Cytokines in chronic rheumatic diseases: is everything lack of homeostatic balance?

Biological systems have powerful inbuilt mechanisms of control intended to maintain homeostasis. Cytokines are no exception to this rule, and imbalance in cytokine activities may lead to inflammation with subsequent tissue and organ damage, altered function, and death. Balance is achieved through multiple, not mutually exclusive, mechanisms including the simultaneous production of agonist and antagonistic cytokines, expression of soluble receptors or membrane-bound nonsignaling receptors, priming and/or reprogramming of signaling, and uncoupling of ligand/receptor pairing from signal transduction. Insight into cytokine balance is leading to novel therapeutic approaches particularly in autoimmune conditions, which are intimately linked to a dysregulated cytokine production

Genetic polymorphism and drug interactions: their importance in the treatment of pain

Résumé: Objectif: Evaluer ľimpact de certains polymorphismes génétiques sur la variabilité de réponse aux analgésiques. Sources: Revue systématique par recherche informatisée structurée dans la base Medline (1966-2004), mots clés : pharmacogénétique, polymorphisme, cytochrome P450 (CYP), glycoprotéine P (P-gp), douleur, antalgiques, opiacés, morphine, codéine, tramadol, anti-inflammatoires non stéroïdiens (AINS). Sélection ďarticles de langue anglaise et française. Bibliographies ďarticles pertinents également sélectionnées. Constatations principales: La plupart des analgésiques sont métabolisés via les isoenzymes du CYP soumis à un polymorphisme génétique. Les AINS sont métabolisés par le CYP2C9; les opioïdes qualifiés de " faibles ” (codéine, tramadol), antidépresseurs et dextrométhorphane par le CYP2D6 et certains opioïdes "forts” (buprénorphine, méthadone ou fentanyl) par le CYP3A4/5. Après administration de doses usuelles, une toxicité médicamenteuse ou, au contraire, une inefficacité thérapeutique peut survenir en fonction du polymorphisme et de la substance. Les interactions médicamenteuses, en mimant les défauts génétiques du fait de ľexistence ďinhibiteurs et ďinducteurs des CYP, participent également à la variabilité de réponse aux analgésiques. Certains opioïdes sont substrats de la P-gp, transporteur transmembranaire également soumis à un polymorphisme génétique. La P-gp ne pourrait toutefois jouer chez ľhomme qu'un röle modulateur mineur sur les effets centraux de la morphine, de la méthadone et du fentanyl. Conclusion: La pharmacogénétique devrait dans un avenir proche permettre ďoptimaliser la thérapeutique en individualisant ľapproche analgésique médicamenteuse et en améliorant la sécurité ďemploi et ľefficacité de nombreux analgésiques. Ľutilité clinique de ces approches individualisées devra être démontrée par des études et des analyses pharmacoéconomiques appropriée

Treatment of congenital thoracic scoliosis with associated rib fusions using VEPTR expansion thoracostomy: a surgical technique

Abstract : Introduction: Untreated growing patients with congenital scoliosis and fused ribs will develop finally thoracic insufficiency syndrome. The technique of expansion thoracoplasty with implantation of a vertical expandable prosthetic titanium rib (VEPTR) was introduced initially to treat these children. Methods: This article attempts to provide an overview of the surgical technique of opening-wedge thoracostomy and VEPTR instrumentation in children with congenital thoracic scoliosis and fused ribs. Results: Our modification of the surgical approach using a posterior midline incision rather than the modified thoracotomy incision initially described could potentially help to diminish wound dehiscence and secondary infection, while preserving a more acceptable esthetic appearance of the back. Conclusions: Vertical expandable prosthetic titanium rib-based treatments should be undertaken only with a good knowledge of its numerous specific complications. Every aspect of the treatment should be oriented to minimize these complications. At the same time it should be kept in mind that the ultimate step of this long-term fusionless treatment strategy will be a technically demanding spine fusion

Intraocular penetration of penciclovir after oral administration of famciclovir: a population pharmacokinetic model

Objectives We developed a population model that describes the ocular penetration and pharmacokinetics of penciclovir in human aqueous humour and plasma after oral administration of famciclovir. Methods Fifty-three patients undergoing cataract surgery received a single oral dose of 500 mg of famciclovir prior to surgery. Concentrations of penciclovir in both plasma and aqueous humour were measured by HPLC with fluorescence detection. Concentrations in plasma and aqueous humour were fitted using a two-compartment model (NONMEM software). Inter-individual and intra-individual variabilities were quantified and the influence of demographics and physiopathological and environmental variables on penciclovir pharmacokinetics was explored. Results Drug concentrations were fitted using a two-compartment, open model with first-order transfer rates between plasma and aqueous humour compartments. Among tested covariates, creatinine clearance, co-intake of angiotensin-converting enzyme inhibitors and body weight significantly influenced penciclovir pharmacokinetics. Plasma clearance was 22.8 ± 9.1 L/h and clearance from the aqueous humour was 8.2 × 10−5 L/h. AUCs were 25.4 ± 10.2 and 6.6 ± 1.8 μg · h/mL in plasma and aqueous humour, respectively, yielding a penetration ratio of 0.28 ± 0.06. Simulated concentrations in the aqueous humour after administration of 500 mg of famciclovir three times daily were in the range of values required for 50% growth inhibition of non-resistant strains of the herpes zoster virus family. Conclusions Plasma and aqueous penciclovir concentrations showed significant variability that could only be partially explained by renal function, body weight and comedication. Concentrations in the aqueous humour were much lower than in plasma, suggesting that factors in the blood-aqueous humour barrier might prevent its ocular penetration or that redistribution occurs in other ocular compartment

The active metabolite of leflunomide, A77 1726, increases the production of IL-1 receptor antagonist in human synovial fibroblasts and articular chondrocytes

Leflunomide is an immunomodulatory agent used for the treatment of rheumatoid arthritis. In this study, we investigated the effect of A77 1726 – the active metabolite of leflunomide – on the production of IL-1 receptor antagonist (IL-1Ra) by human synovial fibroblasts and articular chondrocytes. Cells were incubated with A77 1726 alone or in combination with proinflammatory cytokines. IL-1Ra production was determined by ELISA. A77 1726 alone had no effect, but in the presence of IL-1β or tumour necrosis factor-α it markedly enhanced the secretion of IL-1Ra in synovial fibroblasts and chondrocytes. The effect of A77 1726 was greatest at 100 μmol/l. In synovial fibroblasts and de-differentiated chondrocytes, A77 1726 also increased IL-1β-induced IL-1Ra production in cell lysates. Freshly isolated chondrocytes contained no significant amounts of intracellular IL-1Ra. A77 1726 is a known inhibitor of pyrimidine synthesis and cyclo-oxygenase (COX)-2 activity. Addition of exogenous uridine did not significantly modify the effect of A77 1726 on IL-1Ra production, suggesting that it was not mediated by inhibition of pyrimidine synthesis. Indomethacin increased IL-1β-induced IL-1Ra secretion in synovial fibroblasts and de-differentiated chondrocytes, suggesting that inhibition of COX-2 may indeed enhance IL-1β-induced IL-1Ra production. However, the stimulatory effect of indomethacin was consistently less effective than that of A77 1726. A77 1726 increases IL-1Ra production by synovial fibroblasts and chondrocytes in the presence of proinflammatory cytokines, and thus it may possess chondroprotective effects. The effect of A77 1726 may be partially mediated by inhibition of COX-2, but other mechanisms likely concur to stimulate IL-1Ra production

CBT/DBT SKILLS TRAINING FOR ADULTS WITH ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)

Background: Attention deficit hyperactivity disorder (ADHD) is associated with marked impairments in familial, social, and professional functioning. Although stimulant treatments can be effective in adult ADHD, some patients will respond poorly or not at all to medication. Previous studies demonstrated that cognitive behavioural therapy- (CBT) and dialectical behavior therapy- (DBT) oriented interventions are effective in reducing the burden of the disease, which is mainly marked by depression, interpersonal difficulties, low self-esteem, and low quality of life. In order to determine the effectiveness of this intervention, we assessed the benefits of a CBT/DBT programme to reduce residual symptoms and help patients improve their quality of life. Subjects and methods: 49 ADHD-patients, poor responders to medication, were enrolled in a one-year programme where they received individual therapy, associated with weekly sessions of group therapy with different modules: Mindfulness, Emotion Regulation, Interpersonal Effectiveness and Distress Tolerance, Impulsivity/Hyperactivity and Attention. Each subject was assessed at baseline, at months 3 and 6, and at the end of the treatment for ADHD severity (ASRS v1.1), depression severity (BDI-II), hopelessness (BHS), mindfulness skills (KIMS), anger expression and control (STAXI), impulsivity (BIS-11), quality of life (WHOQOL-BREF), and social functioning (QFS). The 49 ADHD patients were compared with 13 ADHD subjects on a waiting list. Linear mixed models were used to measure response to treatment. Results: Overall, the psychotherapeutic treatment was associated with significant improvements in almost all dimensions. The most significant changes were observed for BDI-II (b=-0.30; p<0.0001), ASRS total score (b=-0.16; p<0.0001), and KIMS AwA (b=0.21; p<0.0001), with moderate to large effect sizes. Compared with the waiting list controls, ADHD patients showed a better, albeit non-significant, pattern of response. Conclusions: Individual and structured psycho-educational DBT/CBT groups support existing data suggesting that a structured psychotherapeutic approach is useful for patients who respond partially or not at all to drug therapy

CYP2E1 genotype and isoniazid-induced hepatotoxicity in patients treated for latent tuberculosis

Objective: To determine whether pharmacogenetic tests such as N-acetyltransferase 2 (NAT2) and cytochrome P4502E1 (CYP2E1) genotyping are useful in identifying patients prone to antituberculosis drug-induced hepatotoxicity in a cosmopolite population. Methods: In a prospective study we genotyped 89 patients treated with isoniazid (INH) for latent tuberculosis. INH-induced hepatitis (INH-H) or elevated liver enzymes including hepatitis (INH-ELE) was diagnosed based on the clinical diagnostic scale (CDS) designed for routine clinical practice. NAT2 genotypes were assessed by fluorescence resonance energy transfer probe after PCR analysis, and CYP2E1 genotypes were determined by PCR with restriction fragment length polymorphism analysis. Results: Twenty-six patients (29%) had INH-ELE, while eight (9%) presented with INH-H leading to INH treatment interruption. We report no significant influence of NAT2 polymorphism, but we did find a significant association between the CYP2E1 *1A/*1A genotype and INH-ELE (OR: 3.4; 95% CI:1.1-12; p=0.02) and a non significant trend for INH-H (OR: 5.9; 95% CI: 0.69-270; p=0.13) compared with other CYP2E1 genotypes. This test for predicting INH-ELE had a positive predictive value (PPV) of 39% (95% CI: 26-54%) and a negative predictive value (NPV) of 84% (95% CI: 69-94%). Conclusion: The genotyping of CYP2E1 polymorphisms may be a useful predictive tool in the common setting of a highly heterogeneous population for predicting isoniazid-induced hepatic toxicity. Larger prospective randomized trials are needed to confirm these result

A novel transversion in the intron 5 donor splice junction of CYP2C19 and a sequence polymorphism in exon 3 contribute to the poor metabolizer phenotype for the anticonvulsant drug S-mephenytoin. J Pharmacol Exp Ther

ABSTRACT Cytochrome P-450 (CYP) 2C19 is responsible for the metabolism of a number of therapeutic agents such as S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine. Genetic polymorphisms in this enzyme are responsible for the poor metabolizers (PM) of mephenytoin, which represent ϳ13-23% of Asians and 3-5% of Caucasians. Several polymorphisms contribute to this phenotype. We have isolated two new allelic variants that contribute to the PM phenotype in Caucasians. CYP2C19*7 contained a single T 3 A nucleotide transversion in the invariant GT at the 5Ј donor splice site of intron 5. The second PM allele, CYP2C19*8, consisted of a T358C nucleotide transition in exon 3 that results in a Trp120Arg substitution. In a bacterial expression system, CYP2C198 protein exhibited a dramatic (ϳ90% and 70%) reduction in the metabolism of S-mephenytoin and tolbutamide, respectively, when compared with the wild-type CYP2C191B protein. Restriction fragment length polymerase chain reaction tests were developed to identify the new allelic variants

Uptake/Efflux Transport of Tramadol Enantiomers and O-Desmethyl-Tramadol: Focus on P-Glycoprotein

The analgesic effect of tramadol (TMD) results from the monoaminergic effect of its two enantiomers, (+)-TMD and (-)-TMD as well as its opioid metabolite (+)-O-desmethyl-tramadol (M1). P-glycoprotein (P-gp) might be of importance in the analgesic and tolerability profile variability of TMD. Our study investigated the involvement of P-gp in the transepithelial transport of (+)-TMD, (-)-TMD and M1, using a Caco-2 cell monolayer model. The bidirectional transport of racemic TMD and M1 (1-100 microM) across the monolayers was investigated at two pH conditions (pH 6.8/7.4 and 7.4/7.4) in the presence and absence of P-gp inhibitor cyclosporine A (10 microM) and assessed with the more potent and specific P-gp inhibitor GF120918 (4 microM). Analytical quantification was performed by liquid chromatography coupled to the fluorescence detector. A net secretion of (+)-TMD, (-)-TMD and M1 was observed when a pH gradient was applied (TR: P(app)(B - A)/P(app)(A - B): 1.8-2.7; P < 0.05). However, the bidirectional transport of all compounds was equal in the non-gradient system. In the presence of P-gp inhibitors, a slight but significant increase of secretory flux was observed (up to 26%; P < 0.05) at both pH conditions. In conclusion, (+)-TMD, (-)-TMD and M1 are not P-gp substrates. However, proton-based efflux pumps may be involved in limiting the gastrointestinal absorption of TMD enantiomers as well as enhancing TMD enantiomers and M1 renal excretion. A possible involvement of uptake carriers in the transepithelial transport of TMD enantiomers and M1 is suggested