Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.36 (hyaluronidase)
 4,606 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A murine (BALB/c) skin toxicity model was used to evaluate various possible antagonists to vinca alkaloid-induced skin ulceration. Reproducible dose-response relationships were developed for vinblastine (VBL) and vindesine (VDS). With vincristine (VCR) only about 70% of mice developed dose-dependent ulceration. On an equal weight basis, VCR proved to be significantly more toxic than either VBL or VDS (P less than .05 by Student's t-test). Effective local intradermal antidotes to VBL, VDS, and VCR included hyaluronidase, normal saline, and calcium leucovorin (P less than .05 by the Student's Newman-Keuls multiple range test). Mild, topical skin heating significantly reduced VCR ulceration. In contrast, diphenhydramine and sodium bicarbonate were ineffective as local antidotes. Topical skin cooling, however, significantly increased vinca-induced skin ulcers for VBL, VDS, and VCR (P less than .05). Hydrocortisone, vitamin A topical cream, and isoproterenol increased skin toxicity. [3H]VBL was given intradermally to follow the drug's pharmacokinetic disposition from the skin and adherent panniculus carnosus muscle. [3H]VBL exhibited two phases of elimination: a rapid early phase [half-life (t 1/2) of approximately equal to 30 min] and a prolonged terminal phase (t 1/2 of approximately equal to 17 hr). The application of heat increased the distributive, early phase by 0.5-2.5 hours and did not enhance the terminal elimination of the drug from skin. Intradermal hyaluronidase significantly reduced the area under the ulceration multiplied by the time curve to one-seventh the control value, the peak [3H]VBL skin concentration to one-half the control value and the terminal [3H]VBL t 1/2 in skin to one-third the control level (P less than .05 by Student's t-test). These results show hyaluronidase to be an effective antidote for vinca-induced skin ulceration. Local glucocorticosteroids and topical cooling are definitely contraindicated in the management of inadvertent vinca alkaloid extravasations.
 ...
PMID:Vinca alkaloid skin toxicity: antidote and drug disposition studies in the mouse. 385 72

1 The anti-inflammatory activity of crotalaburnine (=anacrotine) was investigated against increased vascular permeability and oedema produced by formalin, carrageenin, hyaluronidase, 5-hydroxytryptamine, dextran, bradykinin and prostaglandin, and against formation of granulation tissues by cotton-pellet in rats. The effect was compared with the activity of hydrocortisone, phenylbutazone, sodium salicylate and cyproheptadine against different types of inflammation.2 Crotalaburnine (40 mg/kg s.c. x 5 alternate days) had no significant inhibitory effect against formalin-induced arthritis, while hydrocortisone (40 mg/kg s.c. x 10 days) was effective from the fifth day onwards.3 Against carrageenin-induced oedema both crotalaburnine (10 mg/kg s.c.) and phenylbutazone (100 mg/kg oral) produced a similar degree of inhibition. Hydrocortisone (10 mg/kg s.c.) produced slightly greater inhibition.4 In normal rats crotalaburnine (10 mg/kg s.c.), phenylbutazone (100 mg/kg oral) and sodium salicylate (500 mg/kg i.p.) inhibited hyaluronidase-induced oedema. However, in adrenalectomized rats, there was a reduction of the inhibitory effect of sodium salicylate but not of phenylbutazone or crotalaburnine.5 Crotalaburnine (40 mg/kg s.c. and 30 mg/kg i.p., respectively) was ineffective against 5-hydroxytryptamine- and dextran-induced oedema but against bradykinin- and prostaglandin-induced oedema (in a dose of 20 mg/kg i.p.) it was quite effective. In a parallel series cyproheptadine (10 mg/kg oral and i.p., respectively) produced significant inhibition of 5-hydroxytryptamine- and dextran-induced oedema, while phenylbutazone (100 mg/kg i.p.) failed to produce any significant inhibition of prostaglandin-induced oedema.6 Against cotton-pellet granuloma crotalaburnine, in half the dose of hydrocortisone, produced similar inhibition while phenylbutazone produced much greater inhibition in five times the dose of crotalaburnine given orally.7 The possible mode of action of crotalaburnine as an anti-oedema agent is discussed.
 ...
PMID:Inhibitory effect of a pyrrolizidine alkaloid, crotalaburnine, on rat paw oedema and cotton pellet granuloma. 445 64

Interactions between the epithelial and lymphocytic components of the thymus are required for T cell maturation, yet the molecular bases for these interactions remain elusive. In the development and function of other endodermally derived organs, glycosaminoglycan-containing proteins are known to play a critical role. In contrast, virtually nothing is known about the macromolecules that are major constituents of thymic interstitial spaces. For these reasons, we undertook metabolic labeling studies in vitro with D-(6-3H)glucosamine and 35SO4(-2) to begin to characterize systematically the relative amounts and types of glycosaminoglycans made by enriched subpopulations of cells within the thymus. Hydrocortisone, which depletes the thymus of 90% of its lymphocytes, was used both to enrich for epithelium-derived glycoconjugates and to determine if significant alterations in glycoconjugate metabolism accompany drug-induced premature thymic involution. Results indicate: 1) glycosaminoglycans account for a substantial proportion of the total glycoconjugates synthesized by both thymocytes and epithelium; 2) Glycosaminoglycans show a tissue-specific distribution. Hyaluronic acid is the major glycosaminoglycan synthesized by thymic epithelium, whereas it accounts for less than 15% of the total glycosaminoglycans made by thymocytes; 3) Similar proportions of sulfated glycosaminoglycans are made by thymic epithelium and thymocytes. Chondroitin sulfates predominate (75 to 90%) over heparan sulfates (10 to 25%). Chondroitin sulfates from both nonstimulated thymocytes and epithelium are nearly exclusively sulfated at the 4-position of their N-acetylgalactosamine residues; 4) The major high m.w. glycoconjugate of thymocytes, however, is nonsulfated and is resistant to pronase, hyaluronidase, chondroitinase ABC, nitrous acid, keratanase, and neuraminidase; 5) Although hydrocortisone treatment causes a dramatic inhibitory effect on the incorporation of radioactivity into smaller oligosaccharide side-chains by "cortisone-resistant" thymocytes, the drug exerts negligible effects on the metabolism of glycoconjugates by epithelium. These data, which quantify and categorize the complex arrays of glycoconjugates synthesized by the major cell types of the thymus, establish the necessary foundations for further investigations into the functional roles of these glycoconjugates in thymic epithelium-induced maturation of T lymphocytes.
 ...
PMID:Biosynthesis of glycosaminoglycans by epithelial and lymphocytic components of murine thymus. 660 Nov 42

Proteoglycan breakdown was studied in a coculture model which mimics the confrontation between synovium and cartilage that occurs in rheumatoid arthritis. Bovine nasal-septum cartilage discs radioactively labeled (35SO2-4 with or without [3H]glucosamine) and 'chased' in non-radioactive medium were cultured in contact with minced rheumatoid synovial membranes for intervals up to 8 days. Synovium-stimulated (2-3-fold) cartilage breakdown was unaffected by ascorbate supplementation. Labeled products (small molecules plus proteoglycan complexes) in culture media were characterized by chromatographic, sedimentation and enzymic digestion methods. Breakdown was dominated by the release of a range of proteoglycan products, fully disaggregated and incapable of reaggregation with added hyaluronate. Because constituent glycosaminoglycans were of uniform size, proteoglycan polydispersity was attributed to differences in core protein length. Hydrocortisone inhibited degradation and partially prevented the shift of proteoglycans to lower average molecular weight. An additional breakdown pattern occasionally noted during the initial 48 h of coculture was characterized by release of a subpopulation of low charge-density proteoglycan bearing shortened glycosaminoglycan chains, consistent with glycosidase action. We conclude that rheumatoid synovia exhibit two distinct cartilage degradative potencies in vitro that may be important in vivo: (a) A variable hyaluronidase-like activity at early culture times, and (b) a dominant proteolytic activity generating an array of disaggregated proteoglycan products that differ largely on the basis of their core lengths. The response to hydrocortisone is consistent with inhibition of proteolysis through the stabilization of cellular membranes.
 ...
PMID:Breakdown of cartilage proteoglycan in a tissue culture model of rheumatoid arthritis. 683 6