Efficacy and safety of certolizumab pegol in an unselected crohn's disease population: 26-week data of the FACTS II survey.

BACKGROUND: Certolizumab pegol (Cimzia, CZP) was approved for the treatment of Crohn's disease (CD) patients in 2007 in Switzerland as the first country worldwide. This prospective phase IV study aimed to evaluate the efficacy and safety of CZP over 26 weeks in a multicenter cohort of practice-based patients. METHODS: Evaluation questionnaires at baseline, week 6, and week 26 were completed by gastroenterologists in hospitals and private practices. Adverse events were evaluated according to World Health Organization (WHO) guidelines. RESULTS: Sixty patients (38F/22M) were included; 53% had complicated disease (stricturing or penetrating), 45% had undergone prior CD-related surgery. All patients had prior exposure to systemic steroids, 96% to immunomodulators, 73% to infliximab, and 43% to adalimumab. A significant decrease of the Harvey-Bradshaw Index (HBI) was observed under CZP therapy (12.2 ± 4.9 at week 0 versus 6.3 ± 4.7 at week 6 and 6.7 ± 5.3 at week 26, both P < 0.001). Response and remission rates were 70% and 40% (week 6) and 67% and 36%, respectively (week 26). The complete perianal fistula closure rate was 36% at week 6 and 55% at week 26. The frequency of adverse drug reactions attributed to CZP was 5%. CZP was continued in 88% of patients beyond week 6 and in 67% beyond week 26. CONCLUSIONS: In a population of CD patients with predominantly complicated disease behavior, CZP proved to be effective in induction and maintenance of response and remission. This series provides the first evidence of CZP's effectiveness in perianal fistulizing CD in clinical practice.

Colloidal systems for the delivery of cyclosporin A to the anterior segment of the eye.

Due to the eye's specific anatomical and physiological conformation, the treatment of eye diseases is a real challenge for pharmaceutical therapy. The presence of efficient protective barriers (i.e., the conjunctival and corneal membranes) and protective mechanisms (i.e., blinking and nasolachrymal drainage) makes this organ particularly impervious to local drug therapy. To overcome these issues, numerous strategies have been envisioned using pharmaceutical technology. Many formulations currently on the market or still under development are emulsions or colloidal systems intended to enhance precorneal residence time and corneal penetration, causing a consequent increase in drug bioavailability after instillation. After a review of some recent developments in the field of cyclosporin A formulations for the eye, a novel micellar formulation of cyclosporine A based on a diblock methoxy-poly(ethylene glycol)-hexysubstituted poly(lactides) (MPEG-hexPLA) is described.

Hépatite D:oubliée mais pas disparue [Hepatitis D: forgotten but not gone].

Hepatitis D virus (HDV) is a subviral agent which depends on the envelope proteins (HBsAg) of hepatitis B virus (HBV). Therefore, hepatitis D is observed only in patients infected with HBV. Chronic hepatitis D is the least frequent albeit most severe form of chronic viral hepatitis. A resurgence of chronic hepatitis D has been observed in Northern and Central Europe, mainly due to immigration of patients from regions with high prevalence. Every HBsAg-positive patient should be screened for concurrent HDV infection. Standard treatment consists of pegylated interferon-alpha for at least one year. Sustained virological response rates are approximately 20%. Liver transplantation should be considered in patients with advanced cirrhosis or limited hepatocellular carcinoma. Preventive measures for hepatitis D are the same as for hepatitis B.

Neurologie [Neurology].

In 2011, new oral anticoagulants for atrial fibrillation are available and the ABCD3-I score predicting stroke after TIA updates the ABCD2 score. New McDonald criteria allow faster MS diagnosis and the first oral treatment (fingolimod) for MS can be prescribed. A new anti-antiepileptic drug (retigabine) is available and sodium valproate has long term neurological adverse effects after in utero exposure. Among Parkinson disease treatments, deep brain stimulation is extending applications and dopamine agonists with extended release are as efficient and well tolerated as standard forms at long term scale. Monoclonal antibodies and immunosuppressant agents are proposed as good alternatives in the treatment of chronic dysimmune polyneuropathies. Gene therapy for the treatment of genetic myopathies is progressing.

Sensitive headspace gas chromatography analysis of free and conjugated 1-methoxy-2-propanol in urine

Glycol ethers still continue to be a workplace hazard due to their important use on an industrial scale. Currently, chronic occupational exposures to low levels of xenobiotics become increasingly relevant. Thus, sensitive analytical methods for detecting biomarkers of exposure are of interest in the field of occupational exposure assessment. 1-Methoxy-2-propanol (1M2P) is one of the dominant glycol ethers and the unmetabolized urinary fraction has been identified to be a good biological indicator of exposure. An existing analytical method including a solid-phase extraction and derivatization before GC/FID analysis is available but presents some disadvantages. We present here an alternative method for the determination of urinary 1M2P based on the headspace gas chromatography technique. We determined the 1M2P values by the direct headspace method for 47 samples that had previously been assayed by the solid-phase extraction and derivatization gas chromatography procedure. An inter-method comparison based on a Bland-Altman analysis showed that both techniques can be used interchangeably. The alternative method showed a tenfold lower limit of detection (0.1 mg/L) as well as good accuracy and precision which were determined by several urinary 1M2P analyses carried out on a series of urine samples obtained from a human volunteer study. The within- and between-run precisions were generally about 10%, which corresponds to the usual injection variability. We observed that the differences between the results obtained with both methods are not clinically relevant in comparison to the current biological exposure index of urinary 1M2P. Accordingly, the headspace gas chromatography technique turned out to be a more sensitive, accurate, and simple method for the determination of urinary 1M2P.[Authors]

Long circulating half-life and high tumor selectivity of the photosensitizer meta-tetrahydroxyphenylchlorin conjugated to polyethylene glycol in nude mice grafted with a human colon carcinoma.

In a mode of nude mice bearing a human colon carcinoma xenograft, the biodistribution and tumor localization of metatetrahydroxyphenylchlorin (m-THPC) coupled to polyethylene glycol (PEG) were compared with those of the free form of this photosensitizer used in photodynamic therapy (PDT). At different times after i.v. injection of both forms of 125I-labeled photosensitizer, m-THPC-PEG gave on average a 2-fold higher tumor uptake than free m-THPC. In addition, at early times after injection, m-THPC-PEG showed a 2-fold longer blood circulating half-life and a 4-fold lower liver uptake than free m-THPC. The tumor to normal tissue ratios of radioactivity concentrations were always higher for m-THPC-PEG than for free m-THPC at any time point studied from 2 to 96 hr post-injection. Significant coefficients of correlation between direct fluorescence measurements and radioactivity counting were obtained within each organ tested. Fluorescence microscopy studies showed that m-THPC-PEG was preferentially localized near the tumor vessels, whereas m-THPC was more diffusely distributed inside the tumor tissue. To verify whether m-THPC-PEG conjugate remained phototoxic in vivo, PDT experiments were performed 72 hr after injection and showed that m-THPC-PEG was as potent as free m-THPC in the induction of tumor regression provided that the irradiation does for m-THPC-PEG conjugate was adapted to a well-tolerated 2-fold higher level. The overall results demonstrate first the possibility of improving the in vivo tumor localization of a hydrophobic dye used for PDT by coupling it to PEG and second that a photosensitizer conjugated to a macromolecule can remain phototoxic in vivo.

Influence of IL28B polymorphisms on response to a lower-than-standard dose peg-IFN-α 2a for genotype 3 chronic hepatitis C in HIV-coinfected patients.

BACKGROUND Data on which to base definitive recommendations on the doses and duration of therapy for genotype 3 HCV/HIV-coinfected patients are scarce. We evaluated the efficacy of a lower peginterferon-α 2a dose and a shorter duration of therapy than the current standard of care in genotype 3 HCV/HIV-coinfected patients. METHODS AND FINDINGS Pilot, open-label, single arm clinical trial which involved 58 Caucasian HCV/HIV-coinfected patients who received weekly 135 µg peginterferon-α 2a plus ribavirin 400 mg twice daily during 20 weeks after attaining undetectable viremia. The relationships between baseline patient-related variables, including IL28B genotype, plasma HCV-RNA, ribavirin dose/kg, peginterferon-α 2a and ribavirin levels with virological responses were analyzed. Only 4 patients showed lack of response and 5 patients dropped out due to adverse events related to the study medication. Overall, sustained virologic response (SVR) rates were 58.3% by intention-to-treat and 71.4% by per protocol analysis, respectively. Among patients with rapid virologic response (RVR), SVR and relapses rates were 92.6% and 7.4%, respectively. No relationships were observed between viral responses and ribavirin dose/kg, peginterferon-α 2a concentrations, ribavirin levels or rs129679860 genotype. CONCLUSIONS Weekly 135 µg pegIFN-α 2a could be as effective as the standard 180 µg dose, with a very low incidence of severe adverse events. A 24-week treatment duration appears to be appropriate in patients achieving RVR, but extending treatment up to just 20 weeks beyond negativization of viremia is associated with a high relapse rate in those patients not achieving RVR. There was no influence of IL28B genotype on the virological responses.

Off-label uses of anti-TNF therapy in three frequent disorders: Behçet's disease, sarcoidosis, and noninfectious uveitis.

Tumoral necrosis factor α plays a central role in both the inflammatory response and that of the immune system. Thus, its blockade with the so-called anti-TNF agents (infliximab, etanercept, adalimumab, certolizumab pegol, and golimumab) has turned into the most important tool in the management of a variety of disorders, such as rheumatoid arthritis, spondyloarthropatties, inflammatory bowel disease, and psoriasis. Nonetheless, theoretically, some other autoimmune disorders may benefit from these agents. Our aim is to review these off-label uses of anti-TNF blockers in three common conditions: Behçet's disease, sarcoidosis, and noninfectious uveitis. Due to the insufficient number of adequate clinical trials and consequently to their lower prevalence compared to other immune disorders, this review is mainly based on case reports and case series.

Que faire des nouveaux anti-épileptiques [Clinical utilization of new anti-epileptic agents].

Since the beginning of the 1990's, a dozen of new anti-epileptic drugs have been on the market or will be soon. This article reviews the daily clinical utilisation of new anti-epileptic drugs. It considers, without being complete, the current opinions and tendencies. The new anti-epileptic substances are generally as efficient as conventional medications. However, they are better tolerated and are more easily used in combination with conventional anti-epileptic drugs. Polytherapy is certainly the form of treatment, which is used in the most cases of resistant epilepsies. The surgical treatment can be used in only a very limited number of cases. The objective of treatment is the complete control of seizures, with minimum secondary effects. Though this objective is rarely reached, the NAE significantly improves the quality of life of patients suffering from severe epilepsy. The utilisation of NAE is not without risk. Increase in the frequency and severity of seizures may occur; we should remember that severe adverse effects appeared in the post-marketing period of the use of Vigabatrine and Felbamate. Therefore, we must remain vigilant in the clinical use of the anti-epileptic drugs.

Immune cell impact of three differently coated lipid nanocapsules: pluronic, chitosan and polyethylene glycol.

Lipid nanocapsules (NCs) represent promising tools in clinical practice for diagnosis and therapy applications. However, the NC appropriate functionalization is essential to guarantee high biocompatibility and molecule loading ability. In any medical application, the immune system-impact of differently functionalized NCs still remains to be fully understood. A comprehensive study on the action exerted on human peripheral blood mononuclear cells (PBMCs) and major immune subpopulations by three different NC coatings: pluronic, chitosan and polyethylene glycol-polylactic acid (PEG) is reported. After a deep particle characterization, the uptake was assessed by flow-cytometry and confocal microscopy, focusing then on apoptosis, necrosis and proliferation impact in T cells and monocytes. Cell functionality by cell diameter variations, different activation marker analysis and cytokine assays were performed. We demonstrated that the NCs impact on the immune cell response is strongly correlated to their coating. Pluronic-NCs were able to induce immunomodulation of innate immunity inducing monocyte activations. Immunomodulation was observed in monocytes and T lymphocytes treated with Chitosan-NCs. Conversely, PEG-NCs were completely inert. These findings are of particular value towards a pre-selection of specific NC coatings depending on biomedical purposes for pre-clinical investigations; i.e. the immune-specific action of particular NC coating can be excellent for immunotherapy applications.

Treatment of hepatitis C in HCV mono-infected and in HIV-HCV co-infected patients: an open-labelled comparison study.

BACKGROUND/AIMS: Treatment of chronic HCV infection has become a priority in HIV+ patients, given the faster progression to end-stage liver disease. The primary endpoint of this study was to evaluate and compare antiviral efficacy of Peginterferon alpha 2a plus ribavirin in HIV-HCV co-infected and HCV mono-infected patients, and to examine whether 6 months of therapy would have the same efficacy in HIV patients with favourable genotypes 2 and 3 as in mono-infected patients, to minimise HCV-therapy-related toxicities. Secondary endpoints were to evaluate predictors of sustained virological response (SVR) and frequency of side-effects. METHODS: Patients with genotypes 1 and 4 were treated for 48 weeks with Pegasys 180 microg/week plus Copegus 1000-1200 mg/day according to body weight; patients with genotypes 2 and 3 for 24 weeks with Pegasys 180 microg/week plus Copegus 800 mg/day. RESULTS: 132 patients were enrolled in the study: 85 HCV mono-infected (38: genotypes 1 and 4; 47: genotypes 2 and 3), 47 HIV-HCV co-infected patients (23: genotypes 1 and 4; 24: genotypes 2 and 3). In an intention-to-treat analysis, SVR for genotypes 1 and 4 was observed in 58% of HCV mono-infected and in 13% of HIV-HCV co-infected patients (P = 0.001). For genotypes 2 and 3, SVR was observed in 70% of HCV mono-infected and in 67% of HIV-HCV co-infected patients (P = 0.973). Undetectable HCV-RNA at week 4 had a positive predictive value for SVR for mono-infected patients with genotypes 1 and 4 of 0.78 (95% CI: 0.54-0.93) and of 0.81 (95% CI: 0.64-0.92) for genotypes 2 and 3. For co-infected patients with genotypes 2 and 3, the positive predictive value of SVR of undetectable HCV-RNA at week 4 was 0.76 (95%CI, 0.50-0.93). Study not completed by 22 patients (36%): genotypes 1 and 4 and by 12 patients (17%): genotypes 2 and 3. CONCLUSION: Genotypes 2 or 3 predict the likelihood of SVR in HCV mono-infected and in HIV-HCV co-infected patients. A 6-month treatment with Peginterferon alpha 2a plus ribavirin has the same efficacy in HIV-HCV co-infected patients with genotypes 2 and 3 as in mono-infected patients. HCV-RNA negativity at 4 weeks has a positive predictive value for SVR. Aggressive treatment of adverse effects to avoid dose reduction, consent withdrawal or drop-out is crucial to increase the rate of SVR, especially when duration of treatment is 48 weeks. Sixty-one percent of HIV-HCV co-infected patients with genotypes 1 and 4 did not complete the study against 4% with genotypes 2 and 3.

Effect of age on toxicokinetics among human volunteers exposed to propylene glycol methyl ether (PGME)

Aging adults represent the fastest growing population segment in many countries. Physiological and metabolic changes in the aging process may alter how aging adults biologically respond to pollutants. In a controlled human toxicokinetic study (exposure chamber; 12 m³), aging volunteers (n=10; >58 years) were exposed to propylene glycol monomethyl ether (PGME, CAS no. 107-98-2) at 50 ppm for 6 h. The dose-dependent renal excretion of oxidative metabolites, conjugated and free PGME could potentially be altered by age. AIMS: (1) Compare PGME toxicokinetic profiles between aging and young volunteers (20-25 years) and gender; (2) test the predictive power of a compartmental toxicokinetic (TK) model developed for aging persons against urinary PGME concentrations found in this study. METHODS: Urine samples were collected before, during, and after the exposure. Urinary PGME was quantified by capillary GC/FID. RESULTS: Differences in urinary PGME profiles were not noted between genders but between age groups. Metabolic parameters had to be changed to fit the age adjusted TK model to the experimental results, implying a slower enzymatic pathway in the aging volunteers. For an appropriate exposure assessment, urinary total PGME should be quantified. CONCLUSION: Age is a factor that should be considered when biological limit values are developed.

Maladies inflammatoires de l'intestin [Main therapeutic advances in IBD in 2007].

In 2008 three biological agents against TNFalpha will be available. The combination of infliximab with azathioprine is no longer recommended, as hepatosplenic lymphomas with a particularly bad prognosis have been associated with this combined therapy. Regular maintenance therapy with infliximab is as effective in preventing the development of anti-infliximab antibodies as co-administration of this anti-TNFalpha agent with an immunomodulator. The benefit of regular maintenance therapy is probably linked to the presence of residual trough levels of infliximab between perfusions.