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1.
EMBO Mol Med ; 5(10): 1569-85, 2013 10.
Article in English | MEDLINE | ID: mdl-24014378

ABSTRACT

Absence of dystrophin makes skeletal muscle more susceptible to injury, resulting in breaches of the plasma membrane and chronic inflammation in Duchenne muscular dystrophy (DMD). Current management by glucocorticoids has unclear molecular benefits and harsh side effects. It is uncertain whether therapies that avoid hormonal stunting of growth and development, and/or immunosuppression, would be more or less beneficial. Here, we discover an oral drug with mechanisms that provide efficacy through anti-inflammatory signaling and membrane-stabilizing pathways, independent of hormonal or immunosuppressive effects. We find VBP15 protects and promotes efficient repair of skeletal muscle cells upon laser injury, in opposition to prednisolone. Potent inhibition of NF-κB is mediated through protein interactions of the glucocorticoid receptor, however VBP15 shows significantly reduced hormonal receptor transcriptional activity. The translation of these drug mechanisms into DMD model mice improves muscle strength, live-imaging and pathology through both preventive and post-onset intervention regimens. These data demonstrate successful improvement of dystrophy independent of hormonal, growth, or immunosuppressive effects, indicating VBP15 merits clinical investigation for DMD and would benefit other chronic inflammatory diseases.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Myoblasts/drug effects , Pregnadienediols/pharmacology , Animals , Anti-Inflammatory Agents/toxicity , Cell Line , Cell Membrane/drug effects , Cell Membrane/physiology , Immunosuppressive Agents/pharmacology , Immunosuppressive Agents/toxicity , Lasers , Mice , Mice, Inbred mdx , Muscular Dystrophies/metabolism , Muscular Dystrophies/pathology , Myoblasts/cytology , Myoblasts/radiation effects , NF-kappa B/antagonists & inhibitors , NF-kappa B/metabolism , Necrosis/etiology , Phenotype , Prednisolone/pharmacology , Prednisolone/toxicity , Pregnadienediols/toxicity , Protein Interaction Maps/drug effects , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/metabolism , Signal Transduction/drug effects , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Transcription, Genetic/drug effects
2.
Toxicol Pathol ; 39(6): 958-68, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21885873

ABSTRACT

The purpose of this study was to compare the toxicity of three marketed corticosteroid receptor agonists (mometasone furoate, budesonide, or flunisolide) to the stomach of female CD-1 mice following oral administration via the diet for up to 52 weeks, with a 16-week recovery period (budesonide and flunisolide). A range of tissues was examined by light microscopy, accompanied by clinical pathology measurements to assess anticipated corticosteroid effects as a surrogate marker of systemic drug exposure. Microscopic changes seen in the stomach with each corticosteroid included pyloric hyalinization. This previously unreported finding was investigated using histochemical and immunohistochemical techniques and was found to consist of hyalinized collagen, in association with increased immunohistochemical signal for transglutaminase-2 and osteopontin. The significance of the osteopontin finding is unclear; however, the ability of transglutaminase-2 to facilitate the formation of degradation resistant protein bonds implies this protein may be involved in the pathogenesis of this change. Furthermore, published evidence that transglutaminase-2 may be induced by a corticosteroid agonist raises the possibility that pyloric stomach hyalinization may be a class effect of corticosteroids via the action of this enzyme.


Subject(s)
Adrenal Cortex Hormones/agonists , Anti-Inflammatory Agents/toxicity , Budesonide/toxicity , Fluocinolone Acetonide/analogs & derivatives , Hyalin/metabolism , Pregnadienediols/toxicity , Pylorus/metabolism , Administration, Oral , Adrenal Cortex Hormones/metabolism , Animals , Anti-Inflammatory Agents/administration & dosage , Budesonide/administration & dosage , Female , Fluocinolone Acetonide/administration & dosage , Fluocinolone Acetonide/toxicity , GTP-Binding Proteins/metabolism , Mice , Mice, Inbred Strains , Microscopy, Electron , Mometasone Furoate , Osteopontin/metabolism , Pregnadienediols/administration & dosage , Protein Glutamine gamma Glutamyltransferase 2 , Pylorus/anatomy & histology , Transglutaminases/metabolism
3.
Int J Pharm ; 365(1-2): 109-15, 2009 Jan 05.
Article in English | MEDLINE | ID: mdl-18822361

ABSTRACT

The main purpose of this study was to prepare a novel in situ gel system for nasal delivery of MF and study its efficacy on allergic rhinitis model. An ion-activated in situ gel was developed and characterized with gellan gum as a carrier. The system was stable kept at 40+/-2 degrees C for 6 months, and the micrographic results showed that in situ gel was safety without mucosa irritation when given at 20 microg once daily for 1 month to rats with allergic rhinitis. MF in gellan gum produced obviously effect on allergic rhinitis at the doses of 20 microg/body following intranasal administration, and the efficacy was significantly superior to that of the common suspension (P<0.01). The in situ gel system is a promising approach for the intranasal delivery of MF for the therapeutic effects improvement.


Subject(s)
Anti-Allergic Agents/administration & dosage , Polysaccharides, Bacterial/chemistry , Pregnadienediols/administration & dosage , Rhinitis, Allergic, Perennial/drug therapy , Administration, Intranasal , Animals , Anti-Allergic Agents/toxicity , Anura , Disease Models, Animal , Drug Carriers/chemistry , Drug Stability , Drug Storage , Female , Gels , Male , Mometasone Furoate , Nasal Mucosa/drug effects , Nasal Mucosa/metabolism , Pregnadienediols/toxicity , Rats , Rats, Wistar , Toxicity Tests
4.
Surv Ophthalmol ; 52 Suppl 1: S35-40, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17240255

ABSTRACT

A number of preclinical safety pharmacology and toxicity studies have been performed on the angiostatic cortisene anecortave acetate in various species and using different routes of administration (oral, intravenous, subcutaneous, topical ocular, intraocular injection, posterior juxtascleral) and a wide range of doses (0-1,000 mg/kg). Anecortave acetate did not interact with a broad panel of pharmacological receptors and had no apparent pharmacological effects on major organ systems including the central nervous, gastrointestinal, renal, cardiovascular, and respiratory systems. Oral, topical ocular, and posterior juxtascleral administration of anecortave acetate had no significant ocular or systemic side effects or toxicity. In addition, there was no significant carcinogenic or reproductive/developmental toxicity associated with anecortave acetate in genotoxicity, carcinogenicity, and reproductive toxicity studies.


Subject(s)
Angiogenesis Inhibitors/toxicity , Drug Evaluation, Preclinical , Pregnadienediols/toxicity , Angiogenesis Inhibitors/pharmacology , Animals , Carcinogenicity Tests , Eye/blood supply , Mutagenicity Tests , Neovascularization, Pathologic/drug therapy , Pregnadienediols/pharmacology
5.
Arch Otolaryngol Head Neck Surg ; 130(4): 440-5, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15096427

ABSTRACT

OBJECTIVE: To measure the influence of topical steroids and the preservative potassium sorbate on the ciliary beat frequency (CBF) of human nasal mucosa in vitro. DESIGN: In vitro study of cultured ciliated cells of human nasal mucosa. METHODS: Human nasal mucosa was removed endoscopically and cultured for 10 days. Cell cultures with ciliated cells grown on an object slide were exposed to benzalkonium chloride and topical steroids in an exposure chamber. The CBF was measured with a photometer. RESULTS: The preservative potassium sorbate did not influence CBF in different concentrations. The glucocorticoid budesonide spray containing potassium sorbate did not affect CBF at 10% dilution and showed moderate reversible decrease of CBF at 50% dilution. The glucocorticoid sprays fluticasone propionate and mometasone fuorate containing the preservative benzalkonium chloride caused a reversible decrease of CBF at 10% dilution and a complete irreversible standstill at 50% dilution. CONCLUSIONS: In vitro, the steroid sprays containing fluticasone or mometasone, both with benzalkonium chloride, caused slowing or standstill of CBF depending on the concentration. The isolated preservative potassium sorbate and the budesonide nasal spray containing this preservative did not have negative influence on CBF in vitro. Potassium sorbate can therefore be considered harmless to the motility of ciliated cells.


Subject(s)
Anti-Inflammatory Agents/toxicity , Glucocorticoids/toxicity , Mucociliary Clearance/drug effects , Nasal Mucosa/drug effects , Preservatives, Pharmaceutical/toxicity , Administration, Inhalation , Aerosols , Androstadienes/toxicity , Benzalkonium Compounds/toxicity , Budesonide/toxicity , Culture Techniques , Dose-Response Relationship, Drug , Fluticasone , Humans , Mometasone Furoate , Pregnadienediols/toxicity , Sorbic Acid/toxicity
6.
Farmakol Toksikol ; 54(2): 43-6, 1991.
Article in Russian | MEDLINE | ID: mdl-1884795

ABSTRACT

In the experiments on mature females of 50 rats, 10 rabbits, 8 dogs it was established that a new gestagenic drug acetomepregenol was not toxic both for pregnant and nonpregnant animals. The two-month administration of the drug in the therapeutic and maximal doses did not exert the irreversible effects on the reproductive function and did not influence the embryonal and postnatal development of the offspring. A single administration of acetomepregenol in the critical periods of pregnancy was found to exert the embryotoxic effect which did not manifest itself during daily administration of the drug from the 6th through the 16th days of pregnancy.


Subject(s)
Contraceptives, Oral, Combined/pharmacology , Pregnadienediols/pharmacology , Animals , Contraceptives, Oral, Combined/toxicity , Dogs , Dose-Response Relationship, Drug , Embryo, Mammalian/drug effects , Female , Pregnadienediols/toxicity , Pregnancy , Rabbits , Rats , Reproduction/drug effects , Teratogens , Time Factors
8.
Arzneimittelforschung ; 26(7b): 1476-9, 1976.
Article in German | MEDLINE | ID: mdl-1036942

ABSTRACT

On the basis of absolute DL50 values 6alpha,9-difluor-11beta-hydroxy-16alpha-methyl-21-valeryloxy-1,4-pregnadiene-3,20-dione (diflucortolone valerate, Nerisona) is virtually non-toxic after single oral administration (mouse greater than 4 g/kg, rat ca. 3.1 g/kg, dog greater than 1 g/kg). Given s.c. (LD50 mouse ca. 180 mg/kg, rat ca. 13 mg/kg) and i.p. (LD50 mouse ca. 450 mg/kg, rat ca. 98 mg/kg) it is highly active and therefore produces also toxic effects. The formulations Nerisona ointment, fatty ointment and cream have proven practically non-toxic in rats after single oral gavage (LD50 greater than 33 g/kg). The daily s.c. administration over 6 weeks revealed systemic glucocorticoid effects in rats at 0.0004 mg/kg and in dogs at 0.04 mg/kg. Similar effects were seen in dogs after daily dermal treatment for 13-14 weeks with Nerisona ointment at 100 mg/kg body weight. On the skin of rabbits and dogs there were no differences in the reaction at the application site between Nerisona ointment, fatty ointment and cream and the corresponding ointment, or cream bases by daily dermal administration for 28 days. However, the 13-14 week dermal study in dogs with Nerisona ointment revealed atrophy of the epidermis at the application site in several cases. The daily dermal application of Nerisona ointment during organogenetic phases of pregnancy caused embryotoxic effects in rats at 500 mg/kg and in rabbits at 50 mg/kg. All of these findings are discusses as well-known glucocorticosteroid effects.


Subject(s)
Anti-Inflammatory Agents/toxicity , Pregnadienediols/toxicity , Administration, Oral , Administration, Topical , Animals , Anti-Inflammatory Agents/administration & dosage , Dogs , Female , Fetal Death/chemically induced , Glucocorticoids , Injections, Intraperitoneal , Injections, Subcutaneous , Lethal Dose 50 , Mice , Ointment Bases , Pregnadienediols/administration & dosage , Pregnancy , Rabbits , Rats , Skin Diseases/chemically induced , Steroids, Fluorinated/administration & dosage , Steroids, Fluorinated/toxicity , Teratogens
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