Dissecting the reaction of Phase II metabolites of ibuprofen and other NSAIDS with human plasma protein

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs on the market. Whilst they are considered safe, several NSAIDs have been withdrawn from the market as a result of adverse drug reactions. NSAIDs are extensively metabolised to their 1-β-O-acyl glucuronides (AGs), and the risk of NSAID AGs covalently modifying biomacromolecules such as proteins or DNA, leading to immune responses and cellular dysfunction constitutes a major concern in drug discovery and development. The assessment of the degree of protein modification and potential toxicity of individual NSAID AGs is therefore of importance in both drug monitoring and development. Herein, we report the covalent reaction of 1-β-O-acyl glucuronides of ibuprofen and several NSAID analogues with human serum albumin (HSA) protein in vitro under concentrations encountered in therapy. Stable transacylation and glycosylation adducts are formed; the observed protein product ratios can be rationalised by the degree of α-substitution in the acyl group. Structure-based protein reactivity correlations of AGs, such as these, may prove a useful tool in distinguishing between carboxylic acid-containing drugs of similar structure that ultimately prove beneficial (e.g., ibuprofen) from those that prove toxic (e.g., ibufenac). © 2014 the Partner Organisations

Dissecting the reaction of Phase II metabolites of ibuprofen and other NSAIDS with human plasma protein

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs on the market. Whilst they are considered safe, several NSAIDs have been withdrawn from the market as a result of adverse drug reactions. NSAIDs are extensively metabolised to their 1-β-O-acyl glucuronides (AGs), and the risk of NSAID AGs covalently modifying biomacromolecules such as proteins or DNA, leading to immune responses and cellular dysfunction constitutes a major concern in drug discovery and development. The assessment of the degree of protein modification and potential toxicity of individual NSAID AGs is therefore of importance in both drug monitoring and development. Herein, we report the covalent reaction of 1-β-O-acyl glucuronides of ibuprofen and several NSAID analogues with human serum albumin (HSA) protein in vitro under concentrations encountered in therapy. Stable transacylation and glycosylation adducts are formed; the observed protein product ratios can be rationalised by the degree of α-substitution in the acyl group. Structure-based protein reactivity correlations of AGs, such as these, may prove a useful tool in distinguishing between carboxylic acid-containing drugs of similar structure that ultimately prove beneficial (e.g., ibuprofen) from those that prove toxic (e.g., ibufenac). © 2014 the Partner Organisations

Institutionalizing Telemedicine Applications: The Challenge of Legitimizing Decision-Making

During the last decades a variety of telemedicine applications have been trialed worldwide. However, telemedicine is still an example of major potential benefits that have not been fully attained. Health care regulators are still debating why institutionalizing telemedicine applications on a large scale has been so difficult and why health care professionals are often averse or indifferent to telemedicine applications, thus preventing them from becoming part of everyday clinical routines. We believe that the lack of consolidated procedures for supporting decision making by health care regulators is a major weakness

Lumbar spondylolysis: a life long dynamic condition? A cross sectional survey of 4.151 adults

Lumbar spondylolysis (LS) has been the subject of several studies focusing on adolescent athletes. Few, if any, studies have examined LS in the general population. Lysis of the pars interarticularis of the vertebra may be associated with slipping (olisthesis), or it may be stable. In the present survey of lumbar radiographs and general epidemiological data recorded from the Copenhagen Osteoarthritis Study cohort of 4.151 subjects (age range, 22–93 years), we identified the distribution and individual risk factors for LS-development. Men were significantly more at risk of L5 spondylolysis (P = 0.002). There were no sex-specific significant differences regarding LS-incidence at the L4 level. We found no significant differences of risk of LS between nulliparous or multiparous women (L4 P = 0.54/L5 P = 0.35). Furthermore, we found no significant relationship between age at menopause and LS-development. Increased lumbar lordosis was associated to L4/L5 spondylolysis in men (L4 P < 0.001/L5 P = 0.008). In women increased lumbar lordosis had a significant association with L5 spondylolysis (P < 0.001). Increased pelvic inclination was associated with L5 spondylolysis in both men and women (P < 0.001). There were no sex-specific differences regarding the occurrence of simultaneous slips/non-slips. In men, no individual risk factors for L4 slips with concomitant LS were found. In women slipped LS of L4 were significantly associated to aging (P < 0.001) and with decreased pelvic inclination (P = 0.001). In men slipped LS of L5 was significantly associated to increased BMI (P = 0.002), but not to aging (P = 0.10). In women, slips of L5 LS were significantly correlated to aging (P = 0.005), to BMI recorded at the time of radiographic examination (P = 0.006), and BMI measured 17 years before radiographic index examination (P = 0.004). The present study contrasts with commonly held views regarding lumbar spondylolysis. The prevalence of LS increases throughout life and is apparently not a condition restricted to adolescence. Although the cross-sectional nature of the present study prevents an exact estimate of the age at onset; future, sequential studies of the cohort may provide us with some important answers on this topic. Apart from aging–obesity, lordotic angle and pelvic inclination were found to be individual risk factors for LS