Tumor Necrosis Factor Neutralization Combined With Chemotherapy Enhances Mycobacterium Tuberculosis Clearance and Reduces Lung Pathology.

Tumor necrosis factor neutralization combined with chemotherapy enhances Mycobacterium tuberculosis clearance and reduces lung pathology.

Am J Clin Exp Immunol. 2013; 2(1): 124-34
Bourigault ML, Vacher R, Rose S, Olleros ML, Janssens JP, Quesniaux VF, Garcia I

Tuberculosis (TB) is a major health problem requiring sustained immunity to inhibit Mycobacterium tuberculosis growth and appropriate antimicrobial therapy to prevent dissemination and drug resistance. Cell-mediated immune responses to M. tuberculosis involve the activation of cytokines such as Tumor Necrosis Factor (TNF) which is critical for granuloma formation and host resistance against TB. TNF inhibition, used as therapy for the treatment of inflammatory diseases, disrupts granuloma allowing replication of mycobacteria which may increase the efficacy of TB chemotherapy. To test this hypothesis mice infected with M. tuberculosis were treated with isoniazid (INH) and rifampicin (RMP) in the presence or absence of Enbrel, a soluble TNF receptor antagonist during three phases of M. tuberculosis infection. Inhibition of TNF with Enbrel augmented the efficacy of TB chemotherapy as shown by enhanced mycobacterial clearance from the lung of acute and established infection as well as in chronically infected mice. Furthermore, TNF inhibition significantly reduced lung pathology as compared to TB chemotherapy alone. Therefore, the experimental data suggest that TB chemotherapy may be more effective in the presence of a TNF inhibitor, which may be relevant to eradicate mycobacteria during chronic M. tuberculosis infection or reactivation. HubMed – drug

Adjudin disrupts spermatogenesis by targeting drug transporters: Lesson from the breast cancer resistance protein (BCRP).

Spermatogenesis. 2013 Apr 1; 3(2): e24993
Qian X, Cheng YH, Jenardhanan P, Mruk DD, Mathur PP, Xia W, Silvestrini B, Cheng CY

For non-hormonal male contraceptives that exert their effects in the testis locally instead of via the hypothalamic-pituitary-testicular axis, such as adjudin that disrupts germ cell adhesion, a major hurdle in their development is to improve their bioavailability so that they can be efficiently delivered to the seminiferous epithelium by transporting across the blood-testis barrier (BTB). If this can be done, it would widen the gap between their efficacy and general toxicity. However, Sertoli cells that constitute the BTB, peritubular myoid cells in the tunica propria, germ cells at different stages of their development, as well as endothelial cells that constitute the microvessels in the interstitium are all equipped with multiple drug transporters, most notably efflux drug transporters, such as P-glycoprotein, multidrug resistance-related protein 1 (MRP1) and breast cancer resistance protein (BCRP) that can actively prevent drugs (e.g., adjudin) from entering the seminiferous epithelium to exert their effects. Recent studies have shown that BCRP is highly expressed by endothelial cells of the microvessels in the interstitium in the testis and also peritubular myoid cells in tunica propria even though it is absent from Sertoli cells at the site of the BTB. Furthermore, BCRP is also expressed spatiotemporally by Sertoli cells and step 19 spermatids in the rat testis and stage-specifically, limiting to stage VII?VIII of the epithelial cycle, and restricted to the apical ectoplasmic specialization [apical ES, a testis-specific F-actin-rich adherens junction (AJ)]. Interestingly, adjudin was recently shown to be capable of downregulating BCRP expression at the apical ES. In this Opinion article, we critically discuss the latest findings on BCRP; in particular, we provide some findings utilizing molecular modeling to define the interacting domains of BCRP with adjudin. Based on this information, it is hoped that the next generation of adjudin analogs to be synthesized can improve their efficacy in downregulating BCRP and perhaps other drug efflux transporters in the testis to improve their efficacy to traverse the BTB by modifying their interacting domains. HubMed – drug

Avoiding emotional bonds: an examination of the dimensions of therapeutic alliance among cannabis users.

Front Psychiatry. 2013; 4: 70
Healey A, Kay-Lambkin F, Bowman J, Childs S

There is a growing need to provide treatment for cannabis users, yet engaging and maintaining this population in treatment is particularly difficult. Although past research has focused on the importance of therapeutic alliance on drug treatment outcomes, this is the first study to examine the dimensions of therapeutic alliance for cannabis users compared with users of alcohol or other drugs in a naturalistic setting. The acceptability of Internet-delivered interventions for drug and alcohol treatments is also investigated. Participants (n?=?77) included clients who were receiving outpatient drug and alcohol treatment at a publicly funded health service, including a Specialist Cannabis Clinic. The results indicated that one particular domain of alliance, Bond, was consistently lower, from both client and clinician perspectives, for current cannabis users relative to those not currently using cannabis. Client perceptions of Bond decreased as the severity of cannabis use increased (r?=?-0.373, p?=?0.02). Cannabis Clinic clients did not report a significantly lower Bond with their clinicians, suggesting that specialized cannabis services may be better placed to provide appropriate treatment for this population than embedding cannabis treatment within traditional drug and alcohol treatment teams. In addition, Internet/computer-based treatments may be one potential way to engage, transition, or retain cannabis users in treatment. HubMed – drug