Hepatitis C virus-mediated mitochondrial dysfunctions are prevented and rescued by cyclophilin inhibition

Alisporivir (Debio-025) is an analogue of cyclosporine A andrepresents the prototype of a new class of non-immunosuppressivecyclophilin inhibitors. In vitro and in vivo studies have shownthat alisporivir inhibits hepatitis C virus (HCV) replication andongoing clinical trials are exploring its therapeutic potential inpatients with chronic hepatitis C. Recent data suggest that theantiviral effect is mediated by inhibition of cyclophilin A whichis an essential host factor in the HCV life cycle. However, alisporiviralso inhibits mitochondrial permeability transition by bindingto cyclophilin D. As HCV is known to affect mitochondrialfunction, we explored the effect of alisporivir on HCV proteinmediatedmitochondrial dysfunction. By the use of inducible celllines, which allow to investigate the effects of HCV polyproteinexpression independent from viral RNA replication and whichrecapitulate the major alterations of mitochondrial bioenergeticsobserved in infectious cell systems, we show that alisporivir preventsHCV protein-mediated cytochrome c redistribution,decrease of cell respiration, collapse of mitochondrial membranepotential, overproduction of reactive oxygen species and mitochondrialcalcium overload. Strikingly, some of the HCV-mediatedmitochondrial dysfunctions could even be rescued byalisporivir. These observations provide new insights into thepathogenesis of HCV-related liver disease and reveal an additionalmechanism of action of alisporivir that is likely beneficialin the treatment of chronic hepatitis C.

Antiangiogenic peptides and proteins: from experimental tools to clinical drugs.

The formation of a 'tumor-associated vasculature', a process referred to as tumor angiogenesis, is a stromal reaction essential for tumor progression. Inhibition of tumor angiogenesis suppresses tumor growth in many experimental models, thereby indicating that tumor-associated vasculature may be a relevant target to inhibit tumor progression. Among the antiangiogenic molecules reported to date many are peptides and proteins. They include cytokines, chemokines, antibodies to vascular growth factors and growth factor receptors, soluble receptors, fragments derived from extracellular matrix proteins and small synthetic peptides. The polypeptide tumor necrosis factor (TNF, Beromun) was the first drug registered for the regional treatment of human cancer, whose mechanisms of action involved selective disruption of the tumor vasculature. More recently, bevacizumab (Avastin), an antibody against vascular endothelial growth factor (VEGF)-A, was approved as the first systemic antiangiogenic drug that had a significant impact on the survival of patients with advanced colorectal cancer, in combination with chemotherapy. Several additional peptides and antibodies with antiangiogenic activity are currently tested in clinical trials for their therapeutic efficacy. Thus, peptides, polypeptides and antibodies are emerging as leading molecules among the plethora of compounds with antiangiogenic activity. In this article, we will review some of these molecules and discuss their mechanism of action and their potential therapeutic use as anticancer agents in humans.

Monitoring drug therapy.

Drug development has improved over recent decades, with refinements in analytical techniques, population pharmacokinetic-pharmacodynamic (PK-PD) modelling and simulation, and new biomarkers of efficacy and tolerability. Yet this progress has not yielded improvements in individualization of treatment and monitoring, owing to various obstacles: monitoring is complex and demanding, many monitoring procedures have been instituted without critical assessment of the underlying evidence and rationale, controlled clinical trials are sparse, monitoring procedures are poorly validated and both drug manufacturers and regulatory authorities take insufficient account of the importance of monitoring. Drug concentration and effect data should be increasingly collected, analyzed, aggregated and disseminated in forms suitable for prescribers, along with efficient monitoring tools and evidence-based recommendations regarding their best use. PK-PD observations should be collected for both novel and established critical drugs and applied to observational data, in order to establish whether monitoring would be suitable. Methods for aggregating PK-PD data in systematic reviews should be devised. Observational and intervention studies to evaluate monitoring procedures are needed. Miniaturized monitoring tests for delivery at the point of care should be developed and harnessed to closed-loop regulated drug delivery systems. Intelligent devices would enable unprecedented precision in the application of critical treatments, i.e. those with life-saving efficacy, narrow therapeutic margins and high interpatient variability. Pharmaceutical companies, regulatory agencies and academic clinical pharmacologists share the responsibility of leading such developments, in order to ensure that patients obtain the greatest benefit and suffer the least harm from their medicines.

Les traitements de l'ostéoporose (à l'exception de la substitution hormonale et de ses dérivés) [Treatment of osteoporosis (with the exception of hormone replacement and its derivates]

Calcium and vitamin D supplementation are warranted for the treatment of osteoporosis, when other specific drugs are used. Vitamin D supplementation is necessary when the plasma level of 25-hydroxy-vitamin D is below 30 nmol/l (12 pg/l) in order to avoid any increase of the plasma parathyroid hormone level. Bisphosphonates are the most widely drugs used. Recent advances will provide patients with a more convenient therapeutically equivalent alternative: the once-weekly oral dosing regimen and probably the possibility to give infusions at intervals of up to one year. Parathyroid hormone administered subcutaneously daily produced a dramatic increase of trabecular and cortical bone mineral density, and an important decrease of vertebral and nonvertebral fracture risk. Strontium is a new original drug, which stimulates bone formation, and inhibits bone resorption. It significantly improves trabecular and cortical bone mass. Calcitonin not only prevents the recurrence of vertebral fractures, but possibly could decrease hip fractures risk. Hydrochlorothiazide preserves the bone mineral density, and decreases nonvertebral fracture risk, as showed in epidemiological studies. Large clinical trials with statins therapy in appropriate populations are required to find out whether these drugs have any role in preventing fractures.

Vaccination with a recombinant protein encoding the tumor-specific antigen NY-ESO-1 elicits an A2/157-165-specific CTL repertoire structurally distinct and of reduced tumor reactivity than that elicited by spontaneous immune responses to NY-ESO-1-expressing Tumors.

In a recent vaccination trial assessing the immunogenicity of an NY-ESO-1 (ESO) recombinant protein administered with Montanide and CpG, we have obtained evidence that this vaccine induces specific cytolytic T lymphocytes (CTL) in half of the patients. Most vaccine-induced CTLs were directed against epitopes located in the central part of the protein, between amino acids 81 and 110. This immunodominant region, however, is distinct from another ESO CTL region, 157-165, that is a frequent target of spontaneous CTL responses in A2+ patients bearing ESO tumors. In this study, we have investigated the CTL responses to ESO 157-165 in A2+ patients vaccinated with the recombinant protein. Our data indicate that after vaccination with the protein, CTL responses to ESO 157-165 are induced in some, but not all, A2+ patients. ESO 157-165-specific CTLs induced by vaccination with the ESO protein were functionally heterogeneous in terms of tumor recognition and often displayed decreased tumor reactivity as compared with ESO 157-165-specific CTLs isolated from patients with spontaneous immune responses to ESO. Remarkably, protein-induced CTLs used T-cell receptors similar to those previously isolated from patients vaccinated with synthetic ESO peptides (Vbeta4.1) and distinct from those used by highly tumor-reactive CTLs isolated from patients with spontaneous immune responses (Vbeta1.1, Vbeta8.1, and Vbeta13.1). Together, these results demonstrate that vaccination with the ESO protein elicits a repertoire of ESO 157-165-specific CTLs bearing T-cell receptors that are structurally distinct from those of CTLs found in spontaneous immune responses to the antigen and that are heterogeneous in terms of tumor reactivity, being often poorly tumor reactive.

The cyclophilin inhibitor alisporivir prevents hepatitis C virus-mediated mitochondrial dysfunction.

Alisporivir (Debio-025) is an analogue of cyclosporine A and represents the prototype of a new class of non-immunosuppressive cyclophilin inhibitors. In vitro and in vivo studies have shown that alisporivir inhibits hepatitis C virus (HCV) replication, and ongoing clinical trials are exploring its therapeutic potential in patients with chronic hepatitis C. Recent data suggest that the antiviral effect is mediated by inhibition of cyclophilin A, which is an essential host factor in the HCV life cycle. However, alisporivir also inhibits mitochondrial permeability transition by binding to cyclophilin D. Because HCV is known to affect mitochondrial function, we explored the effect of alisporivir on HCV protein-mediated mitochondrial dysfunction. Through the use of inducible cell lines, which allow to investigate the effects of HCV polyprotein expression independent from viral RNA replication and which recapitulate the major alterations of mitochondrial bioenergetics observed in infectious cell systems, we show that alisporivir prevents HCV protein-mediated decrease of cell respiration, collapse of mitochondrial membrane potential, overproduction of reactive oxygen species and mitochondrial calcium overload. Strikingly, some of the HCV-mediated mitochondrial dysfunctions could even be rescued by alisporivir. Conclusion: These observations provide new insights into the pathogenesis of HCV-related liver disease and reveal an additional mechanism of action of alisporivir that is likely beneficial in the treatment of chronic hepatitis C. (HEPATOLOGY 2012).

Mucosal healing and deep remission: What does it mean?

The use of specific terms under different meanings and varying definitions has always been a source of confusion in science. When we point our efforts towards an evidence based medicine for inflammatory bowel diseases (IBD) the same is true: Terms such as "mucosal healing" or "deep remission" as endpoints in clinical trials or treatment goals in daily patient care may contribute to misconceptions if meanings change over time or definitions are altered. It appears to be useful to first have a look at the development of terms and their definitions, to assess their intrinsic and context-independent problems and then to analyze the different relevance in present-day clinical studies and trials. The purpose of such an attempt would be to gain clearer insights into the true impact of the clinical findings behind the terms. It may also lead to a better defined use of those terms for future studies. The terms "mucosal healing" and "deep remission" have been introduced in recent years as new therapeutic targets in the treatment of IBD patients. Several clinical trials, cohort studies or inception cohorts provided data that the long term disease course is better, when mucosal healing is achieved. However, it is still unclear whether continued or increased therapeutic measures will aid or improve mucosal healing for patients in clinical remission. Clinical trials are under way to answer this question. Attention should be paid to clearly address what levels of IBD activity are looked at. In the present review article authors aim to summarize the current evidence available on mucosal healing and deep remission and try to highlight their value and position in the everyday decision making for gastroenterologists.

Therapeutic nanoparticles in clinics and under clinical evaluation.

This article reviews nanoparticulate-chemotherapeutic systems that have been developed for human therapy, considering the components of the nanoparticles, the therapeutic agents associated with the nanoparticles and the clinical indications these therapeutic nanoparticles have been developed for. In this evaluation we have put into perspective the types of nanomaterials and their therapeutic indications. We have reviewed the nanoparticulate-chemotherapeutic systems that have been published, approved and marketed and that are currently in clinical use. We have also analyzed the nanoparticulate-chemotherapeutic systems that are in clinical trials and under preclinical development.

Rethinking ovarian cancer: recommendations for improving outcomes.

There have been major advances in our understanding of the cellular and molecular biology of the human malignancies that are collectively referred to as ovarian cancer. At a recent Helene Harris Memorial Trust meeting, an international group of researchers considered actions that should be taken to improve the outcome for women with ovarian cancer. Nine major recommendations are outlined in this Opinion article.

High-grade meningiomas: new avenues for drug treatment?

PURPOSE OF REVIEW: For standard first-line treatment of high-grade meningiomas, surgical resection and radiotherapy are regarded as standard of care. In the recurrent setting after exhaustion of all local treatment options, no effective therapies are known and several drugs have failed to show efficacy, but novel compounds may offer hope for better disease control. RECENT FINDINGS: Upregulation of proangiogenic molecules and dysregulation of some signaling pathways such as the platelet-derived growth factor and mammalian target of rapamycin are recurrently found in high-grade meningiomas. Furthermore, in-vitro studies and single patient experience indicate that trabectedin may be an effective therapy in this tumor type. Unfortunately, so far there is a lack of conclusive clinical trials to draw definite conclusions of efficacy of these approaches. SUMMARY: There remains a significant unmet need for defining the role of medical therapy in recurrent high-grade meningioma, and more basic research and multicentric well designed trials are needed in this rare and devastating tumor type. Potentially promising novel therapeutics include antiangiogenic drugs, molecular inhibitors of signaling cascades, immunotherapeutics or trabectedin. However, more basic research is required to identify more promising drug targets. VIDEO ABSTRACT AVAILABLE: See the Video Supplementary Digital Content 1 (http://links.lww.com/CONR/A22).

The past, present and future of renin-angiotensin aldosterone system inhibition.

The renin-angiotensin aldosterone system (RAAS) is central to the pathogenesis of cardiovascular disease. RAAS inhibition can reduce blood pressure, prevent target organ damage in hypertension and diabetes, and improve outcomes in patients with heart failure and/or myocardial infarction. This review presents the history of RAAS inhibition including a summary of key heart failure, myocardial infarction, hypertension and atrial fibrillation trials. Recent developments in RAAS inhibition are discussed including implementation and optimization of current drug therapies. Finally, ongoing clinical trials, opportunities for future trials and issues related to the barriers and approvability of novel RAAS inhibitors are highlighted.

Enteral nutrition as primary therapy in Crohn's disease

The developments in enteral feeding for Crohn's disease in the past decade are critically reviewed. The advent of amino acid based chemically defined elemental diets signalled the end of 'total bowel rest' in the management of these patients. Subsequently, controlled clinical trials showed that elemental diets were as effective as corticosteroids in inducing clinical remission in patients with acute exacerbations of Crohn's disease. The later use of peptide based elemental diets, in Crohn's disease produced somewhat conflicting results. The initial uncontrolled studies suggest that polymeric whole protein diets might also be effective in the management of acute exacerbations of the disease, casting in turn doubts concerning the role of dietary antigens in the pathogenesis of Crohn's disease. Results of controlled studies comparing the use of elemental and polymeric diets as primary therapy in Crohn's disease have, however, also produced conflicting results. The results of one recent controlled trial in which

Implementation of raltegravir in routine clinical practice: selection criteria for choosing this drug, virologic response rates, and characteristics of failures.

BACKGROUND: Raltegravir (RAL) achieved remarkable virologic suppression rates in randomized-clinical trials, but today efficacy data and factors for treatment failures in a routine clinical care setting are limited. METHODS: First, factors associated with a switch to RAL were identified with a logistic regression including patients from the Swiss HIV Cohort Study with a history of 3 class failure (n = 423). Second, predictors for virologic outcome were identified in an intent-to-treat analysis including all patients who received RAL. Last observation carried forward imputation was used to determine week 24 response rate (HIV-1 RNA >or= 50 copies/mL). RESULTS: The predominant factor associated with a switch to RAL in patients with suppressed baseline RNA was a regimen containing enfuvirtide [odds ratio 41.9 (95% confidence interval: 11.6-151.6)]. Efficacy analysis showed an overall response rate of 80.9% (152/188), whereas 71.8% (84/117) and 95.8% (68/71) showed viral suppression when stratified for detectable and undetectable RNA at baseline, respectively. Overall CD4 cell counts increased significantly by 42 cells/microL (P < 0.001). Characteristics of failures were a genotypic sensitivity score of the background regimen <or=1, very low RAL plasma concentrations, poor adherence, and high viral load at baseline. CONCLUSIONS: Virologic suppression rates in our routine clinical care setting were promising and comparable with data from previously published randomized-controlled trials.

Denervation rénale endovascu- laire par radiofréquence: perspective d'un traitement prometteur de l'hypertension artérielle [Renal sympathetic denervation: perspective of a promising treatment for hypertension].

The crucial role of the sympathetic nervous system activity in the initiation and maintenance of hypertension was already in mind in the 1920s when surgical options were proposed to severely hypertensive patients. Despite constant evolution of pharmacological treatments, one estimates that 15-30% of hypertensive patients are still not well controlled and present resistant hypertension. The development of a new endovascular catheter used for selective sympathetic renal denervation by radiofrequency offers new perspectives of treatment. Encouraged by the recent results of the first clinical trials in a targeted population, this procedure could be used in some more indications in the future. However, long term morbidity and mortality of this technique are still not known.