Stereoselective plasma protein binding of ibuprofen enantiomers

Summary We have developed a novel and reproducible method for determining the plasma protein binding of the two ibuprofen enantiomers in the presence of each other. The method involves the use of radiolabelled racemic ibuprofen, equilibrium dialysis, derivatization of the enantiomers to diastereomeric amides, high-performance liquid chromatography, and radiochemical analysis.We have determined the plasma protein binding of R(–)- and S(+)-ibuprofen in 6 healthy male volunteers after the oral administration of 800 mg racemic ibuprofen.The mean time-averaged percentage unbound of the R(–)-enantiomer, 0.419 was significantly less than that of the S(+)-enantiomer, 0.643, consistent with stereoselective plasma protein binding.The percentage unbound of each ibuprofen enantiomer was concentration-dependent over the therapeutic concentration range and was influenced by the presence of its optical antipode.     

Diagnosing abuse: a systematic review of torn frenum and other intra-oral injuries.

INTRODUCTION: A torn labial frenum is widely regarded as pathognomonic of abuse. METHODS: We systematically reviewed the evidence for this, and to define other intra-oral injuries found in physical abuse. Nine studies documented abusive torn labial frena in 27 children and 24 [corrected] were fatally abused: 22 were less than 5 years old. Only a direct blow to the face was substantiated as a mechanism of injury. RESULTS: Two studies noted accidentally torn labial frena, both from intubation. Abusive intra-oral injuries were widely distributed to the lips, gums, tongue and palate and included fractures, intrusion and extraction of the dentition, bites and contusions. CONCLUSIONS: Current literature does not support the diagnosis of abuse based on a torn labial frenum in isolation. The intra-oral hard and soft tissue should be examined in all suspected abuse cases, and a dental opinion sought where abnormalities are found.     

Spread of local anaesthetic solutions following sacral extradural (caudal) block: influence of posture

Extradural sacral (caudal) block was performed in 17 cases (14 patients) of chronic low back pain. In each case 22 ml of a bupivacaine/methylprednisolone solution incorporating a radioopaque dye was injected over a 2-min period. Patients were randomly assigned to receive the injection in the horizontal position or with 15 degrees head-up or head-down tilt applied to the operating table. Results indicate that analgesia is usually more localised than spread of solution determined by x-ray evidence and that higher levels of analgesia are achieved in patients in the head-up position. Possible causes are the differing distribution characteristics of the constituents of the solution and the gravitational effects of posture on cerebrospinal fluid mechanics. Technical problems associated with obesity, congenital abnormalities, vascular uptake of solution, and delayed spread of the injectant due to adhesions are discussed.     

Infectious bronchitis virus S1 gene sequence comparison is a better predictor of challenge of immunity in chickens than serotyping by virus neutralization.

Five strains of infectious bronchitis virus isolated from commercial chickens from the state of Pennsylvania, USA during the years 1998 and 1999 were studied. The strains were selected for cross-challenge in specific pathogen free chickens and virus neutralization in chick embryos on the basis of partial S1 sequence amino acid identity values. The partial sequences analysed spanned the hypervariable amino terminus region of S1 from amino acid residues 48 to 219, based on the Beaudette strain. Using their S1 identity values, the strains represented a continuum of genetic, and thus antigenic, relationships. When compared with strain PA/5083/99, strain PA/Wolgemuth/98 had high sequence identity (96%) followed by PA/171/99 (85%), PA/5344/98 (70%) and PA/1220/98 (34%). The method of Archetti and Horsfall was used for calculating antigenic relatedness values of virus neutralization tests. The same formula was also applied to the percentage protection values of cross-challenge tests to derive protective relatedness values among the strains. The antigenic relatedness values, protective relatedness values, and the partial S1 sequence identity values were then analysed. The findings indicated partial S1 sequence identity values were more strongly correlated with protective relatedness values and than antigenic relatedness values.     

Effectiveness of early orthodontic treatment with the Twin-block appliance: a multicenter, randomized, controlled trial. Part 1: Dental and skeletal effects.

This study evaluated the effectiveness of early orthodontic treatment with the Twin-block appliance for the developing Class II Division 1 malocclusion. This multicenter trial was carried out in the United Kingdom. A total of 174 children, aged 8 to 10 years old, with Class II Division 1 malocclusion were randomly allocated to receive treatment with a Twin-block appliance or to an untreated, control group. Data were collected at the start of the study and 15 months later. Results showed that early treatment with Twin-block appliances resulted in reduction of overjet, correction of molar relationships, and reduction in severity of malocclusion. Most of this correction was due to dentoalveolar change, but some was due to favorable skeletal change. Early treatment with the Twin-block appliance is effective in reducing overjet and severity of malocclusion. The small change in the skeletal relationship might not be considered clinically significant.     

Decreased P-glycoprotein expression in multidrug-sensitive and -resistant human myeloma cells induced by the cytokine leukoregulin.

Modulation of the expression of P-glycoprotein, a plasma membrane protein associated with multidrug resistance, was examined in drug-sensitive and drug-resistant tumor cells treated with leukoregulin, a M(r) 50,000 cytokine from human lymphocytes that rapidly permeabilizes the plasma membrane of many tumor cells facilitating the uptake of doxorubicin and other tumor-inhibitory antibiotics. P-glycoprotein expression was measured flow cytometrically by the binding of C219 or MRK16 monoclonal antibody to multidrug-sensitive human K562 erythroleukemia and 8226/S myeloma cells, compared to multidrug-resistant 8226/DOX40 myeloma cells. Cells were treated for up to 2 h with up to 80 units of leukoregulin/ml or one of a variety of unrelated cytokines including interleukin 1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, colony-stimulating factor, macrophage colony-stimulating factor, granulocyte macrophage colony-stimulating factor, tumor necrosis factor alpha, gamma-interferon, alpha-interferon, epidermal growth factor, platelet-derived growth factor AA, platelet-derived growth factor BB, insulin-like growth factor I, insulin-like growth factor II, fibroblast growth factor, or transforming growth factor beta. Leukoregulin caused a concentration-dependent decrease in P-glycoprotein expression; however, P-glycoprotein expression was unaffected by the other cytokines (< 12% decrease in expression). Leukoregulin-induced membrane permeabilization, determined flow cytometrically by intracellular fluorescein efflux, and decreased P-glycoprotein expression occurred simultaneously within 15 min in drug-sensitive and -resistant cells. Enhanced doxorubicin uptake, measured flow cytometrically by doxorubicin influx, was also present within 15 min. Leukoregulin enhancement of doxorubicin uptake and increased membrane permeability varied directly with the decrease in P-glycoprotein expression. Leukoregulin in combination with doxorubicin enhanced the inhibition of cell proliferation in 8226/DOX40 multidrug-resistant cells over expressing P-glycoprotein. In contrast, combined treatment of HL-60/MX2 multidrug-resistant human promyelocytic leukemia cells that do not overexpress P-glycoprotein in association with their multidrug resistance resulted in no greater growth inhibition than observed with HL-60/MX2 cells treated with doxorubicin alone. This is the first demonstration that a naturally occurring macromolecule with anticancer activities can modulate the expression of P-glycoprotein concomitant with enhanced drug uptake and inhibition of cell proliferation.