Matthieu Roustit

Pharmacokinetics and therapeutic drug monitoring of antiretrovirals in pregnant women

Highly active antiretroviral therapy is recommended for HIV-infected pregnant women to prevent mother-to-child transmission. The specific physiological background induced by pregnancy leads to significant changes in maternal pharmacokinetics, suggesting potential variability in plasma concentrations of antiretrovirals during gestation. Therapeutic drug monitoring (TDM) of protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) is recommended in certain situations, including pregnancy, but its systematic use in HIV-infected pregnant women remains controversial. This review provides an update of the pharmacokinetic data available for PIs and NNRTIs in pregnant women and highlights the clinical interest of systematic TDM of certain antiretroviral drugs during pregnancy, including nevirapine, nelfinavir, saquinavir, indinavir and lopinavir.

Trials and tribulations of skin iontophoresis in therapeutics

Iontophoresis is a method of non‐invasive transdermal drug delivery based on the transfer of charged molecules using a low‐intensity electric current. Both local and systemic administration are possible; however, the skin pharmacokinetics of iontophoretically delivered drugs is complex and difficult to anticipate. The unquestionable theoretical advantages of the technique make it attractive in several potential applications. After a brief review of the factors influencing iontophoresis, we detail the current applications of iontophoresis in therapeutics and the main potential applications under investigation, including systemic and topical drugs and focusing on the treatment of scleroderma‐related ulcerations. Finally, we address the issue of safety, which could be a limitation to the routine clinical use of iontophoresis.

Involvement of cytochrome epoxygenase metabolites in cutaneous postocclusive hyperemia in humans

Several mediators contribute to postocclusive reactive hyperemia (PORH) of the skin, including sensory nerves and endothelium-derived hyperpolarizing factors. The main objective of our study was to investigate the specific contribution of epoxyeicosatrienoic acids in human skin PORH. Eight healthy volunteers were enrolled in two placebo-controlled experiments. In the first experiment we studied the separate and combined effects of 6.5 mM fluconazole, infused through microdialysis fibers, and lidocaine/prilocaine cream on skin PORH following 5 min arterial occlusion. In the second experiment we studied the separate and combined effects of 6.5 mM fluconazole and 10 mM N(G)-monomethyl-l-arginine (l-NMMA). Skin blood flux was recorded using two-dimensional laser speckle contrast imaging. Maximal cutaneous vascular conductance (CVC(max)) was obtained following 29 mM sodium nitroprusside perfusion. The PORH peak at the placebo site averaged 66 ± 11%CVC(max). Compared with the placebo site, the peak was significantly lower at the fluconazole (47 ± 10%CVC(max); P < 0.001), lidocaine (29 ± 10%CVC(max); P < 0.001), and fluconazole + lidocaine (30 ± 10%CVC(max); P < 0.001) sites. The effect of fluconazole on the area under the curve was more pronounced. In the second experiment, the PORH peak was significantly lower at the fluconazole site, but not at the l-NMMA or combination site, compared with the placebo site. In addition to sensory nerves cytochrome epoxygenase metabolites, putatively epoxyeicosatrienoic acids, play a major role in healthy skin PORH, their role being more important in the time course rather than the peak.

Conversion to mammalian target of rapamycin inhibitors increases risk of de novo donor-specific antibodies

In kidney transplantation, conversion to mammalian target of rapamycin (mTOR) inhibitors may avoid calcineurin inhibitor (CNI) nephrotoxicity, but its impact on post‐transplant allo‐immunization remains largely unexplored. This retrospective cohort study analyzed the emergence of donor‐specific antibodies (DSA) in kidney transplant recipients relative to their immunosuppressive therapy. Among 270 recipients without pretransplant immunization who were screened regularly for de novo DSA, 56 were converted to mTOR inhibitors after CNI withdrawal. DSA emergence was increased in patients who were converted to mTOR inhibitors (HR 2.4; 95% CI 1.06–5.41, P = 0.036). DSA were mainly directed against donor HLA‐DQB1 antigens. The presence of one or two DQ mismatches was a major risk factor for DQ DSA (HR 5.32; 95% CI 1.58–17.89 and HR 10.43; 95% CI 2.29–47.56, respectively; P < 0.01). Rejection episodes were more likely in patients converted to mTOR inhibitors, but this difference did not reach significance (16% vs. 7.9%, P = 0.185). Concerning graft function, no significant change was observed one year after conversion (P = 0.31). In conclusion, conversion to mTOR inhibitors may increase the risk of developing class II DSA, especially in the presence of DQ mismatches: this strategy may favor chronic antibody‐mediated rejection and thus reduce graft survival.

Skin microdialysis coupled with laser speckle contrast imaging to assess microvascular reactivity.

OBJECTIVEnLaser speckle contrast imaging (LSCI) can be used to assess real-time responses of skin microcirculation to pharmacological interventions. The main objective of this study was to determine whether intradermal or subdermal microdialysis fiber insertion, coupled with skin flux recording using LSCI, can be used to assess baseline cutaneous flux and the post-occlusive reactive hyperemic response. The microdialysis sites were compared to control area without microdialysis fibers.nnnMETHODSnOne dermal and two subdermal microdialysis fibers were randomly inserted in the right forearm skin of six healthy volunteers. We performed consecutively tests of post-occlusive hyperemia, infusion of 29 mM sodium nitroprusside (SNP), local thermal hyperemia at 43°C and a second 29 mM SNP infusion at the end of the experiment.nnnRESULTSnTwo hours after fiber insertion, cutaneous vascular conductances (CVC) at the subdermal fiber sites were not different from their respective control regions of interest, while at the dermal site CVC remained higher (0.48+/-0.15 versus 0.37+/-0.1 PU.mm Hg(-1), P=0.003). The peak CVC and area under the curve observed during post-occlusive reactive hyperemia were similar at all fiber sites and their respective controls. We observed a similar increase in CVC using 29 mM SNP infusion, 40 min local heating at 43°C, and their combination. Finally, physiological and pharmacological responses of the subdermal sites were reproducible in terms of amplitude, whether expressed as raw CVC or as % CVCmax.nnnCONCLUSIONSnWe showed that studying skin microvascular physiological or pharmacological responses using inserted subdermal microdialysis fibers coupled with LSCI is feasible and reproducible, and provides two-dimensional information. This technique will be useful for future mechanistic studies of skin microcirculation.

Cathodal iontophoresis of treprostinil and iloprost induces a sustained increase in cutaneous flux in rats.

The treatment of scleroderma‐related digital ulcers is still a therapeutic challenge. The most effective drugs are prostacyclin analogues. However, their usage is limited to an intravenous route of administration and by their frequent side effects. The objective of this study was to test whether treprostinil, iloprost and epoprostenol can induce sustained vasodilatation in rats when delivered locally using cutaneous iontophoresis.

Skin microvascular endothelial function as a biomarker in cardiovascular diseases

Skin microvascular endothelial function is impaired in many cardiovascular diseases, and could be therefore considered as a representative vascular bed. However, today, available evidence allows considering skin microvascular endothelial function neither as a diagnostic biomarker nor as a prognostic biomarker in cardiovascular diseases. Large follow-up studies using standardized methods should now be conducted to assess the potential predictive value of skin microvascular function in cardiovascular diseases.

Cathodal Iontophoresis of Treprostinil Induces a Sustained Increase in Cutaneous Blood Flux in Healthy Volunteers

Prostacyclin analogues are the most effective drugs to treat sclerodermic digital ulcers, but their systemic use is limited by their frequent side effects. The authors tested whether the prostacyclin analogues treprostinil and iloprost, delivered by cutaneous iontophoresis, induce sustained vasodilatation.

Sample entropy of laser Doppler flowmetry signals increases in patients with systemic sclerosis

Associated to reactivity tests, laser Doppler flowmetry (LDF) emphasizes abnormal skin microvascular function in diseases affecting digits, such as Raynauds phenomenon (RP) and systemic sclerosis (SSc). However, baseline perfusion value does not discriminate between disease states. We study if LDF sample entropy (SampEn) allows distinguishing healthy subjects, RP and SSc patients. LDF measurements were performed on finger pad and forearm of 108 subjects (27 controls, 28 RP patients, 53 SSc patients), before and after local thermal hyperemia. We also assessed the reproducibility of SampEn [expressed as within-subject coefficients of variation (CV) and intra-class correlation coefficients (ICC)]. Baseline SampEn is significantly increased in patients with SSc compared to RP and controls on finger pad [0.49 (0.19), 0.38 (0.14) and 0.36 (0.15), respectively; P<0.002], but not on forearm. However, local thermal hyperemia increased SampEn at all sites and for all groups. Finally, reproducibility of SampEn computed on two baseline segments was acceptable (CV=26%, ICC=0.63). SampEn of skin blood flow at rest is increased on finger pad of patients with SSc but not on forearm. This is consistent with the pathophysiology of the disease, which predominantly affects digital microcirculation in most patients. SampEn of LDF signal could be a reproducible tool to predict digital microvascular impairment.

Cutaneous iontophoresis of treprostinil, a prostacyclin analog, increases microvascular blood flux in diabetic malleolus area.

Diabetic foot ulcers are one of the most common and serious complications of diabetes mellitus. Few drugs are effective in enhancing the healing of microvascular skin ulcers. The main objective of the present study was to determine whether iontophoresis of treprostinil, a prostacyclin analog, increases skin microvascular blood flux in the malleolus area of healthy subjects and diabetic patients. We recruited 12 healthy subjects and 12 type 2 diabetic patients. Cathodal iontophoresis (40mC/cm²) of treprostinil 250µM and NaCl 0.9% was performed in the malleolus area. Skin hyperemia was quantified using non-invasive laser speckle contrast imaging, and expressed as the area under the curve (AUC) of cutaneous vascular conductance (CVC). In healthy controls and diabetic patients, treprostinil 250µM induced a significant increase in CVC compared with NaCl (for diabetic patients, AUC0-6h was 19970±8697; versus 2893±5481%BL.min, respectively; P=0.002). In both groups, the peak flux was obtained between 30min and 1h after the end of treprostinil iontophoresis and flux remained higher than baseline up to 6h after ending of iontophoresis. No significant side-effect occurred. Cutaneous iontophoresis of 250µM treprostinil increases microvascular blood flux in the malleolus area in healthy volunteers and diabetic patients, without inducing systemic or local side-effects. Treprostinil cathodal iontophoresis should be further investigated as a new local therapy for diabetic ulcers.