Post hoc analysis of reactogenicity trends between dose 1 and dose 2 of the adjuvanted recombinant zoster vaccine in two parallel randomized trials.

In two large clinical trials (ZOE-50 [NCT01165177] and ZOE-70 [NCT01165229]), two doses of the adjuvanted recombinant zoster vaccine (RZV) demonstrated >90% efficacy against herpes zoster in adults ≥50 years of age. Solicited adverse events (AEs) were collected for 7 days post-each dose in a study sub-cohort. The incidence of reported solicited AEs was higher for RZV compared to placebo recipients. Since reactogenicity may contribute to a person's willingness to be vaccinated, knowing about expected reactogenicity might help keep high compliance with the second dose. This post hoc analysis assessed the intensity of solicited AEs post-dose 2 reported to the same event's intensity post-dose 1. Intensity was graded from 0 to 3, grade 3 indicating the highest severity. Of the vaccinees who did not experience a specific AE post-dose 1, 72.6-91.7% did not experience the same event after dose 2. Although the frequency of grade 3 AEs post-dose 2 was the highest in participants reporting the same AEs at grade 3 post-dose 1, 65.8-89.3% of vaccinees with grade 3 specific AEs post-dose 1 reported the same AEs at lower intensity post-dose 2. These data can help inform health-care professionals about the frequency and intensity of AEs post-dose 2 with respect to post-dose 1.

Efficacy of the adjuvanted recombinant zoster vaccine (RZV) by sex, geographic region, and geographic ancestry/ethnicity: A post-hoc analysis of the ZOE-50 and ZOE-70 randomized trials.

BACKGROUND: Herpes zoster (HZ) risk appears to vary by sex and geographic ancestry/ethnicity. METHODS: In 2 randomized clinical trials, participants received 2 doses of adjuvanted recombinant zoster vaccine (RZV) or placebo intramuscularly, 2 months apart. In this post-hoc analysis, we investigate efficacy of RZV against HZ and postherpetic neuralgia (PHN) by sex, geographic region, and geographic ancestry/ethnicity in ≥50-year-olds (ZOE-50: NCT01165177) and ≥70-year-olds (pooled data from ZOE-50 and ZOE-70: NCT01165229). RESULTS: Vaccine efficacy against HZ or PHN was similar in women and men. Across geographic regions, efficacy against HZ ranged between 95.7 and 97.2% in ≥50-year-olds, and between 87.3% and 95.1% in ≥70-year-olds; efficacy against PHN ranged between 86.8 and 100% in ≥70-year-olds. Across ancestral/ethnic groups, efficacy ranged between 88.1 and 100% against HZ and between 65.9 and 100% against PHN in ≥70-year-olds. CONCLUSIONS: While the ZOE-50/70 studies were not powered or pre-designed for these post-hoc analyses, RZV appears efficacious against HZ and PHN irrespective of sex, region, or geographic ancestry/ethnicity.

Diagnostic and therapeutic applications of iontophoresis.

Owing to the excellent barrier properties of the stratum corneum, transdermal delivery remains a challenge for a high number of molecules. Iontophoresis is a noninvasive technique which uses a low current to administer polar and charged species through the skin, thereby enlarging the range of drug candidates for transdermal administration. Unlike other techniques of transdermal delivery enhancement, iontophoresis acts on the molecule itself allowing a better control of the dose applied. The symmetry of the technique can be employed for controlled extraction, allowing a relation to be established between extracted flux and subdermal concentration. This opened the way for innovative applications, notably in the field of noninvasive monitoring of glucose and xenobiotics. Rather than being an extensive review of the literature, this article summarizes the basic rules governing iontophoretic transport, discusses advantages and limitations of the technique, and provides an overview of promising therapeutic applications.

Targeting nanoparticles to M cells with non-peptidic ligands for oral vaccination.

The presence of RGD on nanoparticles allows the targeting of beta1 integrins at the apical surface of human M cells and the enhancement of an immune response after oral immunization. To check the hypothesis that non-peptidic ligands targeting intestinal M cells or APCs would be more efficient for oral immunization than RGD, novel non-peptidic and peptidic analogs (RGD peptidomimitic (RGDp), LDV derivative (LDVd) and LDV peptidomimetic (LDVp)) as well as mannose were grafted on the PEG chain of PCL-PEG and incorporated in PLGA-based nanoparticles. RGD and RGDp significantly increased the transport of nanoparticles across an in vitro model of human M cells as compared to enterocytes. RGD, LDVp, LDVd and mannose enhanced nanoparticle uptake by macrophages in vitro. The intraduodenal immunization with RGDp-, LDVd- or mannose-labeled nanoparticles elicited a higher production of IgG antibodies than the intramuscular injection of free ovalbumin or intraduodenal administration of either non-targeted or RGD-nanoparticles. Targeted formulations were also able to induce a cellular immune response. In conclusion, the in vitro transport of nanoparticles, uptake by macrophages and the immune response were positively influenced by the presence of ligands at the surface of nanoparticles. These targeted-nanoparticles could thus represent a promising delivery system for oral immunization.

Non-invasive diagnosis and monitoring of chronic kidney disease by reverse iontophoresis of urea in vivo.

BACKGROUND: Reverse iontophoresis uses a small current to extract molecules and ions through the skin. The aim of the study was to determine whether reverse iontophoresis of urea can be used (i) to diagnose and monitor non-invasively chronic kidney disease (CKD), and (ii) to track urea levels closely during a hemodialysis session. METHODS: A current of 0.8mA was applied for 2h in 10 healthy volunteers, in 9 patients with CKD, and in 10 patients undergoing hemodialysis. Urea fluxes extracted by reverse iontophoresis and urea concentrations in the blood were measured. RESULTS: Extracted urea fluxes discriminated healthy volunteers from patients with CKD within 90 min. A non-invasive measure of blood urea concentrations can be achieved after 120 min. A urea reservoir in the skin interferes with the extraction and a pre-hemodialysis "depletion" period is required. Mild and transient sensation and erythema induced by iontophoresis were significantly lower in the CKD group. Gelling the formulation of the iontophoresis reservoir gave similar results to those obtained when using a simple aqueous solution. CONCLUSIONS: Reverse iontophoresis can be used to non-invasively diagnose individuals with CKD and to monitor urea concentrations in blood.

Assessment of the "skin reservoir" of urea by confocal Raman microspectroscopy and reverse iontophoresis in vivo.

PURPOSE: To demonstrate the "skin reservoir" of urea by confocal Raman microspectroscopy in vivo and to evaluate its impact on the non-invasive monitoring of the analyte by reverse iontophoresis. METHODS: Urea was extracted iontophoretically over a 2-h period across the skin of adult volunteers and patients with chronic kidney disease. Confocal Raman microspectroscopic profiles of skin were recorded before and after 30 min of current application. RESULTS: Urea extraction was higher at the beginning of current passage, but then decreased to achieve stable values after 2 h of iontophoresis. After 30 min of iontophoresis, the Raman spectra highlighted a clear depletion of urea at the surface of the skin. Lactate distribution was also modified both at the surface and deeper into the skin. CONCLUSIONS: A source of urea in the skin, unrelated to the concentration circulating in the blood, was strongly suggested by extracted urea flux observed over time and by the Raman spectroscopy. This "urea reservoir" must be removed before systemic urea levels can be non-invasively monitored by reverse iontophoresis.

Monitoring of urea and potassium by reverse iontophoresis in vitro.

PURPOSE: Reverse iontophoresis is an alternative to blood sampling for the monitoring of endogenous molecules. Here, the potential of the technique to measure urea and potassium levels non-invasively, and to track their concentrations during hemodialysis, has been examined. MATERIALS AND METHODS: In vitro experiments were performed to test (a) a series of subdermal urea and potassium concentrations typical of the pathophysiologic range, and (b) a decreasing profile of urea and potassium subdermal concentrations to mimic those which are observed during hemodialysis. RESULTS: (a) After 60-120 min of iontophoresis, linear relationships (p < 0.05) were established between both urea and potassium fluxes and their respective subdermal concentrations. The determination coefficients were above 0.9 after 1 h of current passage using sodium as an internal standard. (b) Reverse iontophoretic fluxes of urea and K(+) closely paralleled the decay of the respective concentrations in the subdermal compartment, as would occur during a hemodialysis session. CONCLUSIONS: These in vitro experiments demonstrate that urea and potassium can be quantitatively and proportionately extracted by reverse iontophoresis, even when the subdermal concentrations of the analytes are varying with time. These results suggest the non-invasive monitoring of urea and potassium to diagnose renal failure and during hemodialysis is feasible, and that in vivo measurements are warranted.

Reverse iontophoresis of lithium: electrode formulation using a thermoreversible polymer.

This work investigated the use of a thermoreversible gel as a collector vehicle in reverse iontophoresis applications. A 20% (w/w) aqueous gel of Pluronic F127 was a suitable receptor medium to be used at the cathodal chamber. In vitro iontophoresis experiments investigated the simultaneous extraction of lithium (analyte of interest) and sodium (used as an internal standard) into either a control buffer or a gelled receptor. The gelification process at room temperature provided a suitable consistency and contact with the skin surface during the iontophoresis experiments. Subsequent cooling of the gelled solution to 4 degrees C allows an easy recovery of lithium and sodium for later quantification. Both the lithium extraction fluxes and the lithium to sodium ratio of extraction fluxes were linearly related to the subdermal lithium concentration. On the whole, the results show that thermoreversible polymer solutions offer a simple and convenient way to handle samples in reverse iontophoresis studies.