Significant and persistent improvement of thrombocytopenia after splenectomy in an adult with the wiskott-aldrich syndrome and intra-cerebral bleeding

The Wiskott-Aldrich syndrome is an X-linked inherited immunodeficiency disorder characterized by thrombocytopenia, recurrent infections and eczema. Its best management option is HLA-ldentical bone marrow transplantation; when this is not feasible, splenectomy, followed by continuous prophylactic antibiotics, represents the alternative of choice. The present case report relates the excellent outcome of an adult with the Wiskott-Aldrich syndrome who suffered his first major complication of the disease at age 33 years, an intracerebral hemorrhage. Since an uneventfull splenectomy, thrombocytopenia has significantly improved, and he has remained free of infections for a follow-up period of 3 years while being treated with prophylactic antibiotics. ©1995 Wiley-Liss, Inc.     

The saga of the discovery of IL-1 and TNF and their specific inhibitors in the pathogenesis and treatment of rheumatoid arthritis

In the seventies, the molecule subsequently termed IL-1 was among the first cytokines to attract the attention of rheumatologists due to its biological role in tissue destruction and bone resorption. In the mid-eighties, cachectin/tumor necrosis factor was found to share some of these biological activities, and a strong synergism between the two cytokines became evident. While IL-1 appeared to be more important at the local level, TNF played a more prominent part at the systemic level. In 1984, we became aware of the existence of an antagonist to IL-1 - subsequently termed IL-1Ra (interleukin-1 receptor antagonist) - in urine of febrile patients; its mechanism of action was elucidated in 1987 and the molecule cloned in 1990. The natural inhibitors of TNF were identified in 1996/97 by different investigators and proved to be soluble fragments of the TNF receptor. A concept commonly accepted at present is that disease activity and clinical outcome are controlled by the balance between agonistic and antagonistic cytokines, and at present the principal goal is to understand the underlying mechanisms. This concept is illustrated by observations in numerous animal models. The control of IL-1 and TNF is strongly dependent on the contact between activated lymphocytes and monocytes, the main source of these cytokines. Inhibiting this interaction by interfering with ligands and counter-ligands may be a useful approach if it is possible to maintain the production of the cytokine antagonist. Apolipoproteins A-I and A-II as well as beta2-integrins are molecules that block ligand/counter-ligand interaction. According to animal experiments and clinical data, blocking either IL-1 or TNF, or both, is beneficial. However, to determine not only the benefit but also the side effects of combination therapy in the human system, long-term clinical trials will be required.     

Pharmacogenetics of analgesics: toward the individualization of prescription

The use of analgesics is based on the empiric administration of a given drug with clinical monitoring for efficacy and toxicity. However, individual responses to drugs are influenced by a combination of pharmacokinetic and pharmacodynamic factors that can sometimes be regulated by genetic factors. Whereas polymorphic drug-metabolizing enzymes and drug transporters may affect the pharmacokinetics of drugs, polymorphic drug targets and disease-related pathways may influence the pharmacodynamic action of drugs. After a usual dose, variations in drug toxicity and inefficacy can be observed depending on the polymorphism, the analgesic considered and the presence or absence of active metabolites. For opioids, the most studied being morphine, mutations in the ABCB1 gene, coding for P-glycoprotein (P-gp), and in the micro-opioid receptor reduce morphine potency. Cytochrome P450 (CYP) 2D6 mutations influence the analgesic effect of codeine and tramadol, and polymorphism of CYP2C9 is potentially linked to an increase in nonsteroidal anti-inflammatory drug-induced adverse events. Furthermore, drug interactions can mimic genetic deficiency and contribute to the variability in response to analgesics. This review summarizes the available data on the pharmacokinetic and pharmacodynamic consequences of known polymorphisms of drug-metabolizing enzymes, drug transporters, drug targets and other nonopioid biological systems on central and peripheral analgesics.     

Blockade of intra-articular TNF in peripheral spondyloarthritis: Its relevance to clinical scores,quantitative imaging and synovial fluid and synovial tissue biomarkers

ObjectivesThis open-label study is based on a translational approach with the aim of detecting changes in the clinical condition as well as in imaging and synovial biological markers in both synovial fluid (SF) and synovial tissue (ST) in peripheral spondyloarthritis (SpA) patients following intra-articular (IA) blockade of TNF-α by serial etanercept injections.MethodsTwenty-seven SpA patients with resistant knee synovitis underwent four biweekly IA injections of etanercept (E) (12.5 mg). The primary outcome of Thompson's Knee Index (THOMP), and secondary outcomes of Knee Joint Articular Index (KJAI), C-reactive protein (CRP), HAQ-Disability Index (HAQ-DI), maximal synovial thickness (MST) according to ultrasonography (US) and contrast-enhanced magnetic resonance (C+MR) imaging, ST-CD45+ mononuclear cells (MNC) and ST-CD31+ vessels, IL-1β, IL-1Ra and IL-6 levels in SF were assessed at baseline and at the end of the study.ResultsAt the study end, clinical and imaging outcomes as well as ST and SF biological markers were significantly reduced compared to baseline. There were significant correlations between clinical, imaging and biological markers (CRP with either THOMP, or KJAI, or HAQ-DI or SF-IL-1Ra; US-MST with KJAI, ST-CD45+ with either THOMP, or KJAI, or ST-CD31+, or SF-IL-1β; SF-IL-6 with either THOMP, or KJAI, or SF-IL-1β, or IL-1Ra).ConclusionsThe proof of concept study revealed early improvement either in local and systemic clinical scores, in synovial thickness measures by C+MR and US, or expression of synovial biological markers. CD45+, CD31+ in ST and IL-6 and IL-1β in SF may be considered potential biomarkers of the peripheral SpA response to IA TNF-α blocking.     

The paraoxonase-1 pathway is not a major bioactivation pathway of clopidogrel in vitro

BACKGROUND AND PURPOSE

Clopidogrel is a prodrug bioactivated by cytochrome P450s (CYPs). More recently, paraoxonase-1 (PON1) has been proposed as a major contributor to clopidogrel metabolism. The purpose of this study was to assess the relative contribution of CYPs and PON1 to clopidogrel metabolism in vitro.

EXPERIMENTAL APPROACH

Clopidogrel metabolism was studied in human serum, recombinant PON1 enzyme (rePON1), pooled human liver microsomes (HLMs), HLMs with the CYP2C19*1/*1 genotype and HLMs with the CYP2C19*2/*2 genotype. Inhibition studies were also performed using specific CYP inhibitors and antibodies. Clopidogrel and its metabolites were measured using LC/MS/MS method.

KEY RESULTS

PON1 activity was highest in the human serum and there was no difference in PON1 activity between any of the HLM groups. The production of clopidogrel''s active metabolite (clopidogrel-AM) from 2-oxo-clopidogrel in pooled HLMs was approximately 500 times that in serum. When 2-oxo-clopidogrel was incubated with rePON1, clopidogrel-AM was not detected. Clopidogrel-AM production from 2-oxo-clopidogrel was lower in CYP2C19*2/*2 HLMs compared with CYP2C19*1/*1 HLMs, while PON1 activity in HLMs with both genotypes was similar. Moreover, incubation with inhibitors of CYP3A, CYP2B6 and CYP2C19 significantly reduced clopidogrel bioactivation while a PON1 inhibitor, EDTA, had only a weak inhibitory effect.

CONCLUSION AND IMPLICATIONS

This in vitro study shows that the contribution of PON1 to clopidogrel metabolism is limited at clinically relevant concentrations. Moreover, CYP2C19, CYP2B6 and CYP3A play important roles in the bioactivation of clopidogrel.