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Purpose: Treatment options for chronic low back pain (CLBP) include cognitive behavioral interventions. Most of these interventions only have small and short-lived effects. Using strict inclusion criteria for participation in an intensive combined physical and psychological program, encouraging effects were reported at 1-year follow-up. This study evaluates the long-term follow-up results of the same program. The hypothesis is that previously reported results are maintained.Methods: Structured interviews were conducted in a prospective extended cohort with a minimum of 5-year follow-up in a similar fashion as in the 1-year follow-up report. The median follow-up in this cohort was 6.5 years. The extended cohort consisted of 277 patients (85% response).Results: Outcomes include daily functioning, quality of life, current pain intensity, pain disturbance in daily activities and indicators of the use of pain medication and healthcare services. The previously reported positive 1-year follow-up results were maintained at a minimum of 5-year follow-up. Disability as measured with the Oswestry disability index (ODIv2.1a) decreased from 40 to 27 in the first year. This positive result was maintained at the 6.5-year follow-up with an ODI of 28. Pain intensity (NRS 0-100) improved from 60 to 39 in the first year, and at 6.5 years, this had further improved to 33. Improvement in quality of life (SF 36) at 1-year follow-up was maintained at 6.5-year follow-up, and healthcare consumption had decreased substantially as measured with doctor visits and analgesics used for CLBP.Conclusion: Selected and motivated patients with longstanding CLBP improve fast after an intensive combined physical and psychological program in daily functioning, pain and quality of life. Positive 1-year results are maintained, and healthcare utilization was still reduced at a minimum of 5-year follow-up. These slides can be retrieved under Electronic Supplementary Material. [ABSTRACT FROM AUTHOR]

The clinical development of a candidate p38 kinase inhibitor was terminated because of its unexpectedly rapid clearance in human subjects. Its short half-life and metabolic profile in human beings were vastly different from that in rats, dogs, and monkeys characterized during routine pre-clinical studies. Mice generated the predominant drug (4-hydroxylated) metabolite produced in human beings, which was not found in other species. The data from a murine in vitro drug biotransformation assay that used liver extracts from 14 inbred mouse strains were analyzed by haplotype-based computational genetic analysis. This led to the identification of aldehyde oxidase-1 (AOX1) as the enzyme responsible for the rapid metabolism of this drug. Specific enzyme inhibitors and expressed recombinant enzymes were used to confirm that AOX catalyzed the formation of the 4-hydroxylated drug metabolite in mouse and man. Genetic variation within Aox1 regulated the level of hepatic Aox1 mRNA, AOX1 protein, and enzyme activity among the inbred strains. Thus, computational murine pharmacogenetic analysis can facilitate the identification and characterization of drug metabolism pathways that are differentially utilized by humans and other species. [ABSTRACT FROM AUTHOR]

Objective and Design: To investigate the suppressive effects of the β-agonist clenbuterol on the release of TNF- α and IL-6 in a lipopolysaccharide (LPS)-model of inflammation, both in vitro and in vivo.¶ Material and Subjects: Human U-937 cell line (monocyte-derived macrophages), and male Wistar rats (200-250g).¶ Treatment: U-937 macrophages were incubated with LPS at 1 μg/ml, with or without 1.0mM-0.1nM test drugs (clenbuterol and other cAMP elevating agents) for 1-24h. Rats were administered either 1 or 10 μg/kg clenbuterol (or saline) orally, 1h before intraperitoneal administration of 2mg/kg LPS.¶ Methods and Results: TNF- α and IL-6 time-concentration profiles were determined both in culture media and plasma, using ELISA' s and bioassays. LPS-mediated release of both cytokines was significantly suppressed by clenbuterol.¶ Conclusions: The β-agonist clenbuterol very potently suppresses the LPS-induced release of the pro-inflammatory cytokines TNF- α and IL-6 both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

The effects of novobiocin (range 0.0125–2 mmol/L) on the hydroxylation of testosterone, the N-demethylation of erythromycin, and the glucuronidation of α-naphthol and paracetamol were studied using pig hepatic microsomes, pooled from five animals. The final concentrations of these substrates in the incubation mixtures were selected to meet Vmax conditions. Novobiocin caused a concentration-dependent inhibition of the glucuronidation of paracetamol; the formation of α-naphthol-glucuronide was reduced to a lesser degree. These results confirm and extend earlier findings in laboratory animal species that novobiocin inhibits UDP-glucuronosyltransferases (UDPGTs). Moreover, novobiocin strongly inhibited 6β-hydroxylation of testosterone. The microsomal N-demethylation of erythromycin and hydroxylation of testosterone at the 15α position were less affected by novobiocin. These results suggest that novobiocin inhibits not only UDPGTs, but also cytochrome P450 (CYP) enzyme activities, probably those belonging to the CYP3A subfamily. More research is needed to reveal which CYPs and UDPGTs are affected by novobiocin in vivo, in order to improve the understanding and probably the predictability of potential drug interactions with this antibiotic. [ABSTRACT FROM AUTHOR]