Switching to emtricitabine, tenofovir and rilpivirine as single tablet regimen in virologically suppressed HIV-1-infected patients: a cohort study.

OBJECTIVES: Emtricitabine/tenofovir/rilpivirine as a single-tablet regimen (STR) is widely used without licence in treatment-experienced patients. The purpose of this retrospective observational study was to assess viral suppression of ART-experienced patients switching to STR. METHODS: We assessed 131 pretreated patients switching to STR with HIV RNA <400 HIV-1 RNA copies/mL. The primary outcome measure was the proportion of patients at week 24 with HIV RNA <40 copies/mL. RESULTS: By week 24, eight patients had stopped STR: four because of adverse events and four for other reasons. Three virological failures were observed; among these, at least one patient developed cross-resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs), in particular with the E138K pattern. In intent-to-treat analysis, 92% of participants (120 of 131) achieved HIV RNA <40 copies/mL. Only grade 1 to 2 adverse events were observed, mainly consisting of increased liver enzymes (n=33). Systemic exposure to rilpivirine was above the usually observed steady-state levels for the 18 measurements assessed. CONCLUSIONS: Efficacy and tolerability are similar to those in treatment-naïve patients.

Penetration of daptomycin into bone and synovial fluid in joint replacement.

Daptomycin exhibits clinical activity in the treatment of infections with Gram-positive organisms, including infections due to methicillin-resistant Staphylococcus aureus. However, little is known about its penetration into bone and synovial fluid. The aim of our study was to assess the penetration of daptomycin into bone and synovial fluid after a single intravenous administration. This study was conducted in 16 patients who underwent knee or hip replacement and received a single intravenous dose of 8 mg of daptomycin per kg of body weight prior to surgery. Plasma daptomycin concentrations were measured 1 h after the end of daptomycin infusion and when bone fragments were removed. Daptomycin concentrations were also measured on bone fragments and synovial fluid collected at the same time during surgery. All samples were analyzed with a diode array-high-performance liquid chromatography (HPLC) method. After a single-dose intravenous infusion, bone daptomycin concentrations were above the MIC of daptomycin for Staphylococcus aureus in all subjects, and the median bone penetration percentage was 9.0% (interquartile range [IQR], 4.4 to 11.4). These results support the use of daptomycin in the treatment of Staphylococcus aureus bone and joint infections.

Development of an in vitro fibrin clot model to evaluate fibrinolytic agents for wound care application.

OBJECTIVE: To describe an in vitro fibrin clot model that could reliably assess the fibrinolytic activity of enzymatic debriding agents for wound care application. METHOD: A model of a fibrin clot was reconstructed in vitro by mixture of human fibrinogen and (alpha)-thrombin supplemented with factor XIII. These clots were then treated with enzymatic ointments. Fibrinolytic activity was investigated by measuring D-dimer levels, using an automated immunoturbidimetric Liatest D-dimer assay. RESULTS: Collagenase and papain-urea ointments demonstrated fibrinolytic activity which was macroscopically visible. Their effect was identical on the in vitro reconstructed fibrin clot and ex vivo collected wound fibrin clot; collagenase and papain-urea both induced a complete degradation and dissolution of both fibrin clots after 24 hours of treatment. This was associated with an increase in D-dimer concentration. CONCLUSION: This reconstructed fibrin clot in vitro model has the potential to predict the efficacy of fibrinolytic agents and therefore appears to be a suitable model for in vitro assays. DECLARATION OF INTEREST: This study was supported by a grant from URGO Laboratory.

Can leg ulcer fibroblasts phenotype be influenced by human amniotic membrane extract?

Prevalence of leg ulcer in general population is important and new efficient treatments are now needed, especially for chronic leg ulcers. Human amniotic membrane (HAM) can be used as an alternative treatment for recalcitrant leg ulcers. The aim of this study is to investigate the effects of a HAM extract on normal fibroblasts (NF) and ulcer fibroblasts (UF). NF and UF were obtained from biopsies by explants technique. HAM extract was used at 10 µg of total proteins per ml. Single patient-matched NF and UF were compared, without or with HAM extract. Studied parameters were proliferation rate, retraction of free-floating lattices, alpha smooth muscle actin expression by flow cytometry, and synthesis of elastin, glycosaminoglycans (GAGs), pro-collagen I, MMP-1 and TIMP-1. Our results show that UF had a specific phenotype compared to NF: low proliferation, high expression of alpha-SM actin and high synthesis of MMP-1, TIMP-1 and elastin. HAM extract significantly increased the synthesis of GAGs, pro-collagen I and MMP-1 in NF and decreased retraction of free lattices. HAM extract transiently increased UF proliferation, slowed down lattices retraction and decreased elastin synthesis. In conclusion, HAM extract has little effect on UF for the parameters studied and NF are more responsive than UF. However, clinical beneficial effect of HAM application on leg ulcers was previously observed and might rather be related to an action on keratinocytes and/or a modulation of the highly inflammatory environment of these chronic wounds.

Microclimate next to the skin: influence on percutaneous absorption of caffeine (ex-vivo study).

BACKGROUND/PURPOSE: Contact between skin surface and external environment induces a microclimate at the skin surface. That microclimate affects skin interaction with xenobiotics substances. We have developed a new device to explore the influence of environmental parameters, on percutaneous absorption. The aim of this study was to study the influence of external humidity and temperature on percutaneous absorption of caffeine. METHODS: Six exposure conditions were tested: four by combining two temperatures (27°C and 42°C) with two relative humidities (28% and 70%), performed by our device and two others by using Franz diffusion cell (unoccluded conditions, with skin surface in contact with ambient laboratory environment (27°C/33%) and in occluded conditions with skin surface covering by impermeable membrane). RESULTS: Kinetic curve profile of percutaneous absorption of caffeine revealed different shapes characteristics depending on environmental exposure conditions. These profiles were related to evaporative process, of deposited preparation on skin surface combined with water uptake resulting from water flux through skin. CONCLUSION: Our results highlight a preponderant role of microclimate above the skin on percutaneous absorption of caffeine. The device used in this study will be a useful tool to investigate ex vivo, the influence of microclimate on percutaneous absorption.

Assessment of the efficacy of a new formulation for plantar wart mummification: new experimental design and human papillomavirus identification.

Cutaneous warts are caused by infection of the epidermis with human papillomavirus (HPV). Cryotherapy using liquid nitrogen is one of the most common local treatments. In this study, we used a novel ex vivo approach to compare the efficacy of a new product with conventional liquid-nitrogen cryotherapy by studying epidermal histology and assessing the presence of HPV types 1 and 2 DNA in plantar warts. The studied formulation, which acts by tissues mummification, is a combination of nitric acid, organic acids and metallic salts. We found that, similar to liquid nitrogen, the studied product induced alterations in the wart structure. In addition, unlike liquid nitrogen, this product also reduced the amount of HPV DNA. The results suggest that there is a poor correlation between the histological response and the antiviral efficacy of standard wart treatment.

Intraperitoneal clearance as a potential biomarker of cisplatin after intraperitoneal perioperative chemotherapy: a population pharmacokinetic study.

BACKGROUND: Intraperitoneal (IP) perioperative chemotherapy with cisplatin is an interesting option in ovarian cancer treatment. A combination of cisplatin with IP epinephrine (already shown to improve IP and decrease systemic platinum (Pt) exposure) was evaluated using a population pharmacokinetic analysis. METHODS: Data from 55 patients treated with cisplatin-based IP perioperative chemotherapy with (n=26) or without (n=29) epinephrine were analysed using NONMEM. RESULTS: Epinephrine halves clearance between peritoneum and serum (IPCL) and increases the Pt central volume of distribution, IP exposure and penetration in tissue. IPCL has a better predictive value than any other parameter with respect to renal toxicity. CONCLUSION: This confirms that IPCL could be useful in assessing renal toxicity. As IPCL is also linked to tissue penetration and IP exposure, it may be proposed as biomarker. In addition to a Bayesian estimation, we propose a single-sample calculation-way to assess it. Prospective studies are needed to validate IPCL as a biomarker in this context.

[Human amniotic membrane in the management of chronic venous leg ulcers]. / La membrane amniotique humaine dans la prise en charge des ulcères de jambe veineux chroniques.

BACKGROUND: The aim of our paper is to examine changes in the use of human amniotic membrane for venous leg ulcers through clinical studies and to present different models of tissue engineering employing human amniotic membrane for the purpose of future therapeutic use in wound healing. MATERIALS AND METHODS: This review is based on information obtained from a PubMed search using the following keywords "Amnion"[Mesh] AND "Leg Ulcer"[Mesh]; "Amnion"[Mesh] AND "Dermatology"[Mesh]. The selected articles are in English or French and deal with the sole use of human amniotic membrane in venous leg ulcers alone. RESULTS: Human amniotic membrane has a positive impact on chronic venous leg ulcers by promoting granulation tissue formation, reducing fibrosis and inducing re-epithelialisation. Nevertheless, further randomized clinical studies are needed. At the same time, tissue engineering models using human amniotic membrane may help to reduce wound healing time, thereby creating renewed interest in the use of human amniotic membrane. CONCLUSION: Considering its properties and the clinical studies analysed, human amniotic membrane could be useful in venous leg ulcer care.

Ceramide analogue 14S24 selectively recovers perturbed human skin barrier.

BACKGROUND: Topical ceramide application is an effective therapeutic approach in skin disorders with disturbed barrier function, including atopic dermatitis and psoriasis. OBJECTIVES: To evaluate ceramide analogue N-tetracosanoyl-(l)-serine tetradecyl ester (14S24) using a novel ex vivo model. METHODS: Freshly excised human skin was disrupted by lipid extraction, tape stripping and sodium lauryl sulphate (SLS) treatment. Barrier perturbation was evaluated by the measurement of transepidermal water loss (TEWL), skin hydration and the penetration of model compound, theophylline (TH), assessed by microdialysis. The effect of topical 5% 14S24 was compared with a commercial formulation containing a skin lipid mixture (LR) and control formulation with no skin lipids (L). RESULTS: Both LR and 14S24 produced significant recovery of TEWL and TH penetration in extracted and tape-stripped skin with 14S24 being significantly more effective. In SLS-treated skin, 14S24 decreased TEWL but not TH penetration; LR was inactive. L improved skin hydration but not barrier characteristics. Weak correlation between TEWL and TH penetration was observed in extracted and tape-stripped skin but not in SLS-treated skin. CONCLUSIONS: Cutaneous microdialysis can serve as a useful tool for the evaluation of skin barrier recovery by topical formulations ex vivo whereas TEWL may not be an appropriate measure of skin barrier function in such studies. The excellent barrier repair activity of 14S24 could be beneficial in skin disorders with ceramide deficiency.

[Monitoring free flaps with cutaneous microdialysis: preliminary study in oral cavity reconstruction]. / Microdialyse cutanée des lambeaux libres: étude préliminaire dans la reconstruction de la cavité buccale.

INTRODUCTION: Postoperative monitoring of free flaps with microdialysis allows early diagnosis of anastomotic complications. Feasibi-lity studies are required to examine flap accessibility for oral cavity reconstruction. CASES: We present our preliminary findings in two patients who underwent radial free flap reconstruction of the floor of the mouth. For the first patient, a microprobe was used to monitor the flap for 45 hours. In the second case, an abdominal microprobe served as a control in healthy skin with another probe located in the cutaneous flap for 4 days. Flap monitoring, starting from the recovery room, was successful with easy manipulations for the nurse. Correlation between the monitoring curves and the clinical aspect of the flap was excellent. DISCUSSION: The microprobe should be short (1 cm), and carefully anchored. Naso-gastric feeding is required during monitoring. A close correlation has been found between glucose level and systolic pressure. The use of a comparative microprobe in healthy abdominal skin is helpful in learning to use the dialysis curves.

[Microdialysis of cutaneous free flaps to monitor results of maxillofacial surgery]. / Microdialyse et monitorage des lambeaux libres à palette cutanée en chirurgie maxillo-faciale.

The development of in vivo microdialysis has made it possible to monitor cutaneous free flaps in maxillo-facial surgery. A microprobe inserted in the free flap dermis collects a microdialysate enabling measurement of dermal metabolites such as glucose, lactate, pyruvate, or glycerol. The monitoring curves are predictive of ischemia-related tissue injury. Hourly measurements provide a reliable method for early diagnosis of venous or arterial thrombosis. Revision surgery can then be undertaken if needed to repair microanastomoses before clinical alteration. This technique has been compared with validated flaps monitoring systems such as temperature probe, transcutaneous oxygen tension monitoring, and laser Doppler flowmetry. Microdialysis has several advantages: objective measurements, different curves for venous and arterial thrombosis, early diagnosis. Accessibility to oral cavity or pharyngeal flaps requires careful clinical analysis (microprobe fixation, anatomy and choice of flap).

Ex vivo cutaneous absorption assessmentof a stabilized ascorbic acid formulation using a microdialysis system.

BACKGROUND: Reactive oxygen species generated by ultraviolet light result in photocarcinogenic and photoaging changes in the skin. Antioxidants protect the skin from these insults. OBJECTIVE: The aim of this study was to determine the ex vivo ascorbic acid penetration and its degradation in the skin after its topical application from an 8% new formulation. METHOD: Ascorbic acid was applied to human skin fragments. Ascorbic acid and its metabolites were collected by microdialysis and assessed by gas chromatography mass spectrometry. RESULTS: After topical application of the new formulation, the ascorbic acid level achieved was 8.5% higher than [corrected] times the normal tissue value. This high ascorbic acid dermal concentration remained constant if a topical application was made every 8 h. No degradation of ascorbic acid was detected. CONCLUSION: Ascorbic acid penetrates rapidly after its topical application. The persistent reservoir of ascorbic acid provides an important and attractive photoprotection strategy.

N-acetyltransferase 2 acetylation polymorphism: prevalence of slow acetylators does not differ between atopic dermatitis patients and healthy subjects.

The genetic polymorphism of human N-acetyltransferase 2 (NAT2) divides the human population into groups with rapid, intermediate and slow acetylator status. Slow acetylator status has been considered a predisposing factor for allergic diseases, lupus erythematosus, toxic epidermal necrolysis or Stevens-Johnson syndrome. The aim of this study was to investigate whether Caucasian patients suffering from atopic dermatitis differed from healthy individuals with regard to the genotype and phenotype of NAT2. Twenty unrelated healthy Caucasian volunteers (9 females and 11 males, aged from 22 to 59 years) and twenty unrelated Caucasian patients suffering from atopic dermatitis (9 females and 11 males, aged between 20 and 54 years) participated in this study. For each one, the NAT2 genotype was determined by polymerase chain reaction with DNA extracted from peripheral blood, using specific primers for the wild-type allele (wt) and the 3 most frequent mutated alleles of NAT2 (C481-->T, G590-->A and G857-->A). The NAT2 phenotype was evaluated with dapsone as a test substrate using high-pressure liquid chromatography. Statistical analysis was performed using the chi(2) test. Phenotype and genotype were distributed as follows: (1) of the healthy subjects, 60% were rapid acetylators (RA) and 40% were slow acetylators (SA); 10% of the RA and 15% of the SA were homozygous, 50% of the RA and 25% of the SA were heterozygous; (2) of the patients, 55% were RA, 40% were SA and 5% were intermediate acetylators (IA); 10% of the RA and 10% of the SA were homozygous, 45% of the RA and 35% of the SA were heterozygous. No significant statistical difference was found between the two groups for genotypes (p = 0.75) or phenotypes (p = 0.60). The phenotyping and genotyping results of healthy subjects were comparable to those found in previous studies. The absence of a significant statistical difference between healthy subjects and atopic dermatitis patients is in contrast to the results of previous studies. Some authors considered that allergic patients are mostly SAs. This could be explained by the fact that we only considered patients suffering from atopic dermatitis whereas, in other studies, patients suffered from different (one or several associated) allergic diseases. NAT2 polymorphism does not differ between patients suffering from atopic dermatitis and healthy subjects. The importance attributed to the SA status, which was previously considered a predisposing factor for allergic diseases such as atopic dermatitis, should be reviewed.

[Therapeutic drug monitoring of mycophenolate mofetil, sirolimus and cyclosporine at C2]. / Suivi thérapeutique pharmacologique de l'acide mycophénolique, du sirolimus et de la cilosporine au moyen du C2.

The evolutions in treatments and clinical practices in organ transplantations led to modifications in the therapeutic drug monitoring (TDM) of immunosuppressive drugs. A focus is made regarding the C2 sampling of cyclosporin, as well as the TDM of mycophenolate mofetil and sirolimus. A review of literature about the evolution of drug monitoring, technical methods and sampling strategies is described. Arguments in favour of TDM are thus a decrease in the frequency of both graft rejection and adverse drug reactions, however, new strategies or new targets are needed in new associations or indications.

[Myocardial microdialysis. Importance and potential in cardiovascular research]. / Microdialyse myocardique. Intérêt et potentiel en recherche cardio-vasculaire.

The microdialysis expanded mainly in the field of the neuro- and the dermopharmacology with the study of the transmitters released in the central nervous system and derm. Since ten years, this tool gained other disciplines such as cardiology and cardiovascular surgery. Indeed, the collection and the study of the molecules released in the myocardic interstitial fluid without deteriorating it functioning made microdialysis a powerful tool in the study of the extracellular environment of the cardiomyocyte. The purpose of this study is to point out the principle of the microdialysis and to show its various uses in the field of cardiovascular pharmacology.

[Interest in therapeutic drug monitoring of the main antibiotics]. / Intérêt du suivi thérapeutique pharmacologique des principaux antibiotiques.

The therapeutic drug monitoring aims at optimising the prescribed dosages to improve efficacy and prevent toxicity. The aim of this study were to review the main pharmacodynamic and pharmacokinetic properties of aminoglycosides, glycopeptides and ceftazidime. Then, the therapeutic drug monitoring of these antibiotics and their methods of analysis is reviewed.

[Effects of nitric oxide on cardioprotection prior to ischemia-reperfusion]. / Effets du monoxyde d'azote sur la cardioprotection avant l'ischémie-reperfusion.

This study aimed at evaluating the role of nitric oxide (NO) when generated 24 h prior to ischemia-reperfusion. Three groups were studied in an isolated buffer-perfused heart model: Control (saline = 3.3 mL/kg, n = 10), the precursor of NO, L-arginine, (500 mg/kg, n = 10) and an inhibitor of NO synthase, L-NAME, (10 mg/kg, n = 9). All groups were injected intraperitoneally 24 h before heart extraction. Nitrites, nitrates (an index of nitric oxide release) and cardiac troponine I were assayed. During the reperfusion period, there was a low release of nitric oxide and cardiac troponine I associated with improved recovery of post-ischemic myocardial function. These results indicate that in this model, the pre-treatment improved myocardial function and thus, NO could play a role as a trigger and not as a mediator of cardioprotection.