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1.
J Am Assoc Lab Anim Sci ; 50(4): 507-12, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21838980

RESUMO

Liposome encapsulation of opioids by using an ammonium-sulfate-gradient loading technique significantly slows the release time of the drug. This study evaluated the duration of analgesia in a rodent model of monoarthritis after epidural administration of liposome-encapsulated hydromorphone (LE-hydromorphone; prepared by ammonium-sulfate-gradient loading) compared with standard hydromorphone and a negative control of blank liposomes. Analgesia was assessed by changes in thermal withdrawal latency, relative weight-bearing, and subjective behavioral scoring. Analgesia in arthritic rats was short-lived after epidural hydromorphone; increases in pain threshold were observed only at 2 h after administration. In contrast, thermal pain thresholds after epidural LE-hydromorphone were increased for as long as 72 h, and subjective lameness scores were lower for as long as 96 h after epidural administration. Injection of LE-hydromorphone epidurally was associated with various mild changes in CNS behavior, and 2 rats succumbed to respiratory depression and death. In conclusion, LE-hydromorphone prolonged the duration of epidural analgesia compared with the standard formulation of hydromorphone, but CNS side effects warrant careful administration of this LE-hydromorphone in future studies.


Assuntos
Analgesia Epidural/métodos , Artrite/complicações , Sistemas de Liberação de Medicamentos/métodos , Hidromorfona/uso terapêutico , Lipossomos/uso terapêutico , Dor/tratamento farmacológico , Joelho de Quadrúpedes/patologia , Análise de Variância , Animais , Artrite/patologia , Preparações de Ação Retardada , Hidromorfona/administração & dosagem , Hidromorfona/efeitos adversos , Atividade Motora/efeitos dos fármacos , Dor/etiologia , Medição da Dor , Ratos , Medula Espinal/patologia
2.
J Bacteriol ; 189(14): 5325-33, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17496097

RESUMO

ADP-glucose pyrophosphorylase (ADP-Glc PPase) is the enzyme responsible for the regulation of bacterial glycogen synthesis. To perform a structure-function relationship study of the Escherichia coli ADP-Glc PPase enzyme, we studied the effects of pentapeptide insertions at different positions in the enzyme and analyzed the results with a homology model. We randomly inserted 15 bp in a plasmid with the ADP-Glc PPase gene. We obtained 140 modified plasmids with single insertions of which 21 were in the coding region of the enzyme. Fourteen of them generated insertions of five amino acids, whereas the other seven created a stop codon and produced truncations. Correlation of ADP-Glc PPase activity to these modifications validated the enzyme model. Six of the insertions and one truncation produced enzymes with sufficient activity for the E. coli cells to synthesize glycogen and stain in the presence of iodine vapor. These were in regions away from the substrate site, whereas the mutants that did not stain had alterations in critical areas of the protein. The enzyme with a pentapeptide insertion between Leu(102) and Pro(103) was catalytically competent but insensitive to activation. We postulate this region as critical for the allosteric regulation of the enzyme, participating in the communication between the catalytic and regulatory domains.


Assuntos
Proteínas de Escherichia coli/genética , Escherichia coli/genética , Glucose-1-Fosfato Adenililtransferase/genética , Oligopeptídeos/genética , Trifosfato de Adenosina/farmacologia , Sequência de Aminoácidos , Catálise/efeitos dos fármacos , Códon de Terminação/genética , Escherichia coli/enzimologia , Escherichia coli/metabolismo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Genes Bacterianos , Glucose-1-Fosfato Adenililtransferase/química , Glucose-1-Fosfato Adenililtransferase/metabolismo , Cinética , Cloreto de Magnésio/farmacologia , Dados de Sequência Molecular , Mutagênese Insercional , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Homologia de Sequência de Aminoácidos , Homologia Estrutural de Proteína , Relação Estrutura-Atividade , Especificidade por Substrato
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