0.5 μg for the CH50 (according to Mauzac et al., Biomaterials, 6, 61-63, 1985).
According to the invention, polymers are understood to mean any natural substance, chemically modified natural substance or totally synthetic substance responding to the definition given above.
The following polymers are therefore concerned:
polymers obtained from dextrans but modified by other types of substitutions with other types of radicals,
natural polymers other than those deriving from dextrans but including osidic residues (cellulose, chitin, fucanes, etc.),
polymers obtained by polymerization of monomers of non-osidic nature (malic polyacid, oxalic polyacid, lactic polyacid, polystyrene, polyethylene glycol), whether or not modified.
Advantageously, the said polymer or biopolymer is a polysaccharide which may be principally composed of glucose residues.
It may also comprise glucosamine and/or uronic acid residues, particularly in the form of glucosamine dimer-uronic acid.
Such a polysaccharide advantageously displays a molecular weight of at least 10 kD and advantageously of about 40 kD.
This invention also relates to a pharmaceutical composition containing these polymers.
The polymers and/or biopolymers may be selected from natural substances which may then be modified, if required, by additions of appropriate chemical groups, or again be obtained entirely by synthesis. These natural, semi- or wholly synthetic polymers are then selected on the basis of their ability to interact specifically with several growth factors, notably those of the FGF and the beta TGF families. They are also selected on their ability to protect this (or these) factor(s) against proteolytic degradations. These polymers will be referred to under the generic abbreviation HBGFPP (heparin binding growth factor protectors and promoters). Two prototypes of these polymers or biopolymers are given as examples together with the processes and selection criteria of these polymers.
The first HBGFPP example belongs to the CMDBS family which are known products, namely functionalized biospecific dextrans, substituted by carboxymethyl, benzylamide and benzylamine sulfonate. These polymers illustrate the yielding of HBGFPPs from natural products (dextrans) which are subsequently chemically substituted. The second example describes the selection of wholly natural products, such as purified sulfate proteoglycosaminoglycans from tissular extracts.
These two examples illustrate the ability of these HBGFPPs to interact, stabilize, protect and potentialize the growth factors of the FGF and beta TGF families, and their use in a pharmaceutical composition permitting the protection, healing and/or regeneration of lesions of all origins affecting the digestive tract from the buccal cavity to the anal extremity.
In this patent application, by <<treatment>> is meant any curative or preventive operation carried out for the prophylaxis and the healing of lesions of the digestive tract, whether these lesions be of superficial or profound ulcerous type and whatever their origin, and/or the healing of perforations and/or surgical cuts and incisions as well as anastomoses performed on appropriate regions of the digestive tract.
A drug or a pharmaceutical composition according to the invention contains an effective amount of HBGFPP, for example CMDBS associated with one or more compatible and pharmaceutically acceptable vehicles. It may also be associated with agents such as, for example, anti-inflammatory, antibacterial, antifungal agents, gels, plasters, antacid dressings, H2 anti-receptor agents or anti-proton pump agents used in the treatment of gastric ulcers, and agents commonly used in buccal or dental care or in the treatment of hemorrhoids.
Advantageously, such a composition is designed to be absorbed directly by oral route, deposited on the lesion or injected if the said lesion is directly accessible, notably in subcutaneous, buccal or rectal lesions, or again during surgical interventions by depositing or soaking the extremities of the tissues before restitching or repatching or carrying out anastomoses. The unit dose is from 10 to 2500 μg of CMDBS or HBGFPP per ml.
The vehicle may be physiological serum or buffers, such as PBS, containing 0.15M NaCl or any other compatible solution which does not irritate the damaged tissue. Formulations providing thick solutions or in gel or aerosol according to standard techniques known to the person of ordinary skill in the art may be proposed depending on the type and the accessibility of the lesion.
Thus, for directly accessible lesions, such as buccal aphthas, lesions of the tongue or the palatal vault, or of gums and all support tissues of teeth or of the throat, the composition may be applied in the form of a solution, suspension, spray, powder, gel, unguent or ointment, paste or gelatinous cream, toothpaste, dental fixative, periodontal implant, chewing gum, effervescent tablets or tablets to be sucked, and may also be applied by means of a little pipette, spatula or brush. The composition described in this invention has the effect of curing the lesions, whether these lesions are accidentally caused, as in the case of thermal or chemical cuts and burns of microbial, fungal or viral origin (provided that the cause of the lesion is also treated by associating antimicrobial, antifungal or antiviral agents), or whether the lesions are due to other origins which are not always identifiable or known, or lesions resulting from chemotherapy or radiotherapy.
Similarly, for anorectal lesions, diseases or irritations, the composition concerned by this invention provides a treatment which reduces the irritation, itching and swelling of the tissues, and the suffering caused by anorectal diseases, and leads to the curing of these lesions by favoring tissue repair and regeneration. The anorectal diseases involve the perianal regions, the anal canal and the rectum and include hemorrhoids of extremely varied origin such as constipation, diarrhea, pregnancy, anal infections, rectal carcinomas, and other disorders like anal fistulas and fissures which may have diverse causes sometimes induced by chemotherapy or radiotherapy. As with lesions of the upper passages of the digestive tract, anorectal lesions are directly accessible and the composition may be applied in the form of a solution, suspension, spray, powder, gel, unguent or ointment, paste or gelatinous cream, or a suppository and by using a pipette or syringe whose nozzle is introduced in the anal canal or a spatula, brush or any other appropriate means.
The composition may be associated with other compositions commonly used in the treatment of anorectal diseases which have been listed non exhaustively in a monograph, No. 45 35576 the May 26, 1980, published by the American Food and Drug Administration (FDA). This monograph describes over 75 ingredients, classified in families such as local anesthetics, vasoconstrictors, protectors, anti-irritants, astringent agents, healing agents, antiseptics, keratolytics and anticholinergics.
The results obtained by applying this composition are of a quite different order to those obtained with existing products including sucralfate-based compositions such as those described in U.S. Pat. No. 5,196,405 issued on the of Mar. 23, 1993 for the treatment of hemorrhoids or in U.S. patent application Ser. No. 52407010 (DK102488 and DK505588). Depending on the surface of the wound, the CMDBS or HBGFP product doses correspond to a fraction of an initial solution of 10 to 2500 ug per milliliter (which, for a local application on common wounds, implies a dose which is rarely above a few hundred microliters of solution), this dose being applied once or twice per 24 hours. The sucralfate compositions used are 0.01 to 5% (according to U.S. Pat. No. 5,196,405), in other words at least 10 times higher than those described in this invention, and the effects described in all the examples of the said U.S. Pat. No. 5,196,405 are obtained from 50 milligram per milliliter compositions.
For digestive tract lesions which are not easily accessible by topical route, the administration route of the composition is either oral or rectal. This HBGFP-based composition is effective in the treatment of lesions of the pharynx, the stomach, the esophagus, the duodenum, the small intestine and the colon. Mention may be made, as non exhaustive examples of lesions which may be treated with benefit by the HBGFP-based compositions concerned by this invention, of mucosa lesions of parts of the digestive tract provoking ulcers such as gastric acid or duodenal ulcers; lesions induced by drugs, by accidentally absorbed chemical products, or by treatments by radiation, lesions induced by stress or by foodstuffs, or of surgical or traumatic origin, viral lesions or those associated with inflammations such as hemorrhagic rectolitis, or Crohn's disease.
The stimulating activity of the reparation of digestive tract tissues may also be envisaged for other secondary and primary derived tissues of the endoderm and the mesoderm such as glandular derivatives, for example the liver, the pancreas, the salivary glands, the adenohypophysis, or pharyngeal and respiratory derivatives, for example bronchi, lungs, pleuras.
The HBGPPs may thus be recommended in the reparation of lesions of all origins affecting these other secondary and primary derived tissues of the endoderm and the mesoderm (traumatic lesion induced by surgery or by tumoral or other pathologies).
FIG. 1 represents the CMDBS formula.
FIGS. 2A and 2B illustrate the potentialization of the biological activity of FGF1 (2A) and FGF2 (2B) by heparin, mesoglycan and sulodexide. Biological activity is measured on CCL39 cells by measuring the increased incorporation of tritiated thymidine versus the dose of FGF1 and FGF2 added alone or in the presence of 20 μg of heparin, 10 μg of mesoglycan or 10 μg of sulodexide.
FIGS. 3A, 3B, 4A and 4B illustrate the protective effect of heparin, mesoglycan and sulodexide against a thermal degradation of FGF1 (3) and FGF2 (4) . FGF samples are incubated on their own or in the presence of 20 pg of heparin, 10 μg of mesoglycan or 10 μg of sulodexide at 20� C. (a) and 37� C. (b) for 1, 7, 15, 30 days. The measurement of the biological activity presented in abscissa corresponds to the stimulation unit values (ED50) of the incorporation of tritiated thymidine in CCL39 cells.
FIG. 5A illustrates the protective effect of heparin, mesoglycan and solodexide against a proteolytic degradation of the 125 I-FGF1. Proteolytic digestion was carried out at 37� C. and the samples were separated by 18% polyacrylamide gel electrophoresis. The gels are dried and autoradiographed. The first track contains the 125I-FGF1 on its own. The 125 -FGF1 is incubated in the presence of trypsin (track 2), heparin (track 3), mesoglycan (track 4) or sulodexide (track 5).
FIG. 5B illustrates the protective effect of heparin, mesoglycan and sulodexide against a proteolytic degradation of the 125 I-FGF2. The arrangement of the tracks is identical to that presented for the 125 I-FGF1 in FIG. 5A.
FIGS. 6A and 6B are DEAE-Trisacryl column elution profiles, respectively, of HSM fractions (FIG. 6A) and HSS fractions (FIG. 6B) in the presence of chondroitin sulfate (CSA) fractions for the calibration of the column.
CMDBS preparation and selection
a) CMDBS preparation
CMDBSs are dextrans substituted by carboxymethyl, benzylamide and benzylamide sulfonate groups. The method of synthesizing the CMDBSs may be that described by M. Mauzac and J. Josefonvicz in Biomaterials 1984, 5, pp 301-304.
According to this process, carboxymethyl dextran (CMD) is prepared from dextran by substituting several glycosylated units with carboxyl groups on the carbon in positions 5 and 6.
In the next phase, benzylamide is coupled with the carboxyl groups to form carboxymethyl-benzylamide dextran (or CMBD). Finally, a few aromatic nodes of benzylamide are sulfonated in order to yield carboxymethyl dextran benzylamide sulfonate or CMDBS.
The sodium salts of these derivatives are ultrafiltered, lyophilized and dissolved in the appropriate buffer prior to use.
The general formula of the CMDBSs is illustrated in FIG. 1.
The CMDBSs possess a statistical distribution of the different substituents. The percentages for each CMDBS type are determined by using standard methods.
b) CMDBS selection
i: FGFs protection and stabilization tests
During the synthesis of the CMDBS the substitution rate of each of the groups may be controlled by modifying the substitution reaction conditions. Control of such parameters as temperature, reaction time, relative concentrations of the constituents, substitution reaction number, etc., makes it possible to obtain a very large number of substituted polymers. The substitution of the hydroxyls by carboxymethyl on the carbons in positions 5 and 6 gives carboxymethylation rates ranging from 0 to 200% (100% for each of the carbons in position 5 and 6). The carboxymethyl group may, in turn, be partially or totally used for fixing the benzylamide. The benzylamide groups may be partially or totally used for the sulfonation. The functionalized substituted dextrans used according to the invention are among those specifically described in French Patent 2.461.724. In addition to its ability to stabilize and protect FGF family growth factors, as described in the publication of Tardieu et coll., J. Cell. Physio. 1992, 150, pp 194 to 203 and in French Patent 2.461.724, the selected CMDBS must be able to interact with at least one member of the growth factors family belonging to the beta TGF family according to an evaluation method described below, and to protect the beta TGFs against proteolysis.
ii. Evaluation of the interaction capacities between CMDBS and beta TGF family growth factors.
In order to measure the capacity of certain CMDBSs to interact with members of the beta TGF family and, by means of this interaction, to protect the beta TGFS, a grading test was devised. This test consists in measuring the ability of the selected CMDBS to allow the beta TGF to maintain its biological activity despite a protease treatment.
In the example below, the CMDBS used is batch 26.2 defined by a substitution rate of 110% of carboxymethyl units, 3.6% of benzylamide units and 36.5% of sulfonate units, and possesses an anticoagulant activity of 4 IU/mg (International Units). This batch's anticomplement activity is 1.1 μg of CH50 measured according to Mauzac et al. (previously cited).
The heparin used as control was supplied by the Sanofi company (Choay Institute) and presents an anticoagulant activity of 175 IU/mg.
The beta 1 TFG is prepared from human blood platelets according to a protocol described in numerous publications (for example Growth factors and their receptors, 1992, vol 1 pp 419-472, written by A. Roberts and M. Sporn, edited by A. Roberts and M. Sporn, and published by Springer Verlag Berlin) and is commonly used by persons of ordinary skill in the art. The beta TGF biological activity test used in this example is that of the inhibition of CCL64 cells (from the American Tissue Culture Collection). This inhibition is measured by the ability of the beta TGF to inhibit the incorporation of tritiated thymidine in a dose dependent manner in these CCL64 cells stimulated by the FGF or by fetal calf serum according to the protocol described by Van Zolen in Progress in Growth Factor Research, 1990, 2, pp 131 to 152. Two doses of beta TGF are used, one corresponding to the 50% inhibition capacity of the incorporation of tritiated thymidine (defined as the inhibiting activity unit) and the other corresponding to the 100% inhibition capacity. In this example, the values obtained are 250 pg of TGF for the CCL64 cells cultivated in 1 ml of culture medium.
A 50 ng sample of beta TGF in saline phosphate buffer containing 0.1% bovine albumin serum (from the SIGMA company, Saint Louis USA) is incubated on its own, or associated either with 5000 μg of CMDBS or 5000 μg of heparin, with or without 500 μg of trypsin. The final volume of the incubated solution is adjusted to 1 ml and incubation is carried out at 37� C. for a varying length of time (10 minutes in the example described (Table 1)).
20 μl samples of a volume of are taken from each of the incubation reactions and added to CCL64 cells cultivated in 24-well plates, each well containing one milliliter of culture medium according to the aforementioned protocol described by E. Zohlen. In these conditions, the final concentration of beta TGF per well is 1 ng/ml. Table 1 summarizes the results obtained in various conditions and shows the protective effect of the CMDBS. Thus, after 10 min of incubation at 37� C., 75% of the biological activity of the beta TGF is still present, whereas heparin, despite the fact that it can be fixed to the beta TGF (Mac Caffrey et al., J of Cell. Physiology, 1992, vol 52, pp 430-440), does not protect the beta TGF against this proteolytic degradation (less than 20% of biological activity remain). It should be remembered that, in the case of FGFs, heparin provides protection against proteolysis induced by trypsin (Tardieu et al., Journal of Cellular Physiology, 1992, 150: pp. 194-203).
It was verified that the CMDBS had no inhibiting power on the activity of trypsin (Table 2). Thus, 10 μg of trypsin were incubated, either with a substrate (S.87 supplied by the Serbio company in Paris and used according to the supplier's recommendations) or with this substrate and a trypsin inhibitor such as that originating from soya (such as the soybean trypsin inhibitor or STI from Sigma), these incubations being carried out in the absence or presence of varying quantities of CMDBS (batch AM26). The enzymatic activity of trypsin was measured by spectrophotometric absorption of the transformation product of S 87 versus incubation time.
Selection of other HBGFPPs
A commercial preparation of proteoglycosaminoglycan and glycosaminoglycans, sulodexide, was selected according to its ability to interact with the growth factors of the FGF and beta TGF families.
Preparations of heparan sulfate obtained by fractionating mesoglycan and sulodexide were also tested.
The mesoglycan and sulodexide were supplied by the Sigma Chemical Co, Saint Louis Mo. USA. Their properties are summarized in Table 3.
The cells used in this example are CCL39 cells from the American Tissue Culture Collection. The conditions concerning culture and the measurement test of FGF biological activity are the same as those described in the publication by Tardieu and coll. in the Journal of Cellular Physiology, 1992. The FGF growth factors used are the FGF 1 and FGF 2 recombinant forms.
a) Effect of sulodexide on the in vitro biological activity of the FGFs
In these experiments, the FGF 1 or 2 is used at a dose corresponding to the effective dose (indicated ED50) in order to induce a stimulation of the biological activity of 50% of the dose inducing the maximum stimulation. The biological activity is measured by the ability to induce an increase of the incorporation of tritiated thymidine in the cells according to protocols extensively described in numerous publications such as the previously mentioned publication by Tardieu et coll. and also in French Patent 2 644 066.
In this example, the ED50 is 5 ng/ml for the FGF 1 and 3 ng/ml for the FGF 2, these values being measured experimentally (FIG. 2A and 2B).The same stimulation experiment in function of the FGF dose is carried out in the presence of 10 μg/ml of sulodexide, or 20 μg/ml of heparin. FIG. 2 shows that in these conditions the ED50 becomes 0.4 ng/ml and 0.2 ng/ml respectively for FGF 1 and FGF 2 in the presence of these doses of sulodexide or heparin. In addition to this ability to potentialize the biological activity of the FGFs, the HBGFPPs protect the FGFs against thermal degradations and the inactivation induced by the proteolytic action of trypsin (FIGS. 4 and 5). Similarly, these HBGFPPs protect FGF1 and 2 against an inactivation induced by the proteolytic activity of trypsin (FIGS. 5A and 5B).
b) Protective effects of sulodexide, dextran, dextran sulfate and sucrase with regard to beta TGFs.
Several other compounds were evaluated: dextran sulfate (Sigma Chemical, molecular weight 40.000, the dextran having been used for the synthesis of the CMDBS (also from Sigma)), sucrase or sucrose octasulfate (supplied by D. Bar Shalom, Bukh Medic company, Denmark). Some of these compounds were chosen because they protect and stabilize FGFs, for example sucrase (see. U.S. Pat. No. 5,202,311) or dextran sulfate (see. Japanese Patent 138 907/88). The dextran is the one used in the synthesis of CMDBS AM26.
The protection experiment of the beta TGF biological activity was carried out in the same way as with the CMDBS as described in Example 1 ii. The incubation mixture contained 50 ng of beta TGF (in 0.1% bovine serum albumin) and trypsin (500 μg). Mesoglycan or sulodexide or dextran sulfate or dextran or sucrase are used at the dose of 5000 μg.
The beta TGF biological activity is measured as described above after a dilution of 50 times and by using CCL64 cells.
The results are presented in Table 4.
These results show that, like certain CMDBSs capable of responding to the two selection criteria with regard to the FGFs and beta TGFs, sulodexide presents a significant protective activity for the beta TGFs.
c) Isolation of the heparan sulfate fraction of sulodexide and mesoglycan
Sulodexide and mesoglycan correspond to mixtures of several substances essentially made up of different glycosaminoglycans (GAG).
By means of a first purification stage, it was established that a gram of dry product of each of these two products contained respectively 874 mg for the mesoglycan and 795 mg for the sulodexide of total GAGs.
This purification was obtained by subjecting these solubilized products to ion exchange chromatography (DEAE-Trisacryl) in order to remove all proteic contaminants. The total GAGs were then purified by eluting the DEAE gel with a sodium acetate solution, pH 4, containing 1.5M NaCl.
After an extensive dialysis phase against water, 60 mg of each product of GAG are digested by the ABC chondroitinase overnight at 37� C. (1 unit per mg of GAG). This enzyme degrades all the GAGs with the exception of the heparan sulfates (HS). The products of digestion were subjected to molecular sieve chromatography (G50 Sephadex, 1.8�95 cm column). Elution was then carried out on ammonium bicarbonate buffer at a rate of 18 ml/hour. The non digested material corresponding to HS-type GAGs was collected in the elution dead volume of the column.
The GAG concentrations were calculated from their uronic acid content using the carbazol method (Bitter T. and Muir H. M., 1962, Anal. Biochem 4, pp. 330-334).
From these measurements the following composition of each of the products was obtained:
______________________________________ Sulodexide Mesoglycan______________________________________Total GAGs 79% 87%Heparan Sulfate Fraction (HS) 48% 52%Other GAGs 31% 35%______________________________________
The HS fractions of each of these two products were again chromatographed on a DEAE Trisacryl gel. 1 mg of each HS fraction, purified with mesoglycan (FIG. 6A) or sulodexide (FIG. 6B) in 3 ml, was deposited on a balanced column with 0.05M NaCl buffer, 0.05M TMS-Hcl pH 7.5. After washing of the column with 10 volumes of the same buffer followed by washing with 10 volumes of 0.05M NaCl buffer, 0.05M of sodium acetate pH 4, the material fixed to the column is desorbed by a saline gradient ranging from 0.05M NaCl to 1.5M NaCl in the same acetate buffer. 1 ml of each fraction collected was measured by the carbazole method.
The material corresponding to the HS constituents of each of the original products shows approximately the same elution profile and thus roughly the same apparent load. This elution peak maximum is obtained for a saline concentration of 0.94M NaCl. A defined fraction of chondroitine sulfate (CSA) was subjected to the same protocol in order to calibrate chromatography. This CSA fraction, containing only one sulfate group by disaccharide, is eluted at the ionic strength of 0.72M NaCl.
These results show that the HS fraction contains more sulfate groups than the reference CSAs. The HS fraction presents about two sulfate groups per dissacharidic unit.
These fractions were tested in order to discover their protective power with regard to the beta TGF and the FGF compared to the powers established with the respective raw products.
Semi-quantitative evaluation of the FGF protective effects of the FGF by different polymers
As described above, a constant quantity of radioactive FGF is incubated under various conditions. After autoradiography of the reaction products, the non degraded quantity of radioactive FGF is quantified by densitometry. The values correspond to the percentage of radio-labelled FGF found compared to the quantity deposited at the start of reaction (Table 5).
The results of Tables 4 and 5 show that the HSM and HSS fractions, originating respectively from mesoglycan and sulodexide, show protective effects which are greater than these two compositions and are close to 100%.
In vitro Inhibiting effects of CMDBSs and glycosaminoglycans on the activity of leukocytic elastase and plasmin
The inhibiting powers of different CMDBS and of the intermediate compounds of their synthesis were established for leukocytic elastase and plasmin.
The purified leukocytic elastase was obtained by Elastin Products Co (Owenville, Mo., USA) and the plasmin from SIGMA.
The inhibition of enzymatic activities by these different compounds is carried out at 37� C. in a thermostatic bath. The enzymes under consideration are placed in solution in a 100 mM Tris-HCL buffer, pH 8 for the elastase and pH 7.4 for the plasmin, in the presence of 0.02% sodium azide and 0.01% Triton X100 for the plasmin. The substrate and enzyme concentrations are: 0.10 mM MeO-Suc-Ala-Ala-Pro-Val-pNA (paranitroanilide) for the elastase at 8.3 nM, and 0.20 mM dVal-Leu-dLys-pNA for the plasmin at 77 nM. The IC50 is determined for each of the conditions.
Table 6 gives the results obtained, in which batch AM6 corresponds to a T40 dextran of 40,000 kD. Batch EM5 corresponds to a T10 dextran of 10,000 kD. The intermediate products of synthesis are identified by the symbols given above with an index number specifying the number of each substitution reaction.
The IC50 values show that the CMDBSs have non competitive hyperbolic-type inhibiting effects on leukocytic elastase activity which are comparable to those of heparin, one of the best inhibitors of this activity (Ki of the order of 1 nM). In addition, and unlike heparin, the CMDBSs show inhibiting effects on plasmin.
Table 6 also shows that the inhibiting effects of the HSM and HSS fractions are greater than those of mesoglycan and sulodexide, respectively.
Healing effect of CMDBS on anastomosis of the colon
The batch of CMDBS used in this example is that described in Example 1. A 50 μg per ml solution of CMDBS is made in a physiological serum. Male Wistar rats (Wi/Wi, Ico, Iffa Credo France), weighing 250 to 300 g are anesthetized with sodic pentobarbital. A subumbilical midline laparotomy is performed over 1.5 cm. The rectocolic junction is individualized and then sectioned with bistoury. The two banks of the anastomosis are then imbibed with a solution containing either the CMDBS or a physiological buffer for a period of two minutes. The anastomosis is carried out according to a termino-terminal mode in a plane by five separate stitches of polyglactine 910 thread, diameter 6/0. The knots are made of 6 loops. Parietal closure is performed in two planes. The rats are divided into two groups of 7 rats. The experiments are conducted in double blind. Samples are taken on the 2nd, 4th and 7th days after the operation. The quality of the healing is studied by measuring the rupture pressure of the anastomosis, in millimeters of mercury. The colon is sectioned 2 cm on either side of the anastomosis, one end being connected to a self-pushing syringe which injects water at a low, constant rate, and the other end being linked to a manometer. Pressure is recorded continuously on a reel of paper. The rupture pressure is determined by analyzing the tracing. The values obtained are presented in Table 7 below.
Results: At Day 2 (48 hours after the operation) a very marked difference greater, by the order of three times, is measured between the anastomosis rupture forces realized with and without CMDBS treatment. This mean is statistically significant (p≦0.05). At Day 4 this difference is much smaller and corresponds to an increased resistance of about 10% in favor of the animals treated with CMDBS. At Day 7, there is no longer any difference between the treated and untreated resistances. The benefit of the CMDBS treatment is clearly apparent since it provides a greatly improved anastomosis solidity at the crucial moment, that is to say at the very start of healing, for the risks of anastomosis rupture always occur in the first few days.
Healing effect of the CMDBS on colitis induced by acetic acid
Groups of 6 Sprague Dawley male rats weighing approximately 200 g are placed in hydric fasting 24 hours before the test. On the day of the test, the animals are anesthetized with pentobarbital (30 mg/kg) by intraperitoneal route. After laparotomy, a colic instillation of 2 ml of 5% acetic acid is performed 2 cm from the caecum. The acetic acid is left in contact for 10 seconds and the colon is then rinsed by 3 ml of saline phosphate buffer (PBS) at pH 7. The wound is then closed. The animals are sacrificed 72 hours later by cervical elongation. The colic alterations are noted on the following scale:
0: normal colon
1: congestion
2: superficial necrosis of the mucosa
4: major necrosis of the mucosa with edema
5: perforation
A first control group of six rats does not receive treatment.
A second group receives 50 μg of an aqueous solution of CMDBS (batch AM26), administered orally morning and evening for three days.
A third group receives sucralfate (marketed under the name of ULCAR Pharmaceutical Laboratories Fabre). The supplier's recommended dose is used (500 mg/kg, i.e. 100 mg per rat) administered orally twice a day for three days.
Statistical analysis
The mean and the standard error were calculated for each batch of animals. Statistical comparison is performed using White's non parametric test compared to the control.
The results are presented in Table 8 below.
As these results show, the CMDBS reduces the seriousness of the colic lesions induced by acetic acid by about 75% (significant effect, p≦0.05). In contrast, the sucralfate has no significant effect on the healing of these ulcers.
HBGPP-based compositions
In examples 5 and 6 described above, the CMDBS is a buffered saline aqueous solution (PBS buffer) or physiological serum at concentrations of 50 μg/ml. Administration is local or per os; it may be intravenous. Other compositions may be proposed provided that the dose of CMDBS reaching the site of the lesion lies between 1 μg and 1000 μg.
TABLE 1______________________________________Protective effects of CMDBS and heparinagainst beta TGF degradation by trypsinincubation mixture at 37� C. for 10min and containing, per milliliter, % inhibiting activity of theaccording to the indication: CMDBS incorporation of tritiated thymidineor heparin (5000 μg): βTGF (50 in CCL64 cells (after dilution 50ng): trypsin (500 μg) times of incubation mixture)______________________________________Incubation buffer only 0CMDBS (5000 μg) 0Heparin (5000 μg) 0Trypsin (1000 μg) 0Beta TGF (50 ng) 100Beta TGF + CMDBS (batch AM26) 100Beta TGF + heparin 100Beta TGF + trypsin 5Beta TGF + CMDBS + trypsin 75Beta TGF + heparin + trypsin 10______________________________________
TABLE 2______________________________________Non inhibiting effect of CMDBS on trypsin______________________________________Trypsin (10 ug/ml) + S87 100Trypsin + S87 + 5 μg/ml CMDBS 100Trypsin + S87 + 50 μg/ml CMDBS 100Trypsin + S87 + 500 μg/ml CMDBS 100Trypsin + S87 + STBI 0______________________________________
TABLE 3______________________________________Origin, anticoagulant activity and partial composition of mesoglycanand sulodexide (supplier's information) Sulodexide Mesoglycan______________________________________Origin pig duodenum AortaAnticoagulant activity 50-70 IU/mg <50 IU/mgChemical compositionDermatan sulfate 20-35% 25-60%Chondroitine sulfate 2-7% 3-15%Heparan sulfate + +______________________________________
TABLE 4______________________________________Protection of the beta TGF by various polymers______________________________________Beta TGF 100%Beta TGF + trypsin 0%Beta TGF + mesoglycan 100%Beta TGF + mesoglycan + trypsin 50%Beta TGF + HSM 100%Beta TGF + HSM + trypsin 75%Beta TGF + sulodexide 100%Beta TGF + sulodexide + trypsin 20%Beta TGF + HSS 100%Beta TGF + HSS + trypsin 45%Beta TGF + dextran 100%Beta TGF + dextran + trypsin 0%Beta TGF + dextran sulfate 100%Beta TGF + dextran sulfate + trypsin 0%Beta TGF + sucrase 100%Beta TGF + sucrase + trypsin 0%______________________________________ HSM = Heparan sulfates purified from mesoglycan HSS = Heparan sulfates purified from sulodexide
TABLE 5______________________________________Protection of the FGF by various polymers______________________________________ PROTECTION (in %)______________________________________FGF alone 100%FGF + trypsin 0%FGF + trypsin + heparin 100%FGF + trypsin + mesoglycan 75%FGF + trypsin + sulodexide 70%FGF + trypsin + heparinase treated mesoglycan 0%FGF + trypsin + heparinase treated sulodexide 0%FGF + trypsin + heparinase treated heparin 0%FGF + HSM + trypsin 95%FGF + HSS + trypsin 90%______________________________________
TABLE 6______________________________________Inhibition of elastase and plasmin activities Leukocytic elastase plasminTested compounds IC50 in μg/ml IC50 in μg/ml______________________________________CMDBS, batch AM6 2.2 1.5T40 >100 >100CMDBS, batch EM5 10 7T10 CMD2B 50 53T10 5CMD1B >100 >100T10 3CMD >100 >100T10 >100 >100Mesoglycan 72 65HS mesoglycan 20 22Sulodexide 79 75HS sulodexide 25 20Heparin 1.8Lipo-heparin 0.5______________________________________ HSM = Heparan sulfates purified from mesoglycan HSS = Heparan sulfates purified from sulodexide
TABLE 7______________________________________Study of the healing of the rectocolic junction DAY 2 DAY 4 CONTROLS CMDBS CONTROLS CMDBS______________________________________Rupture pressure in 38 48 112 136mm of Hg 20 96 140 140 18 76 140 148 35 53 121 144 20 82 98 156 18 66 108 50mean 22.45 67.28 119.8 144.8S.D. 8.33 16.87 15.77 6.88n 6 7 6 5______________________________________
TABLE 8______________________________________Effect of CMDBS on colitis induced by acetic acidTreatment Alteration score______________________________________Controls 2.83 � 0.48CMDBS 50 μg/rat per os 0.70 � 0.37Sucralfate 100 mg/rat per os 2.25 � 0.48______________________________________
|Cited Patent
|Filing date
|Publication date
|Apr 3, 1992
|Mar 28, 1995
|Takeda Chemical Industries
|Acid-resistant FGF composition for treating ulcerating diseases of the gastrointestinal tract
|Citing Patent
|Filing date
|Publication date
|Nov 23, 1999
|Oct 16, 2001
|Cytomedix Inc
|Enriched platelet wound healant
|Jun 22, 2001
|May 5, 2009
|Cubist Pharmaceuticals, Inc.
|Compositions and methods for increasing the oral absorption of antimicrobials
|Aug 16, 2011
|Denis Barritault
|Process for treating fibroses with biocompatible polymer
|Apr 16, 2009
|Nov 6, 2012
|International Health Management Associates, Inc.
|Compositions and methods for increasing the oral absorption of antimicrobials
|Jun 14, 2011
|Jul 2, 2013
|Denis Barritault
|Biocompatible polymers, process for their preparation and compositions containing them
|Oct 28, 2004
|Jul 29, 2014
|Organes Tissus Regeneration Reparation Replacement—OTR3
|Use of biocompatible polymers for the preparation of a composition or a medical device
|Apr 12, 2013
|Nov 11, 2014
|Denis Barritault
|Biocompatible polymers, process for their preparation and compositions containing them
|Apr 27, 2006
|Mar 3, 2015
|Cubist Pharmaceuticals, Inc.
|Therapeutic compositions
|Mar 14, 2014
|Dec 1, 2015
|Symic Ip, Llc
|Extracellular matrix-binding synthetic peptidoglycans
|May 24, 2012
|Dec 22, 2015
|Symic Ip, Llc
|Hyaluronic acid-binding synthetic peptidoglycans, preparation, and methods of use
|Jun 22, 2001
|Feb 27, 2003
|Seung-Ho Choi
|Compositions and methods for increasing the oral absorption of antimicrobials
|Oct 28, 2003
|Jul 8, 2004
|Denis Barritault
|Biocompatible polymers, process for their preparation and compositions containing them
|Jul 11, 2003
|Jan 13, 2005
|Fred Wehling
|Effervescent glucosamine composition
|Apr 27, 2006
|Sep 4, 2008
|Cubist Pharmaceuticals, Inc
|Therapeutic Compositions
|Sep 17, 2008
|Jan 8, 2009
|Denis Barritault
|Biocompatible polymers, process for their preparation and compositions containing them
|Oct 22, 2009
|Seung-Ho Choi
|Compositions and methods for increasing the oral absorption of antimicrobials
|Oct 28, 2004
|Sep 22, 2010
|Organes, Tissus : R�g�n�ration, R�paration, Remplacement-OTR3
|Use of biocompatible polymers for the preparation of a medical device or compound
|Oct 28, 2004
|Dec 15, 2010
|Organes, Tissus : R�g�n�ration, R�paration, Remplacement-OTR3
|Biocompatible polymers for a medical composition
|U.S. Classification
|514/54, 514/55, 514/62, 514/882, 514/927, 514/56, 514/57, 514/59, 514/926, 514/925
|International Classification
|Cooperative Classification
|European Classification
|Apr 8, 1997
Owner name: SOCIETE VALBIOFRANCE, FRANCE
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BARRITAULT, DENIS;CARUELLE, JEAN-PIERRE;MEDDAHI, ANNE;REEL/FRAME:008443/0180
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Maxx Dry XL Forced Air Dryer
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While editing older writings, I came across this narrative exercise from my MA coursework. For this assignment we had to take a scenario/vignette and write it in three ways, altering tense and POV in each. I found that changing focalisations significantly altered the narrative for me, in an invigorating way. The next […]
The Sunday Poem: October 11, 2015
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The Sunday Poem: October 4, 2015
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The Sunday Poem: September 27, 2015
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Camera Collectanea: Shine Strong High Tea, Beautiful Things and Paper Cameras
A bit about the Good Housekeeping Pantene Shine Strong High Tea, coffee worship and small camera-shaped boxes.
Madressah Zia-ul-Badr: Uplifting Young and Old
We visited Madressah Zia-ul-Badr, a unique place of learning and care in eastern Jeppestown, Johannesburg.
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Missives to the children I am yet to bear. — I don't know what social media will be like when you're old enough to set up your own profiles. I have a utopian vision of the entire infrastructure imploding, with only true and intimate connections surviving the fallout. I am […]
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May you find the very best of yourself.
TBT: Cameron Highlands, Malaysia,December 2014
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text:
Clocks for Sale
Longcase by Maple of London, circa 1900's
A quality grandfather clock made of solid oak throughout, in a lovely honey hue. A really solid and sound construction.
I would date this clock around 1890-1900, so strictly speaking, it is a "reproduction" of earlier models. It is of great quality, as you would expect from a Maple Clock.
The best materials have been used and it has been built to last, as a result it is not likely to give nasty surprises when it comes to being serviced in the future.
DIMENSIONS: Height 2 metres 3cm (6' 8'')
Depth 27cm (10 5/8'') in depth.
The widest part, at the top, is 54cm (21 1/4'').
This lovely clock would add quality and style to any interior.
It strikes the hours on a gong, producing a very deep sound
Fully serviced with a 1 year guarantee
Price: £2,495
Atmos Clock cal526, 1970's
I find that the cal526-5 is the nicest model of the old calibers(pre cal540) and a very successful model too, as proven by the fact that they can run 25-30 years between sevices
It has very pleasant proportions, slightly smaller than the cal528, "hinged" door and it has a very elegant case design.
The clock case is in very good condition. Please note that this clock is 40 years old and some minor wear signs are to be expected, (see photos) or you very welcome to view it.
Mechanically, it is in perfect condition and of course,.... It never needs winding.
The clock has been thoroughly checked and fully serviced for your peace of mind, the bellow is fine, with the gas at its optimum level.
Approx dimensions in inches: H 8 3/4 " x W 7" x D 5 1/4 "
or cm : 22 x 18 x 13
2 year guarantee, £999
If you would like more details, please get in touch
Collection might be preferred, but I have no problem to sending it by courier, as I send these clocks by courier regularly. Posting to a UK address is £25


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"I used the enclosure card and created my Rehearsal Dinner invitation. It worked out beautifully! I used Wedding Paper Divas for all my wedding needs and am thrilled with the results and products I received. I would use them again and again!"
"We used the enclosure cards to provide information about accommodations and our wedding website. I was initially concerned about getting all of the information on the card but it fit perfectly. The design team adjusted things to ensure it looked great. I appreciated the easy process!"
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shaun---Perhaps you and what was said in the video is right. I will relate a story of this last year regarding this. Know, my mate, she has few dreams that she tells of, only those that foretell of future events or something that is important.
On this occasion she tells me of this event the night before of the two of us being with some tall good looking and strongly built people on a large vessel or house as it was ornate and flowing inside like a sculpture.
Bear with me here as this woman in not into any of this stuff, she is just a normal hard working woman into her own life and simple world. So she relates to me over and over again, "that it was real, it was not a dream, it was real, we were there with them". I asked what they looked like and she told me they were tow headed, blondish, all over six feet high and had unusually roundish eyes, blue in color. The uniforms they wore were also tight fitting and blue. She thought at first they were odd and cultist due to the fact they were quiet and did not seem to talk, they hummed and got a message over without conversation.
There are details which I am leaving out for brevity, but she claimed I was one of them and it made her feel left out and she needed to do some waking up and changing or be left behind which I am unsure of what that means. Myself and them then proceeded to as she put it, leave the vessel and zoomed down onto the world that was below us as we were floating above the clouds and she could not do this making her feel badly. A word about that world, it was in her telling heavenly, colors came from within, not reflected, more like another dimension than here.
Before discounting this know that I was able somehow to fill in gaps when she talked which amazed her as I intuitively knew what was there. She also told me she had been there before as well and knew her way through the vessel. There is more, but perhaps we our family is far more extensive than we know.
sailormon 1157342
interesting, thank you for sharing that with me/us..
show her this video and see if any of these beings look familiar...
link to www.youtube.com
if i can find any more videos with drawings i'll share them..
yes, many of us communicate in different ways with our brothers/sisters from the cosmos..
amazing times we are in huh:)
much more to come, we are just getting started:)
evolution in the twinkle of the eye right?*
for those who choose love and are ready to ascend, have forgiveness and love/light..move on up to a higher density and frequency and dimension along with this beautiful planet/sister..so awesome, so brave, so amazing..
thank you
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13 Important Elements To Look For In Every Staged Shooting Event
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- Swimmer Ryan Lochte reveals one of his worst dates - US Weekly
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- ISIS has claimed responsibility for a bombing that killed at least 80 people in Afghanistan Saturday.
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Steve Kimock - Guitars
Rodney Holmes - Drums
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Notes (2-24-03 AD):
Ron's original mastering had In Reply > Avalon as one track (d2t01). To make this seed conform to the somewhat standard practices of the kimock seeding community, I split d2t01 using CDWave. I renamed the subsequent files as needed, and re-encoded the new tracks.


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Ask Ari
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Feeding Chickens Red Meat
Q: Cleaning out the freezer, I'm finding things like deer kidneys and elk livers that seemed like a good idea at the time, but I don't think I'll be getting to. Is it OK to feed meat scraps to my chickens? I've got turkeys and guinea fowl this year, too, and they're supposed to be getting more protein than the layers. Will meat taint the eggs and meat? Will the taste of blood make the kids go postal?
Sergio Salvador salvadorphoto.com
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Since opening in September, Sushiya has gained a loyal following, and it's easy to see why. The menu is a polished combination of Chinese and Japanese classics, with many twists—and some entire dishes—you probably haven't seen before.
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Who's coming and who's going. Tell us about your job move! Receive the Revolving Door Newsletter with expert analysis by email twice a week.
November 20, 2014: Jason Kravarik has been named Los Angeles bureau producer at CNN. He had been assistant news director at KOIN in Portland, Ore. (TVSpy)


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Tom Smart, Deseret News
SALT LAKE CITY — Which Utah sports franchise is the most profitable? Not the NBA's Utah Jazz, the beehive state's only top-tier professional franchise.
According the U.S. Department of Education, Brigham Young University's football team is the most profitable team in the state. BYU brought in $22.4 million in the 2012 season, posting a $7.41 million profit.
Meanwhile, the Runnin' Utes are also runnin' all the way to the bank. Utah's football team posted $20.7 million in revenue and a $5.9 million profit in 2012.
Even the Utah State Aggies, a team with historically poor earnings in football, posted a profit this past year. According to the U.S. Department of Education, Utah State had football revenue of $5,881,832 and football expenses of $5,881,831 to tally a total profit of $1.
Conversely, the Utah Jazz earned $120 million in revenue but posted a $16.4 million loss, according to Forbes.
According to The Wall Street Journal, some top-tier college football programs' total values are comparable to that of professional franchises. The teams' total value takes into account "each program's revenues and expenses and made cash-flow adjustments, risk assessments and growth projections for each school."
The University of Texas is ranked first with a total value of $761.7 million while the NFL's Jacksonville Jaguars, which ranked last in value among NFL franchises, sold in 2011 for approximately $760 million. However, UT's $71.2 million profit would rank it fourth among NFL teams behind only the Dallas Cowboys, New England Patriots and Washington Redskins.
While professional teams generate more total revenue than most college teams by a wide margin, player salaries and other operating expenses that colleges don't incur carve away at profit margins.
Increased operating expenses for professional franchises, including rising player salaries, have largely offset the record TV and advertising contracts signed by professional franchises. Unlike the NBA, NFL and MLB, the NHL lacks a major television deal and depends heavily on ticket sales to generate revenue. According to Forbes, 13 of the league's 29 franchises were operating at a loss. As of last season, NHL players received 57 percent of the league's total revenue with the owners lobbying to lower that total to as little as 46 percent.
In terms of profit, Utah State is ahead of two NFL franchises, both of which posted losses this season: the Oakland Raiders and the Pittsburgh Steelers. The Utes beat those franchises in addition to the Detroit Lions, and the Cougars additionally beat the St. Louis Rams and Minnesota Vikings.
However, to put those numbers in perspective, both operating costs and revenue of college programs are much, much lower than the revenue and costs of professional francishes.
BYU's $7.41 million profit was $2.5 million less than the New York Yankees, whose value of $1.85 billion makes it one of the most valuable sports franchises in the world.
Not all college sports programs are created equal. Top football programs such as at the University of Texas and Ohio State are so profitable that they bankroll their entire athletic departments. Other universities may have one or two profitable programs, but lose money on athletics as a whole.
According to USA Today's annual survey of sports spending, just 22 of 227 public universities in NCAA Division I turned a profit in 2011.
"What seems to be happening all too often nationwide is that the breadth and depth of athletic departments are being cut. It's becoming the victim of a financial need to feed this commercial beast," said John Nichols, co-chairman of the Coalition on Intercollegiate Athletics in an interview with the Washington Post.
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text: 000 FXUS61 KBUF 241807 AFDBUF Area Forecast Discussion National Weather Service Buffalo NY 207 PM EDT SUN JUL 24 2016 .SYNOPSIS... An upper level trough will slowly cross the region tonight into Monday which will produce a few scattered showers and thunderstorms. A trailing cold front will pass through our region Monday evening, followed by slightly cooler and less humid weather Tuesday before temperatures and humidity trend upward again Wednesday and Thursday. A weak area of low pressure will cross the region Friday and Saturday bringing the next chance of showers and thunderstorms. && .NEAR TERM /THROUGH MONDAY/... Visible satellite imagery showing thicker mid level clouds spreading into western NY this afternoon. Central NY and the North Country are still holding onto a good deal of sunshine, but clouds will increase there as well through the mid to late afternoon. Temperatures are rising efficiently despite the thicker cloud cover, with highs in the upper 80s to around 90 this afternoon across lower elevations, and low to mid 80s across the higher terrain and North Country. Lake breezes will keep areas within a few miles of Lake Erie and Lake Ontario cooler. Upstream deep moist convection, and the remnants of earlier convection, across southern Ontario and Northern Ohio will by in large pass by to our south per latest radar trends and short term mesoscale guidance. A few showers or an isolated thunderstorm may clip Chautauqua and western Cattaraugus counties this evening as more unstable air begins to spread into the southwest corner of the state, but otherwise the rest of the area will stay dry through this evening. Late tonight a weak mid level trough and pre-frontal surface trough will approach western NY. Mesoscale model guidance continues to struggle with the details of timing and placement for convection, but in general expect scattered convection that develops this evening across lower Michigan to spread ESE across southern Ontario and reach western NY late tonight. The convection will have some large scale support, with ascent and deeper moisture increasing ahead of the mid level trough. A modest 30+ knot low level jet will also support an increase in low level convergence and moisture transport across western NY late tonight. Even so, given the ongoing drought and lack of model consensus have kept POPS in the high chance range for late tonight and early Friday. On Friday the morning convection associated with the pre-frontal trough and first mid level trough will continue to move ESE across the area. Following the morning convection, if enough breaks in the clouds are realized, moderate to strong instability will develop with very warm surface temperatures and high boundary layer moisture, while mid level height falls begin to overspread the lower Great Lakes. A stronger mid level trough will approach in the afternoon, with the actual surface cold front not crossing the area until the evening. The main focus for afternoon convection will be along the lake breeze convergence zones, and possibly along residual outflow boundaries from morning convection. Expect coverage to be scattered in nature, with the best coverage from the Southern Tier across the Finger lakes to central NY. If the greater instability values suggested by some operational models are realized, there may be at least some severe weather potential as deep layer shear increases into the 35-40 knot range by mid to late afternoon. By this time much of the convection will likely be east of our area, but a few storms may linger along lake breeze boundaries farther west from the Southern Tier into the Finger Lakes to southern Tug Hill region. The area will be situated in the right entrance region of a 90+ knot upper level jet which will provide upper level divergence and aid in storm intensification. Temperatures will be very warm, with lows in the mid 70s on the lake plains tonight along with steadily increasing dewpoints. Highs on Monday will reach 85-90 depending on how much sun develops in the afternoon. && .SHORT TERM /MONDAY NIGHT THROUGH WEDNESDAY NIGHT/... Monday night through Wednesday night will feature dry and warm conditions as high pressure builds across the region and lingers through mid-week. An upper level trough will exit to our east Monday night giving way to mainly zonal flow with some weak ridging Tuesday into Wednesday. A surface high will build across the Ohio valley Tuesday and remain stalled there through Wednesday. 850 mb temperatures will take a small step back to around +16C on Tuesday behind the departing wave, allowing high temperatures to run near seasonal values, while drier northwesterly flow will cut dew points back into the mid to upper 50s, making the warmth more comfortable. By Wednesday, the modifying airmass under the surface high will push 850 mb temperatures to about +18C, resulting in afternoon temperatures back into in the upper 80s. However, humidity will remain low as the dry high pressure remains in control and dew points again drop into the mid 50s for the afternoon. Overnight lows will run in the mid to upper 60s near the lake plains. Mainly clear skies and light winds allow radiational cooling to drop interior valleys into the mid to upper 50s. && .LONG TERM /THURSDAY THROUGH SATURDAY/... The pattern has the potential to become at least a little more active from late week into the first half of next weekend. The expansive mid/upper level ridge which has dominated the central and eastern CONUS will be knocked back as the longwave pattern buckles across North America, with a western ridge and eastern trough pattern becoming established by next weekend. The developing longwave trough in the Great Lakes and Northeast states will be carved out by several mid level shortwaves, each of which will bring a period of large scale ascent and increased deep layer moisture to our region. Looking at the details, the first relatively weak trough will approach the Great Lakes Thursday afternoon and evening. This system may touch off a few widely scattered showers and thunderstorms with sparse coverage. Models begin to diverge on the timing details of the finer scale features by Friday and Saturday, but most operational and ensemble guidance show a more significant mid level trough and associated surface wave moving through the Ohio Valley and eastern Great Lakes either Friday or Saturday, with a better chance of somewhat more widespread showers and thunderstorms. Temperatures will continue to run hot through Thursday, with 850mb temps of around +18C supporting highs around 90 at lower elevations away from the lakeshores. More clouds and showers will bring temperatures back closer to average by Friday and Saturday. && .AVIATION /18Z SUNDAY THROUGH FRIDAY/... Extensive mid/high clouds from earlier upstream convection will continue to spread from west to east across the area this afternoon and evening with VFR prevailing. Several batches of showers and thunderstorms upstream across northern Ohio will pass mostly to our south, although an isolated shower or thunderstorm cannot be ruled out this evening across the southwest corner of the state near KJHW. Late tonight and Monday morning a trough will cross the lower Great Lakes region and bring an increasing chance of scattered showers and thunderstorms. With the timing and coverage of any thunderstorms still in question, VCSH qualifiers have been used in the TAFs for now until the timing can be refined. By Monday afternoon most of the scattered thunderstorms should be confined from the Southern Tier eastward across central NY and the North Country, with increasing southwest flow off Lake Erie providing an expanding stable lake shadow and reducing the chance of convection across much of western NY. Outlook... Monday night through Wednesday...Mainly VFR. Thursday...Mainly VFR with a chance of showers and thunderstorms. Friday...VFR/MVFR with a chance of showers and thunderstorms. && .MARINE... Light southwest winds will prevail through this evening on Lake Erie with flat wave action. Northeast winds in the 10-15 knot range will continue on Lake Ontario with waves up to 2 feet along the south shore. A cold front will move east across the lower Great Lakes on Monday. Southwest winds will increase along and ahead of the cold front, especially on Lake Erie where winds and waves may approach Small Craft Advisory criteria in the afternoon. Winds will diminish Monday night following the passage of the weak front, with winds and waves then expected to remain below Small Craft Advisory levels through midweek. && .BUF WATCHES/WARNINGS/ADVISORIES... NY...None. MARINE...None. && $$ SYNOPSIS...HITCHCOCK NEAR TERM...HITCHCOCK SHORT TERM...CHURCH LONG TERM...HITCHCOCK AVIATION...HITCHCOCK MARINE...HITCHCOCK


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Florence Florene Lively
Sep. 10, 1926
Williamson County
Texas, USA
Jan. 5, 2011
Williamson County
Texas, USA
Florence Florene was the last child of Tollison and Katherine (Sprott) Lively. Siblings were Clarence Lively,Charles Lively, Lee Lively, Alma Ruth (Lively) Dodd, Mary Estelle (Lively) Wilson.
Florence lived her life in Bartlett - she never attended school as she was a special child. The one day she did go to school, a kid threw her books in the trash and she cried. Her Mama never sent her back. In those days, there was no special needs classes. Every morning, Florence had to get up early to go to the Post Office and check the box. My memories of walking "downtown" to that PO Box are fresh in mind. To this day - I love going to the Post Office and had a PO Box for 20 years! Going to Bill's Dollare Store - spending too much change on candy bubble gum cigars and RC - we knew we would be chastised - then Florence would say "It was Paula's idea!" and Daddy would get after me and she would RUN!! HA! Good Times!!Florece loved ALL Baibies - she raised everyone's babies in town, she babysat, chnaged diapers and played until the end. Her gift of remembering dates - especially birthdays was truly amazing! You could ask her any date and she could tell you what day of the week it fell on -- back to 1900! Never forgetting birthdays - especially her own - she looked so forward to her birthday and let everyone know - "My birthday is coming!" weeks in advance - you were sure not to forget her special day. After her Mother's death - Florence moved in with sister Estelle and after her death moved to Will O Bell Nursing Home. Her big adventure - move to Dallas came in 1990. Florence lived in Red Oak, TX with her sister - Ruth Dodd for a period of time 1990-1991. The sisters helped each other and Florence had fun in the city. When Ruth died 6/30/91 - Florence had a taste of independence for 5 mos. as she lived in the apartment, went to Walmart often and shopped and had nobody telling her what to do anymore. In November, she decided she wanted to return to her friends as Will O Bell - and did so. Florence lived 19 years at Will O Bell - a very helpful and loving resident, everyone knew her. She was a fixture in the visiting room and the town's most well known person. She will rest forever in Davilla Cemetery next to her Mother and Father. Florence's headstone has been sat for over 40 years and she would always tell us - "Look! I am going to be buried next to my Mama and Daddy!". The Livelys are all gone now - the descendants will not forget ...
I think my Dad said it best in his note to his Aunt Florence: Pure in Heart and Soul, Her Spirit revels in the Presence of Our Lord and Savior.
Family links:
Tollison Lively (1883 - 1956)
Katherine Elizabeth
Lively (1891 - 1969)
Infant Curtis Lively
Infant Lillie Mae Lively
Alma Ruth
Dodd (1909 - 1991)
Lee Jordan Lively (1912 - 1986)
Mary Estelle
Wilson (1914 - 1989)
Charlie O Lively (1918 - 1999)
Clarence Aubrey Lively (1923 - 1999)
Florence Florene Lively (1926 - 2011)
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Davilla Cemetery
Milam County
Texas, USA
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Added: Jun. 28, 2016
Haooy Belated Birthday Great-Aunt Florence!
Bling Blinky of TEXAS
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Poor response to Christmas charity efforts
Caritas workers add to funds with own wages
ucanews.com reporter, Lahore
December 26, 2012
Several organizations have reported difficulties and disappointments in their charitable fund raising efforts for Christmas.
Mitchell's Fruit Farms, the oldest food company in Pakistan, makes regular donations to the poor at this time of year.
"One of our sales executives, a parishioner, has been liaising with this for three years," said Anzar Hameed, the company's head of sales. "But this year the idea was almost dropped because of rising operation costs."
However, the company managed to supply food items worth 25,000 rupees (US$256) to Catholic widows at Sacred Heart Cathedral last Sunday.
At Caritas Pakistan Lahore, staff donated two percent of their monthly salary after a poor response to their World Food Day campaign.
"The activity of handing over money boxes to students ran for about three months. We focused on Church schools where children usually belong to well-to-do families," said Caritas manager Anila Gill. "The return from two major institutions was only US$15."
By supplementing the fund with their own two percent salary donations, Caritas was able to bring some cheer to 30 poverty stricken brickmakers' families, who were given toys and sweets for Christmas.
Related Reports
New Delhi domestic workers protest rape
Many are young Christian girls from tribal areas looking to better their lives
World Youth Day a time to share faith with others
In communist Vietnam, young Catholics find it difficult to live out their faith
Pakistan takes steps to end 'honor killings'
Further steps must be taken to ensure women their right to marry according to their own free will, says priest
Hundreds of Malaysians head to World Youth Day
For one young Catholic, the event will be like a spiritual shot-in-the-arm
Nepalese Christian jailed over religious conversion
Police accuse her of trying to convert Hindu children in orphanage she runs with husband


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