Hépatite C: traitement actuel [Hepatitis C: current therapy].

Le traitement de l'hépatite C chronique a été révolutionné par l'introduction de nouveaux antiviraux (directly acting antivirals [DAA]). Ces inhibiteurs de protéase, de la protéine NS5A et de la polymérase peuvent être associés dans des traitements oraux hautement efficaces et bien tolérés sans interféron. Dans cet article, nous fournissons un aperçu du traitement actuel de l'hépatite C chronique avec considération particulière des DAA actuellement autorisés en Suisse. Treatment of chronic hepatitis C is currently being revolutionised, with the introduction of directly acting antivirals (DAA), including protease, NS5A and polymerase inhibitors. These can be combined in interferon-free oral therapies with unprecedented efficacy and good tolerance. Here, we review the current therapy of chronic hepatitis C, with a particular focus on DAA that are approved in Switzerland today.

Low-level laser therapy for the prevention of low salivary flow rate after radiotherapy and chemotherapy in patients with head and neck cancer

Abstract Objective: To determine whether low-level laser therapy can prevent salivary hypofunction after radiotherapy and chemotherapy in head and neck cancer patients. Materials and Methods: We evaluated 23 head and neck cancer patients, of whom 13 received laser therapy and 10 received clinical care only. An InGaAlP laser was used intra-orally (at 660 nm and 40 mW) at a mean dose of 10.0 J/cm2 and extra-orally (at 780 nm and 15 mW) at a mean dose of 3.7 J/cm2, three times per week, on alternate days. Stimulated and unstimulated sialometry tests were performed before the first radiotherapy and chemotherapy sessions (N0) and at 30 days after the end of treatment (N30). Results: At N30, the mean salivary flow rates were significantly higher among the laser therapy patients than among the patients who received clinical care only, in the stimulated and unstimulated sialometry tests (p = 0.0131 and p = 0.0143, respectively). Conclusion: Low-level laser therapy, administered concomitantly with radiotherapy and chemotherapy, appears to mitigate treatment-induced salivary hypofunction in patients with head and neck cancer.

The emergence of YMDD mutants precedes biochemical flare by 19 weeks in lamivudine-treated chronic hepatitis B patients: an opportunity for therapy reevaluation

Given the loss of therapeutic efficacy associated with the development of resistance to lamivudine (LMV) and the availability of new alternative treatments for chronic hepatitis B patients, early detection of viral genotypic resistance could allow the clinician to consider therapy modification before viral breakthrough and biochemical relapse occur. To this end, 28 LMV-treated patients (44 ± 12 years; 24 men), on their first therapy schedule, were monitored monthly at four Brazilian centers for the emergence of drug resistance using the reverse hybridization-based INNO-LiPA HBV DR assay and occasionally sequencing (two cases). Positive viral responses (HBV DNA clearance) after 6, 12, and 18 months of therapy were achieved by 57, 68, and 53% of patients, while biochemical responses (serum alanine aminotransferase normalization) were observed in 82, 82, and 53% of cases. All viral breakthrough cases (N = 8) were related to the emergence of YMDD variants observed in 7, 21, and 35% of patients at 6, 12, and 18 months, respectively. The emergence of these variants was not associated with viral genotype, HBeAg expression status, or pretreatment serum alanine aminotransferase levels. The detection of resistance-associated mutations was observed before the corresponding biochemical flare (41 ± 14 and 60 ± 15 weeks) in the same individuals. Then, if highly sensitive LMV drug resistance testing is carried out at frequent and regular intervals, the relatively long period (19 ± 2 weeks) between the emergence of viral resistance and the onset of biochemical relapse can provide clinicians with ample time to re-evaluate drug therapy.

How frequently should a patient taking amiodarone be screened for thyroid dysfunction?

Amiodarone-induced thyroid dysfunction (AITD) is a common complication of amiodarone therapy and its prevalence varies according to iodine intake, subclinical thyroid disorders and the definition of AITD. There is no consensus about the frequency of screening for this condition. We evaluated 121 patients on chronic regular intake of amiodarone (mean intake = 248.5 ± 89 mg; duration of treatment = 5.3 ± 3.9 years, range = 0.57-17 years) and with stable baseline cardiac condition. Those with no AITD were followed up for a median period of 3.2 years (range: 0.6-6.7) and the incidence rate of AITD, defined by clinical and laboratorial findings as proposed by international guidelines, was obtained (62.8 per 1000 patients/year). We applied the Cox proportional hazard model to adjust for potential confounding factors and used sensitivity analysis to identify the best screening time for follow-up. We detected thyroid dysfunction in 59 (48.7%) of the 121 patients, amiodarone-induced hypothyroidism in 50 (41.3%) and hyperthyroidism in 9 (7.5%). Compared with patients without AITD, there was no difference regarding dosage or duration of therapy, heart rhythm disorder or baseline cardiac condition. During the follow-up of the 62 patients without AITD at baseline evaluation, 11 developed AITD (interquartile range, IR: 62.8 (95%CI: 31.3-112.3) cases per 1000 patients/year), 9 of them with hypothyroidism - IR: 11.4 (95%CI: 1.38-41.2), and 2 hyperthyroidism - IR: 51.3 (95%CI: 23.4-97.5). Age, gender, dose, and duration of treatment were not significant after adjustment. During the first 6 months of follow-up the incidence rate for AITD was 39.3 (9.2-61.9) cases per 1000 patients/year. These data show that AITD is quite common, and support the need for screening at 6-month intervals, unless clinical follow-up dictates otherwise or further information regarding the prognosis of untreated subclinical AITD is available.

Polymer-drug conjugates: current status and future trends

Polymer conjugates are nano-sized, multicomponent constructs already in the clinic as anticancer compounds, both as single agents or as elements of combinations. They have the potential to improve pharmacological therapy of a variety of solid tumors. Polymer-drug conjugation promotes passive tumor targeting by the enhanced permeability and retention (EPR) effect and allows for lysosomotropic drug delivery following endocytic capture. In the first part of this review, we analyze the promising results arising from clinical trials of polymer-bound chemotherapy. The experience gained on these studies provides the basis for the development of a more sophisticated second-generation of polymer conjugates. However, many challenges still lay ahead providing scope to develop and refine this field. The "technology platform'' of polymer therapeutics allows the development of both new and exciting polymeric materials, the incorporation of novel bioactive agents and combinations thereof to address recent advances in drug therapy. The rational design of polymer drug conjugates is expected to realize the true potential of these "nanomedicines".

Correlation of the in vitro antifungal drug susceptibility with the in vivo activity of fluconazole in a murine model of cerebral infection caused by Cryptococcus gattii

Forty Cryptococcus gattii strains were submitted to antifungal susceptibility testing with fluconazole, itraconazole, amphotericin B and terbinafine. The minimum inhibitory concentration (MIC) ranges were 0.5-64.0 for fluconazole, < 0.015-0.25 for itraconazole, 0.015-0.5 for amphotericin B and 0.062-2.0 for terbinafine. A bioassay for the quantitation of fluconazole in murine brain tissue was developed. Swiss mice received daily injections of the antifungal, and their brains were withdrawn at different times over the 14-day study period. The drug concentrations varied from 12.98 to 44.60 mu g/mL. This assay was used to evaluate the therapy with fluconazole in a model of infection caused by C. gattii. Swiss mice were infected intracranially and treated with fluconazole for 7, 10 or 14 days. The treatment reduced the fungal burden, but an increase in fungal growth was observed on day 14. The MIC for fluconazole against sequential isolates was 16 mu g/mL, except for the isolates obtained from animals treated for 14 days (MIC = 64 mu g/mL). The quantitation of cytokines revealed a predominance of IFN-gamma and IL-12 in the non-treated group and elevation of IL-4 and IL-10 in the treated group. Our data revealed the possibility of acquired resistance during the antifungal drug therapy.

Light-Emitting Diode Therapy in Chemotherapy-Induced Mucositis

Background and Objective: Mucositis is the most common oral complication of cancer chemotherapy, which causes pain on mastication and swallowing, impairs patients` ability to eat and take oral drugs and may determine interruption of the treatment. The aim of this study was to evaluate the effect of light-emitting diode (LED) therapy on chemotherapy-induced mucositis in hamsters. Study Design/Materials and Methods: Animals of both experimental (Group 1; n = 32) and positive control (Group II; n = 32) groups received intraperitoneal injections of 5-fluorouracil on days 0 and 2. All animals had their right and left cheek pouch irritated by superficial scratching on days 3 and 4. In Group I, LED irradiation (630 nm +/- 10 nm, 160 mW, 12 J/cm(2)) was applied during 37.5 seconds at days 3, 4, 6, 8, 10, 12, and 14. In Group II, mucositis was induced, but LED therapy was not performed. The oral mucosa was photographed from day 4 to 14 at 2-day intervals. Photographs were randomly scored according to the severity of induced mucositis (0 to 5). In the negative control group (Group III; n = 6), no mucositis was induced. Biopsies of the cheek pouches of 8 animals (Group I and Group II) were surgically obtained on days 5, 9, 13 and 15 and processed for histological examination. Results: The statistical analysis showed significant differences between irradiated and non-irradiated groups (P < 0.05). However, muscular degeneration was observed in 18% of the samples of Group I. Conclusion: It may be concluded that the LED therapy protocol established for this in vivo study was effective in reducing the severity of oral mucositis, although the oral lesions were not completely prevented. Lasers Surg. Med. 40:625-633, 2008. (c) 2008Wiley-Liss, Inc.

Light-Emitting Diode Therapy in Chemotherapy-Induced Mucositis

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Comparison of clinical features and drug therapies among European and Latin American patients with juvenile dermatomyositis

ObjectiveTo compare the demographic features, presenting manifestations, diagnostic investigations, disease course, and drug therapies of children with juvenile dermatomyositis (JDM) followed in Europe and Latin America.MethodsPatients were inception cohorts seen between 1980 and 2004 in 27 paediatric rheumatology centres. The following information was collected through the review of patient charts: sex; age at disease onset; date of disease onset and diagnosis; onset type; presenting clinical features; diagnostic investigations; course type; and medications received during disease course.ResultsFour hundred and ninety patients (65.5% females, mean onset age 7.0 years, mean disease duration 7.7 years) were included. Disease presentation was acute or insidious in 57.1% and 42.9% of the patients, respectively. The course type was monophasic in 41.3% of patients and chronic polycyclic or continuous in 58.6% of patients. The more common presenting manifestations were muscle weakness (84.9%), Gottron's papules (72.9%), heliotrope rash (62%), and malar rash (56.7%). Overall, the demographic and clinical features of the 2 continental cohorts were comparable. European patients received more frequently high-dose intravenous methylprednisolone, cyclosporine, cyclophosphamide, and azathioprine, while methotrexate and antimalarials medications were used more commonly by Latin American physicians.ConclusionThe demographic and clinical characteristics of JDM are similar in European and Latin American patients. We found, however, several differences in the use of medications between European and Latin American paediatric rheumatologists.

ACAO ANTIARRITMICA DA METOCLOPRAMIDA (PLASIL®) EM INTOXICACAO DIGITALICA EXPERIMENTAL. COMPARACAO COM A DIFENIL-HIDANTOINA

The antiarrhythmic action of metoclopramide in cardiac arrhythmias caused by toxic doses of desacetyl-lanatoside C and digitoxin was studied in dogs. A comparison was made between the efficacy of metoclopramide and diphenylhydantoin in arrhythmias caused by digitoxin. The results indicate that metoclopramide antagonized the arrhythmias induced by desacetyl-lanatoside C, while causing a transitory reversion of those induced by digitoxin in most of the experiments. Diphenylhydantoin failed to show an arrhythmic effect in the majority of the tested animals.

A comparative evaluation of open loop and closed loop drug administration strategies in the treatment of AIDS.

In recent years, many researchers in the field of biomedical sciences have made successful use of mathematical models to study, in a quantitative way, a multitude of phenomena such as those found in disease dynamics, control of physiological systems, optimization of drug therapy, economics of the preventive medicine and many other applications. The availability of good dynamic models have been providing means for simulation and design of novel control strategies in the context of biological events. This work concerns a particular model related to HIV infection dynamics which is used to allow a comparative evaluation of schemes for treatment of AIDS patients. The mathematical model adopted in this work was proposed by Nowak & Bangham, 1996 and describes the dynamics of viral concentration in terms of interaction with CD4 cells and the cytotoxic T lymphocytes, which are responsible for the defense of the organism. Two conceptually distinct techniques for drug therapy are analyzed: Open Loop Treatment, where a priori fixed dosage is prescribed and Closed Loop Treatment, where the doses are adjusted according to results obtained by laboratory analysis. Simulation results show that the Closed Loop Scheme can achieve improved quality of the treatment in terms of reduction in the viral load and quantity of administered drugs, but with the inconvenience related to the necessity of frequent and periodic laboratory analysis.

Efficacy of hormone therapy with and without methyltestosterone augmentation of venlafaxine in the treatment of postmenopausal depression: A double-blind controlled pilot study

Objective: This study evaluated the augmentation of venlafaxine with hormone therapy in the treatment of postmenopausal depression. The hormones evaluated were estrogen (0.625 mg) in combination with medroxyprogesterone acetate (2.5 mg) and methyltestosterone (2.5 mg). Design: Seventy-two menopausal women (mean age: 53.6 ± 4.27 years) diagnosed with depression (Montgomery-Åsberg Depression Rating Scale [MADRS] scores ≥ 20) were treated with venlafaxine and one of the following hormone therapy combinations, in a double-blind regimen: estrogen + medroxyprogesterone + methyltestosterone (group 1, n = 20); estrogen + medroxyprogesterone acetate (group 2, n = 20); methyltestosterone only (group 3, n = 16); and no hormone therapy (group 4, n = 16). Study duration was 24 weeks. Primary efficacy outcome was remission according to the MADRS, whereas secondary efficacy measures included the Clinical Global Impression (CGI), Blatt-Kupperman Index, and Women's Health Questionnaire (WHQ). Results: Forty-eight patients completed the study. All groups showed significant improvement from baseline. Group 3 demonstrated significant improvement on the MADRS compared with placebo (group 4) at weeks 20 (P = 0.048) and 24 (P = 0.030); effect size 8.04 (0.83; 15.26) (P = 0.029), but also had the highest dropout rate. Groups 1 and 3 had significant CGI improvement rates compared with placebo: 42.23% (P = 0.012) and 44.45% (P = 0.08), respectively. There were no differences in the WHQ or BKI scores among the groups. Conclusions: Methyltestosterone 2.5 mg had the highest effect size compared with placebo, but the high dropout rate prevented its efficacy from being determined. Estrogen plus medroxyprogesterone, combined with methyltestosterone or otherwise, demonstrated a trend toward increased efficacy of venlafaxine. Further larger-scale clinical trials are needed to elucidate the findings of this pilot study. © 2006 by The North American Menopause Society.

Effects of Chronic Stress and Alendronate Therapy on the Osseointegration of Titanium Implants

Purposes: The purposes of this study were to evaluate the influence of chronic stress (CS) on implant osseointegration and also to analyze whether alendronate (ALN) therapy could prevent these eventual stress-negative effects. Materials and Methods: Adult male Holtzmann rats were assigned to one of the four experimental groups: AL (ALN; 1mg/kg/week; n=12), ALS (ALN+CS; 1mg/kg/week; n=12), CTL (sterile physiological saline; n=12), or CTLS (sterile physiological saline+CS; n=12). After 58 days of drug therapy, the ALS and CTLS groups were exposed to CS, and 2 days later all animals underwent tibial implant installation. The animals were euthanized 28 days following the operative surgical procedure. Results: It was observed that the CTLS group presented an impairment of bone metabolism represented by lowest levels of bone-specific alkaline phosphatase and bone area fraction occupancy values. Furthermore, these animals presented a higher proportion of empty osteocytic lacunae. In contrast, the ALN therapy showed increased osseointegration and torque value parameters, regardless of stress exposition. Conclusions: Analysis of the data presented suggests that CS partially impairs the osseointegration of tibial implants and that ALN therapy is able to prevent these negative effects. © 2013 Wiley Periodicals, Inc.

Influence of clinical therapy and nutritional counseling on the recurrence of urolithiasis

PURPOSE: To evaluate the influence of combined clinical therapy and nutritional guidance on the recurrence of urolithiasis. METHODS: From our registry of patients with recurrent urolithiasis we selected 57 who had at least 5-years of follow-up. We collected 24h urine samples in order to analyze Ca, Na, uric acid, citrate, oxalate, and Mg concentrations and to assess urine volume. Patients filled out a clinical questionnaire before treatment, and abdominal radiographs and/or ultrasound were performed both before treatment and during the follow-up period. During follow-up, specific and individualized dietary advice was given based on the individual's metabolic disorders. Patients also received specific pharmacological treatment for their metabolic alterations. Outcome measures were metabolites in urine and the urolith recurrence rate. Pre- and post- intervention values were compared using tests as appropriate. RESULTS: Fifty six of the patients were male and the majority of patients were overweight. The mean BMI was 27 kg/m2. Urinary excretion of calcium, uric acid and sodium decreased significantly over the five year follow-up period. The number of uroliths that formed during the 5-year follow-up also decreased significantly compared to pre-treatment values. CONCLUSION: Individualized dietary advice combined with pharmacological treatment significantly reduces long-term urolithiasis recurrence.