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.

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.

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.

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.

Psoralens percutaneous permeation across the human whole skin and the epidermis in respect to their polarity (in vitro study).

8-methoxypsoralen (8-MOP), 5-methoxypsoralen (5-MOP) and 4,5',8-trimethylpsoralen (TMP) are commonly used in PUVA therapy [psoralen (P) + ultraviolet light A (UVA) irradiation] to treat skin diseases such as psoriasis and vitiligo. In order to predict the choice of the suitable drug(s) for topical applications, with appropriate dosage, percutaneous permeation of the psoralens, in connection with their solubilities and partition coefficients in an octanol/water system, were investigated. The percutaneous penetration experiments were accomplished by the deposit of ethanolic psoralen solution onto human skin and epidermis fragments mounted on Franz cells. Six cells were employed for each psoralen solution and for the whole skin layer as well as for the epidermis. The diffused psoralens in the receptor solution (1.4%, of human serum albumin) were quantified by using high performance liquid chromatography. The solubilities and the partition coefficients (PC) were carried out in an octanol/water system, in triplicate by using spectrofluorimetry. The results demonstrated that cumulated permeated quantities (ng/cm2) over 24 h, across the whole skin and the epidermis were in the following order for the three psoralens: 8-MOP > 5-MOP > TMP. The lipophilicity, expressed via the log PC, was as follows: 1.93 +/- 0.01 (8-MOP), 2.00 +/- 0.01 (5-MOP) and 3.14 +/- 0.01 (TMP). It was inversely correlated with cumulated penetrated amounts over 24 h in both whole skin and epidermis. From these results, TMP could be predicted as the most convenient psoralen for topical applications, because of its weak penetrability. Considering the relationship between psoralens lipophilicity and permeation, only 5-MOP and 8-MOP could be used, topically or orally, especially in the case of generalised skin disorders.

Effects of L-arginine administration before cardioplegic arrest on ischemia-reperfusion injury.

BACKGROUND: Administration of L-arginine during reperfusion or its addition to cardioplegic solution has been shown to protect myocardium against ischemia-reperfusion injury. This study aimed at evaluating the role of L-arginine in ischemia-reperfusion injury when administered intraperitoneally 24 hours before cardioplegic arrest. METHODS: Two groups of Sprague-Dawley rats (control, n = 10; and L-arginine, n = 10) were studied in an isolated buffer-perfused heart model. Both groups were injected intraperitoneally 24 hours before ischemia. Before experimentation blood samples were collected for cardiac troponin I and cGMP analysis. In the coronary effluents, cardiac troponin I, adenosine, cyclic guanosine monophosphate, and nitric oxide metabolites were assayed. RESULTS: Before heart excision, serum cardiac troponin I concentrations were higher in the L-arginine than in the control group (0.037 +/- 0.01 versus 0.02 +/- 0.05 microg x L(-1); p < 0.05). During reperfusion, cardiac troponin I release was lower in the L-arginine than in the control group (0.04 +/- 0.01 versus 0.19 +/- 0.03 ng x min(-1); p < 0.05). The coronary flow as well as the left ventricular developed pressure were higher in the L-arginine than in the control group before ischemia and remained so throughout the experimentation. CONCLUSIONS: These results indicate that L-arginine administered intraperitoneally 24 hours before cardioplegic arrest reduced myocardial cell injury and seems to protect myocardium against ischemia-reperfusion injury.

Treatment of psoriasis with a new micronized 5-methoxypsoralen tablet and UVA radiation.

Since 1974, phototherapy with psoralen and ultraviolet A (UVA) has been used successfully for the treatment of psoriasis. However, undesirable side effects, including phototoxicity, nausea, stomach pain and headaches, have led investigators to develop new psoralen compounds. 5-Methoxypsoralen (5-MOP) has thus been introduced as an alternative to 8-MOP because of its less pronounced side effects. Since the absorption kinetics and bioactivity of 5-MOP are known to be variable, a new micronized tablet form (5-MOPm) has been developed. In an open randomized study, oral treatments with 5-MOP or 5-MOPm plus UVA radiation were compared in 22 psoriatic patients. Skin type and initial psoriasis area severity index did not differ significantly between treatment groups. Serum concentrations were significantly higher (320 vs 85.82 ng/ml) and occurred earlier (51.8 vs 229.09 min) with 5-MOPm. In addition, a reduction in PASI of more than 90% was achieved sooner (10.63 vs 17.27 treatments) and with a lower cumulative UVA dose (145.89 vs 232.11 J/cm2), in the group treated with 5-MOPm. No side effects were observed with 5-MOPm. Our data indicate that 5-MOPm has a higher bioavailability, clinical efficacy and tolerability than the commonly used 5-MOP.

Serum free 5-methoxypsoralen fraction in health and psoriasis: relationship with human serum albumin concentration.

Human serum albumin is known to be the main carrier of 5-methoxypsoralen (5-MOP) in serum. As hypoalbuminaemia may occur in psoriasis with inflammatory syndrome, variability of the free 5-MOP fraction in serum can be expected. The free 5-MOP fraction was determined by equilibrium dialysis in serum samples obtained from 18 psoriatic patients and 18 control subjects. The median free 5-MOP fraction was not significantly different in the psoriatic group (fu = 4.75%) than in the control group (fu = 5%). However, there was a significantly larger variability of the free fraction in the psoriatic group (2.7 to 8.6%) than in the healthy group (3.2 to 6.8%) (p = 0.002). The binding index of 5-MOP (ratio of bound to free concentrations) was correlated with human serum albumin level (r = 0.784). This work confirms that the 5-MOP fraction in human serum is principally serum albumin dependent, as has been described with in vitro models. Free drug monitoring of 5-MOP is discussed.

Lipophilicity determination of psoralens used in therapy through solubility and partitioning: comparison of theoretical and experimental approaches.

The aim of this study was to determine and to compare experimental and theoretical solubilities (S) as well as partition coefficients (PC) in an octanol/water system of psoralen (P), 8-methoxypsoralen (8-MOP), 5-methoxypsoralen (5-MOP) and 4,5',8-trimethylpsoralen (TMP). For each psoralen, experimental results were performed in triplicate with a spectrofluorimetric technique. The measurements were achieved 10 times for each solution. The obtained order of the solubilities in pure octanol was 5-MOP approximately TMP > P > 8-MOP, while in water-saturated octanol it was expressed as follows: TMP approximately 5-MOP > P > 8-MOP. However, the following order was found for hydrophobicity: TMP > 5-MOP > 8-MOP > P. The solubility ratios (SR) in pure octanol and water were assessed (mean +/- SD): 3.13 +/- 0.01 (P), 2.60 +/- 0.01 (8-MOP), 3.75 +/- 0.01 (5-MOP), and 5.11 +/- 0.01 (TMP). In saturated phases, they were 3.27 +/- 0.01, 2.63 +/- 0.01, 3.85 +/- 0.01, and 5.32 +/- 0.01, respectively. The PCs were determined with low concentrations according to the Dearden and Bresnen32 method and they were 1.67 +/- 0.01, 1.93 +/- 0.01, 2.00 +/- 0.01, and 3.14 +/- 0.01, respectively. Solubility parameters (delta), in Hildebrand unit (H) or in (cal/cm3)1/2, were evaluated. They confirmed the polarity of psoralens, previously expressed through the PC, although the positional isomers (5-MOP and 8-MOP) revealed no difference. Hildebrand's approach to the solubility of regular solutions and Yalkowsky's concept of the solubility of nonelectrolytes and weak electrolytes in an octanol/water system permitted a comparison of the theoretical and experimental results. The perspective of this work is to use the physicochemical properties of the psoralens in practice for insuring convenient experimental assays and the prediction, in vitro, of the percutaneous absorption of these compounds.

[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.

[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.

[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.