ABSTRACT
THe case of a 57-year-old man with dissection of an allograft ascending aorta 2 months after aortic root replacement is presented. Most likely traumatic in origin, this unusual complication was managed by Dacron graft replacement of the ascending aorta using hypothermia and circulatory arrest.
Subject(s)
Aorta/transplantation , Aortic Aneurysm/etiology , Aortic Dissection/etiology , Postoperative Complications , Aortic Dissection/surgery , Aortic Aneurysm/surgery , Blood Vessel Prosthesis , Humans , Male , Middle Aged , Transplantation, Homologous , Treatment FailureABSTRACT
Vascular endothelial cells respond to cytokines such as IL-1 beta or TNF-alpha by undergoing a number of functional alterations. Among these alterations is the induction of cell surface adhesion molecules, including VCAM-1. In this report, we investigated the effects of a 3-alkoxybenzo[beta]thiophene-2-carboxamide (BZT) on the cytokine induction of VCAM-1 expression and activation of the transcription factor NF-kappa B in human endothelial cells. BZT blocked the IL-1 beta induced cell surface expression of VCAM-1 in human endothelial cells but did not prevent nuclear translocation of NF-kappa B. This study demonstrates that BZT is a potent inhibitor of VCAM-1 expression in human endothelial cells.
Subject(s)
Endothelium, Vascular/metabolism , Gene Expression Regulation/drug effects , Interleukin-1/pharmacology , NF-kappa B/metabolism , Thiophenes/pharmacology , Vascular Cell Adhesion Molecule-1/genetics , Base Sequence , Biological Transport , Cell Nucleus/metabolism , Cells, Cultured , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Humans , Molecular Sequence Data , Promoter Regions, Genetic , RNA, Messenger/analysis , Thiophenes/chemical synthesis , Tosylphenylalanyl Chloromethyl Ketone/pharmacology , Umbilical VeinsABSTRACT
A series of 5-aryl-3-azabicyclo[3.2.0] heptan -6-one ketals 6 were synthesized by hydride reduction of 1-aryl-4, 4-dimethoxy-1,2- cyclobutanedicarboximides 5. Imides 5 were obtained as the sole, regioselective products of the [2 + 2] photocycloaddition of 1,1- dimethoxyethylene to 2- arylmaleimides . The m-methoxyphenyl-N-methyl analogue 6a was demethylated to phenol 7 with EtSNa -DMF. Both 6a and 7 were similar to morphine in analgesic potency in rats and mice and showed physiological effects that were identical with those of morphine and that were completely reversed by naloxone. Compound 7 was identical with morphine in its ability to displace [3H]naloxone from homogenates of rat brain minus cerebellum. A molecular mechanics analysis of the m-methoxyphenyl analogue 6a showed that the nitrogen atom, the methoxyphenyl group, and the methoxyl oxygen cis to the phenyl group can be superimposed on the corresponding features of the morphine molecule, and perhaps this accounts for the observed opiate-receptor binding properties of 7.
Subject(s)
Analgesics/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Bridged-Ring Compounds/chemical synthesis , Morphine , Analgesia , Analgesics/pharmacology , Animals , Biological Assay , Bridged Bicyclo Compounds/pharmacology , Gait/drug effects , Indicators and Reagents , Naloxone/metabolism , Pain/physiopathology , Rats , Receptors, Opioid/drug effects , Receptors, Opioid/metabolism , Structure-Activity RelationshipSubject(s)
Analgesics, Opioid/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Bridged-Ring Compounds/chemical synthesis , Animals , Binding, Competitive , Bridged Bicyclo Compounds/pharmacology , Cycloheptanes/chemical synthesis , Cycloheptanes/pharmacology , Gait , Male , Mice , Naloxone/metabolism , Rats , Reaction Time/drug effectsABSTRACT
A series of 1-aryl-3-azabicyclo[3.1.0]hexanes was synthesized by hydride reduction of 1-arylcyclopropanedicarboximides. Hydroxyphenyl analogues 20, 22, and 24 were prepared by EtSNa--DMF ether cleavage of the corresponding methoxyphenyl analogues 2m, 2n, and 23, respectively, with the secondary amines 20 and 22 going through the N-formyl intermediate 19 and 21. The p-ethoxy analogue 26 was obtained by O-ethylation of 19, followed by base hydrolysis of the amide 25. The greatest analgesic potency in mouse writhing and rat paw-pain assays was observed for para-substituted compounds. Bicifadine, 1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane (2b), was the most potent member of the series and is presently undergoing clinical trials in man. Analgesic activity of 2b is limited to the (+) enantiomer 2v, which has the 1R,5S absolute configuration as determined by single-crystal X-ray analysis. The N-methyl analogue (27d) of 2b showed significant analgesic potency, whereas the N-allyl (27a), N-(cyclopropylmethyl) (27b), and N-(n-hexyl) (27c) analogues were inactive. Bicifadine (2b) showed a nonnarcotic profile different from analogous azabicycloalkane and 3-phenylpyrrolidine analgesics.
