ABSTRACT
LPS is a fundamental constituent of the outer membrane of all Gram-negative bacteria, and the lipid A domain plays a central role in the induction of inflammatory responses. We identified genes of the Neisseria gonorrhoeae lipid A biosynthetic pathway by searching the complete gonococcal genome sequence with sequences of known enzymes from other species. The lpxLII gene was disrupted by an insertion-deletion in an attenuated aroA mutant of the gonococcal strain MS11. Lipopolysaccharide (LPS) and lipid A analysis demonstrated that the lpxLII mutant had synthesized an altered LPS molecule lacking a single lauric fatty acid residue in the GlcN II of the lipid A backbone. LPS of the lpxLII mutant had a markedly reduced ability to induce the proinflammatory cytokines tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6 and IL-8 from human macrophages and IL-8 from polymorphonuclear cells. This study demonstrates that the lpxLII gene in gonococci encodes for a late-functioning lauroyl acyl transferase that adds a lauric acid at position 2' in the lipid A backbone. The presence of lauric acid at such a position appears to be crucial for the induction of full inflammatory responses by N. gonorrhoeae LPS.
Subject(s)
Acyltransferases/genetics , Bacterial Proteins , Lipid A/genetics , Neisseria gonorrhoeae/genetics , Acyltransferases/chemistry , Acyltransferases/metabolism , Amino Acid Sequence , Cells, Cultured , Genes, Bacterial , Humans , Interleukin-1/metabolism , Interleukin-6/metabolism , Interleukin-8/metabolism , Lipid A/biosynthesis , Lipid A/chemistry , Lipid A/isolation & purification , Macrophages/metabolism , Molecular Sequence Data , Molecular Structure , Mutation , Neisseria gonorrhoeae/enzymology , Neutrophils/metabolism , Sequence Alignment , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Intravascular clot formation is an important factor in a number of cardiovascular diseases. Therefore, the prevention of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (FXa), the enzyme directly responsible for thrombin activation. Herein we report a series of isoxazoline derivatives which are potent FXa inhibitors. Optimization of the side chain at the quaternary position of the isoxazoline ring led to SK549 which showed subnanomolar FXa potency (K(i) 0.52 nM). SK549 shows good selectivity for FXa compared to thrombin and trypsin, potent antithrombotic effect in the rabbit arterio-venous thrombosis model, and improved pharmacokinetics relative to other compounds evaluated from this series.
Subject(s)
Factor Xa Inhibitors , Fibrinolytic Agents/chemical synthesis , Isoxazoles/chemical synthesis , Tetrazoles/chemical synthesis , Animals , Arteriovenous Shunt, Surgical , Binding Sites , Crystallography, X-Ray , Dogs , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacology , Humans , Isoxazoles/chemistry , Isoxazoles/pharmacology , Models, Molecular , Rabbits , Structure-Activity Relationship , Tetrazoles/chemistry , Tetrazoles/pharmacology , Thrombin/antagonists & inhibitors , Thrombosis/drug therapy , Trypsin/metabolism , Trypsin Inhibitors/chemical synthesis , Trypsin Inhibitors/chemistry , Trypsin Inhibitors/pharmacokinetics , Trypsin Inhibitors/pharmacologyABSTRACT
Thrombosis is a major cause of mortality in the industrialized world. Therefore, the prevention of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (FXa), the enzyme directly responsible for prothrombin activation. We report a series of novel biaryl-substituted isoxazoline derivatives in which the biaryl moiety was designed to interact with the S(4) aryl-binding domain of the FXa active site. Several of the compounds herein have low nanomolar affinity for FXa, have good in vitro selectivity for FXa, and show potent antithrombotic efficacy in vivo. The three most potent compounds (33, 35, and 37) have inhibition constants for human FXa of 3.9, 2.3, and 0.83 nM, respectively, and ID(50)'s ranging from 0.15 to 0.26 micromol/kg/h in the rabbit arterio-venous thrombosis model.
Subject(s)
Acetates/chemical synthesis , Factor Xa Inhibitors , Fibrinolytic Agents/chemical synthesis , Isoxazoles/chemical synthesis , Acetates/chemistry , Acetates/pharmacology , Animals , Arteriovenous Shunt, Surgical , Binding Sites , Biphenyl Compounds , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacology , Humans , Isoxazoles/chemistry , Isoxazoles/pharmacology , Models, Molecular , Rabbits , Structure-Activity Relationship , Thrombosis/drug therapyABSTRACT
LITERATURE REVIEW AND CASE REPORT: A literature review of Herpes zoster of the trigeminal nerve is presented. Included are differential diagnosis and treatment modalities that will enable the dental practitioner to identify and manage this disease. A case report is provided to amplify this timely information.
Subject(s)
Cranial Nerve Diseases , Herpes Zoster , Toothache/etiology , Trigeminal Nerve/virology , Acyclovir/therapeutic use , Cranial Nerve Diseases/complications , Cranial Nerve Diseases/diagnosis , Cranial Nerve Diseases/therapy , Dental Pulp Diseases/etiology , Diagnosis, Differential , Female , Herpes Zoster/complications , Herpes Zoster/diagnosis , Herpes Zoster/therapy , Herpesvirus 3, Human , Humans , Middle AgedSubject(s)
Denture, Partial , Ethics, Dental , Oral Hygiene , Treatment Refusal , Chronic Disease , Humans , Informed Consent , Male , Middle Aged , Periodontitis/prevention & control , Refusal to TreatABSTRACT
We report a case of cutaneous odontogenic sinus tract to the chin. The patient first noticed the cutaneous condition in 1977. Inappropriate medical and dental treatment was ineffective. Correct diagnosis and treatment was completed in 1993. We offer diagnostic and treatment guidelines for the management of similar cases.
Subject(s)
Cutaneous Fistula/diagnosis , Cutaneous Fistula/therapy , Dental Fistula/diagnosis , Adult , Chin , Chronic Disease , Cutaneous Fistula/etiology , Dental Fistula/etiology , Dental Fistula/therapy , Dental Pulp Necrosis/complications , Diagnosis, Differential , Humans , Male , Periapical Abscess/complications , Practice Guidelines as Topic , Root Canal TherapySubject(s)
Dental Assistants , Ethics, Dental , Professional Impairment , Substance-Related Disorders , Adult , Female , Humans , Personnel ManagementABSTRACT
The identification of the AT1 and AT2 receptor subtypes has stimulated interest in developing balanced angiotensin II receptor antagonists. A series of 5-(3-amidopropanoyl)imidazoles has been prepared which possess balanced affinity for the AT1 and AT2 receptors. XR510 (1), 1-[[2'-[[(isopentoxycarbonyl)amino]sulfonyl]-3- fluoro(1,1'-biphenyl)-4-yl]methyl]-5-[3-(N-pyridin-3- ylbutanamido)propanoyl]-4-ethyl-2-propyl-1H-imidazole, potassium salt, exhibits subnanomolar affinity for both receptor sites. XR510 is very active in lowering blood pressure in renal hypertensive rats and furosemide-treated dogs following oral administration.
