ABSTRACT
Three hexasaccharides, having from low to very high affinity for antithrombin, were synthesised from disaccharide building block precursors. One of them, methyl(sodium 2,3-di-O-methyl-4-O- sodium sulfonato-alpha-L-idopyranosyluronate)-(1-->4)-[(2,3,6-tri-O-sodiu m sulfonato-alpha-D-glucopyranosyl)-(1-->4)-(sodium 2,3-di-O-methyl-alpha-L-idopyranosyluronate)-(1-->4)]2-2,3,6-tri-O-sodiu m sulfonato-alpha-D-glucopyranoside, obtainable from a single disaccharide building block precursor, constitutes a good starting point for obtaining simple oligosaccharidic heparin mimetics able to inhibit the two coagulation factors thrombin and Factor Xa.
Subject(s)
Factor Xa Inhibitors , Fibrinolytic Agents/chemistry , Oligosaccharides/chemistry , Oligosaccharides/pharmacology , Thrombin/antagonists & inhibitors , Binding Sites , Carbohydrate Conformation , Carbohydrate Sequence , Heparin/chemistry , Indicators and Reagents , Molecular Sequence Data , Nuclear Magnetic Resonance, Biomolecular , Oligosaccharides/chemical synthesis , Optical Rotation , PolymersABSTRACT
Deca- to eicosasaccharides having the generic structure methyl(sodium 2,3-di-O-methyl-4-O-sodium sulfonato-alpha-L-idopyranosyluronate)-(1-->4)-[(2,3,6-tri-O-sodiu m sulfonato-alpha-D-glucopyranosyl)-(1-->4)-(sodium 2,3-di-O-methyl-alpha-L-idopyranosyluronate)-(1-->4)]n-2,3,6-tri-O-sodiu m sulfonato-alpha-D-glucopyranoside have been synthesized from a single disaccharide precursor. All of them bind to and activate antithrombin. When n < or = 6 only Factor Xa inhibition is observed, whereas when n > 6 Factor Xa and thrombin are both inhibited in the presence of antithrombin. These results indicate that, in heparin, the sequence involved in antithrombin-catalyzed thrombin inhibition is a pentadeca- or a hexadecasaccharide.
Subject(s)
Factor Xa Inhibitors , Fibrinolytic Agents/chemical synthesis , Heparin/chemical synthesis , Oligosaccharides/chemical synthesis , Thrombin/antagonists & inhibitors , Carbohydrate Sequence , Disaccharides/chemical synthesis , Disaccharides/chemistry , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacology , Heparin/chemistry , Heparin/pharmacology , Indicators and Reagents , Models, Molecular , Molecular Sequence Data , Nuclear Magnetic Resonance, Biomolecular , Oligosaccharides/chemistry , Oligosaccharides/pharmacology , Optical RotationABSTRACT
The synthetic pentasaccharide (1) corresponding to the heparin sequence which binds to, and activates, antithrombin III (AT III) is a potent antithrombotic compound in several animal models of venous thrombosis. We describe here the preparation and the pharmacological properties of 34, an analogue of oligosaccharide 1 with the latter's N-sulfates being replaced by sulfate esters and hydroxyl groups being methylated. These structural modifications allow a simpler and more efficient synthesis of such anionic oligosaccharides. Affinity for human AT III, anti-factor Xa activity, ability to inhibit thrombin generation, antithrombotic activity in a rat model of venous thrombosis, and elimination half-life in the rat have been determined for 1 and 34. Surprisingly, introduction of O-sulfates in place of N-sulfates, and methylation of hydroxyl groups, contributes to reinforce the binding to AT III, resulting in an improved pharmacological profile.
Subject(s)
Fibrinolytic Agents/chemical synthesis , Fibrinolytic Agents/pharmacology , Oligosaccharides/chemistry , Oligosaccharides/chemical synthesis , Oligosaccharides/pharmacology , Animals , Antithrombin III/metabolism , Factor Xa Inhibitors , Half-Life , Humans , Hydroxylation , Male , Methylation , Molecular Structure , Oligosaccharides/metabolism , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfates/chemistry , Thrombin/antagonists & inhibitors , Thrombosis/drug therapyABSTRACT
The use of oxygen increases the risk of fire during ophthalmic surgery. A prospective clinical study was conducted involving 100 patients without pulmonary disease who had cataract surgery under local anesthesia using either oxygen or compressed air. No clinically significant difference in oxygen saturation between the two groups was found. There was no statistically significant difference in the net change in saturation, and the significant difference found in overall mean saturation between the two groups was invalidated by inherent machine error. Using compressed air instead of oxygen is suggested to reduce fire hazard during ophthalmic surgery.
Subject(s)
Air , Cataract Extraction , Fires/prevention & control , Oxygen/administration & dosage , Humans , Prospective Studies , Surgical Procedures, OperativeABSTRACT
Known methyl (prop-1-enyl 2,3-di-O-benzyl-alpha-D-glucopyranosid)uronate was first converted into methyl (prop-1-enyl 2,3-di-O-benzyl-4-O-levulinyl-alpha-D-gluco-pyranosid)uro nat e. Acid hydrolysis, followed by treatment with (bromomethylene)-dimethylammonium bromide, gave methyl (2,3-di-O-benzyl-4-O-levulinyl-alpha-D-glucopyranosyl bromide)uronate. Condensation of this bromide with 1,6-anhydro-2-azido-3-O-benzyl-2-deoxy-beta-D-glucopyranose gave 1,6-anhydro-2-azido-3-O-benzyl-2-deoxy-4-O-(methyl 2,3-di-O-benzyl-4-O- levulinyl-beta-D-glucopyranosyluronate)-beta-D-glucopyranose. Acetolysis, followed by selective anomeric O-deacetylation and treatment with (bromomethylene)dimethylammonium bromide then gave 6-O-acetyl-2-azido-3-O-benzyl-2-deoxy-4-O-(methyl 2,3-di-O-benzyl-4-O-levulinyl -beta-D-glucopyranosyluronate)-alpha-D-glucopyranosyl bromide. Condensation of this bromide with benzyl 6-O-acetyl-3-O-benzyl-2-benzyloxycarbonylamino-2-deoxy-4- O-(methyl 2-O-acetyl-3-O-benzyl-alpha-L-idopyranosyluronate)-alpha-D- glucopyranoside provided benzyl O-(methyl 2,3-di-O-benzyl-4-O-levulinyl-beta-D- glucopyranosyluronate)-(1----4)-O-(6-O-acetyl-2-azido-3-O-benzyl-2-deoxy - alpha-D-glucopyranosyl)- (1----4)-O-(methyl 2-O-acetyl-3-O-benzyl-alpha-L-idopyranosyluronate)-(1----4)- 6-O-acetyl-3-O-benzyl-2-benzyloxycarbonylamino-2-deoxy-alpha-D-glu copyranoside. Removal of the levulinyl group followed by condensation with 6-O-acetyl-2-azido-3,4-di-O -benzyl-2-deoxy-alpha-D-glucopyranosyl bromide provided benzyl O-(6-O-acetyl-2- azido-3,4-di-O-benzyl-2-deoxy-alpha-D-glucopyranosyl)-(1----4)-O-(methyl 2,3-di- O-benzyl-beta-D-glucopyranosyluronate)-(1----4)-O-(6-O-acetyl-2-azido-3- O- benzyl-2- deoxy-alpha-D-glucopyranosyl)-(1----4)-O-(methyl 2-O-acetyl-3-O-benzyl-alpha-L- idopyranosyluronate)-(1----4)-6-O-acetyl-3-O-benzyl-2-benzyloxycarbon ylamino-2- deoxy-alpha-D-glucopyranoside in 78% yield. O-Deacetylation followed by re-esterification, O-sulfation, catalytic hydrogenolysis, saponification, and N-sulfation gave the non-sodium salt of O-(2-deoxy-6-O-sulfo-2-sulfoamino-alpha-D-glucopyranosyl)-(1----4) -O- (beta-D-glucopyranosyluronic acid)-(1----4)O-(2-deoxy-6-O-sulfo-2-sulfoamino- alpha-D-glucopyranosyl)-(1----4)-O-(2-O-sulfo-alpha-L-idopyranosyluronic acid)- (1----4)-2-deoxy-6-O-sulfo-2-sulfoamino-D-glucopyranose. This synthetic pentasaccharide neither binds to antithrombin III nor induces anti-factor Xa activity.
Subject(s)
Antithrombin III/metabolism , Glucosamine/analogs & derivatives , Heparin/metabolism , Oligosaccharides/chemical synthesis , Sulfates/metabolism , Alcohols , Benzyl Compounds , Bromides , Carbohydrate Conformation , Chemical Phenomena , Chemistry , Ethers , Glucosamine/metabolism , Oligosaccharides/metabolism , Structure-Activity RelationshipABSTRACT
An 87-year-old woman, who had undergone cataract surgery and vitrectomy OD two years previously, had a blind, painful right eye secondary to intraocular hemorrhage and glaucoma. At the initial examination, a flat area of darkly pigmented tissue was noted at the wound site of the previous cataract surgery, and uveal prolapse was diagnosed. One year later, pigmented tissue was also seen at the inferior limbus. Intraocular malignant melanoma was considered, and the eye was enucleated. Histologic study revealed areas of hemorrhage and epithelioid malignant melanoma. It is important to recognize that prolapse of tissue at a surgical wound site may represent an extension of an intraocular malignancy.
Subject(s)
Eye Neoplasms/diagnosis , Melanoma/diagnosis , Uveal Diseases/diagnosis , Aged , Aged, 80 and over , Diagnosis, Differential , Eye Neoplasms/pathology , Female , Humans , Melanoma/pathology , ProlapseABSTRACT
The synthesis is described of the methyl alpha-glycoside of the pentasaccharide which represents the sequence in heparin responsible for binding and activation of the anticoagulant protein Antithrombin III. It was obtained in a yield much better than that of the previously synthesised pentasaccharide and exhibited the same biological properties.
Subject(s)
Antithrombin III/metabolism , Heparin/chemical synthesis , Oligosaccharides/chemical synthesis , Heparin/metabolism , Indicators and Reagents , Magnetic Resonance Spectroscopy , Oligosaccharides/metabolism , Optical Rotation , Structure-Activity RelationshipABSTRACT
Known allyl 4,6-O-benzylidene-alpha-D-glucopyranoside was first converted into methyl (prop-1-enyl 2,3-di-O-benzyl-4-O-chloroacetyl-alpha-D-glucopyranosid)-uronate. Acid hydrolysis, followed by treatment with (bromomethylene)dimethyl-ammonium bromide, gave methyl (2,3-di-O-benzyl-4-O-chloroacetyl-alpha-D-glucopyranosyl bromide)uronate. Condensation of this bromide with 3-O-acetyl-1,6-anhydro-2-azido-2-deoxy-4-O-(methyl 2,3-di-O-benzyl-4-O-chloroacetyl-beta-D-glucopyranosyluronate)-bet a-D-glucopyranose. Acetolysis, followed by treatment with titanium tetrabromide, then gave 3,6-di-O-acetyl-2-azido-2-deoxy-4-O-(methyl 2,3-di-O-benzyl-4-O-chloroacetyl-beta-D-glucopyranosyluronate)-alp ha-D-glucopyranosyl bromide. Condensation of this bromide with benzyl 6-O-acetyl-3-O-benzyl-2-benzyloxy- carbonylamino-2-deoxy-4-O-(methyl 2-O-acetyl-3-O-benzyl-alpha-L- idopyranosyluronate)-alpha-D-glucopyranoside provided benzyl O-(methyl 2,3-di-O-benzyl-4-O-chloroacetyl-beta-D-glucopyranosyluronate)-(1- ---4)-O-(3,6-di-O-acetyl- -2-azido-2-deoxy-alpha-D-glucopyranosyl)-(1----4)-O-(methyl 2-O-acetyl-3-O-benzyl-alpha-L-idopyranosyluronate)-(1----4)-6-O-ac etyl-3-O- acetyl-3-O-benzyl-2-benzyloxycarbonylamino-2-deoxy-alpha-D-gluc opyranoside. O-Dechloroacetylation followed by condensation with 6-O-acetyl-2-azido-3,4-di-O-benzyl-2-deoxy-alpha-D-glucopyranosyl bromide provided benzyl O-(6-O-acetyl-2-azido-3,4-di-O-benzyl-2-deoxy-beta-D-glucopyranosyl)- (1----4)-O-(methyl 2,3-di-O-benzyl-beta-D-glucopyranosyluronate)-(1----4)- O-(3,6-di-O-acetyl-2-azido-2-deoxy-alpha-D-glucopyranosyl)-(1----4)-O-(m ethyl 2-O-acetyl-3-O-benzyl-alpha-L-idopyranosyluronate)-(1----4)-6-O-ac etyl-3-O- benzyl-2-benzyloxycarbonylamino-2-deoxy-alpha-D-glucopyranoside in 70% yield. O-Deacetylation followed by re-esterification, O-sulfation, saponification, catalytic hydrogenolysis, and N-sulfation gave the decasodium salt of O-(2-deoxy-2-sulfamido-6-O-sulfo-alpha-D- glucopyranosyl)-(1----4)-O-(beta-D-glucopyranosyluronic acid)-(1----4)-O-(2-deoxy-2-sulfamido-3,6-di-O-sulfo-alpha-D-gl ucopyranosyl)-(1----4)-O-(2-O-sulfo-alpha-L-idopyranosyluronic+ ++ acid)-(1----4)-2-deoxy-2-sulfamido-6-O-sulfo-D-glucopyranose. This synthetic pentasaccharide binds to antithrombin III with an association constant similar to that of high-affinity heparin and elicits a potent anti-factor Xa activity in plasma.
Subject(s)
Antithrombin III/metabolism , Heparin/chemical synthesis , Oligosaccharides/chemical synthesis , Carbohydrate Conformation , Carbohydrate Sequence , Chemical Phenomena , Chemistry , Indicators and Reagents , Magnetic Resonance Spectroscopy , Oligosaccharides/metabolism , Optical Rotation , Protein BindingABSTRACT
A plastic surgical drape was ignited by a disposable cautery during cataract surgery performed under local anesthesia. The flame was quickly extinguished, and the procedure was completed without complications. The patient did well postoperatively and attained a corrected visual acuity of 20/25. Precautions should be taken to minimize the possibility of fire occurring during ophthalmic surgery.
Subject(s)
Electrocoagulation , Fires/prevention & control , Cataract Extraction , Cellulose , Female , Humans , Middle Aged , Oxygen , PlasticsABSTRACT
A 50-year-old man sustained severe head injury, including a brief loss of consciousness, in an automobile accident. Skull X-ray films disclosed a fracture of the right superior orbit. Computed tomography demonstrated pneumocephalus and extension of the fracture into the sella turcica. Perimetric testing disclosed a bitemporal hemianopia along the vertical meridian. Visual acuity was 6/6 (20/20) in both eyes. Right macular sparing and left macular splitting were demonstrated by Amsler grid analysis as well as by the patient's description of target grids projected onto his maculas. Diplopia was attributed to direct grids projected onto his maculas. Diplopia was attributed to direct injury of the right superior rectus muscle and to the effect of bitemporal field loss. There was no evidence of pituitary dysfunction. No treatment of the patient's visual loss was undertaken. A six-month follow-up examination disclosed no change in the patient's visual field abnormalities.
Subject(s)
Hemianopsia/etiology , Pneumocephalus/complications , Sella Turcica/injuries , Skull Fractures/complications , Accidents, Traffic , Humans , Male , Middle Aged , Orbit/injuries , Pneumocephalus/diagnostic imaging , Sella Turcica/diagnostic imaging , Tomography, X-Ray Computed , Visual FieldsABSTRACT
A case of visual loss associated with surgical repair of a zygomatic-orbital floor fracture is presented. A review of the literature indicates relatively few cases of blindness reported in association with surgical intervention for these fractures; however, it must be recognized that this serious complication does occur. The patient's ocular status should be evaluated before, during, and after orbital surgery.
Subject(s)
Orbit/injuries , Postoperative Complications , Skull Fractures/surgery , Vision Disorders/etiology , Zygomatic Fractures/surgery , Humans , Male , Middle Aged , Vision Disorders/physiopathology , Visual AcuityABSTRACT
In our continued efforts to elucidate the relationship between the structure and the immunoadjuvant, antiinfectious or mitogenic activity of N-acetyl-muramyl-L-alanyl-D-isoglutamine (MDP), we report the synthesis of 11 new analogs. Five of them present some modifications in the N-acetyl-muramyl moiety.
Subject(s)
Adjuvants, Immunologic/chemical synthesis , Glycopeptides/chemical synthesis , Amino Acid Sequence , Anti-Infective Agents/pharmacology , Glycopeptides/pharmacology , Mitogens/pharmacologyABSTRACT
A relatively easy synthetic method is reported for the production of the immunoadjuvant glycopeptide, N-acetyl-muramy-L-alanyl-D-isoglutamine (MDP). Most of the details in this method were also applied to the preparation of some analogs, that were synthesized in order to study structure-activity relationships.