Tolerability of loteprednol/tobramycin versus dexamethasone/tobramycin in healthy volunteers: results of a 4-week,randomized, double-masked,parallel-group study

ABSTRACT

Objective: To compare the ocular comfort and tolerability of loteprednol etabonate 0.5%/tobramycin 0.3% (LE/T; Zylet^*) with dexamethasone 0.1%/tobramycin 0.3% (DM/T; TobraDex^?) in healthy volunteers.

Research design and methods: In this multicenter, randomized, double-masked, parallel-group study, healthy volunteers (n?=?306) were randomized to receive LE/T or DM/T four times per day for 28 days. Subjects recorded subjective ratings for seven comfort/tolerability parameters using an electronic patient diary (EPD). The primary endpoint was the difference at week 4 from the ratings of an artificial tear at baseline in comfort/tolerability parameters between treatment groups, using a noninferiority paradigm.

Clinical trials registration: ClinicalTrials.gov, NCT 00532961.

Results: The 97.5% confidence intervals for the lower bound were within –10 for all of the seven comfort/tolerability parameters evaluated (pain, stinging/burning, irritation, itchiness, foreign-body sensation, dryness, and light sensitivity). Secondary analysis revealed small but significant within-treatment differences in pain favoring LE/T over tears and in light sensitivity favoring tears over DM/T (p?<?0.01). Small between-treatment differences in the changes from baseline tear ratings to individual study visits favored LE/T for pain, stinging/burning, irritation, itchiness, foreign-body sensation, and light sensitivity at visit 4 (p?≤?0.04); for pain, stinging/burning, and foreign-body sensation at visit 5 (p?≤?0.03), and for dryness and light sensitivity at visit 6 (p?≤?0.05).

Conclusions: LE/T satisfied all conditions of noninferi-ority to DM/T in comfort and tolerability. Subjects receiving LE/T were more likely to report better ocular comfort/tolerability ratings relative to baseline artificial tears than subjects receiving DM/T.

Limitations: The study population consisted of healthy volunteers.     

Variation in skin biology to climate in Shanghai,China

Purpose: To explore the relationship between climate and skin condition, and to investigate the variation of skin biology to climatic change.

Methods: In total, 2005 healthy Chinese volunteers living in Shanghai (aged 13–69 years) were recruited. Transepidermal water loss (TEWL) and SCH were tested on six sites (forehead, cheek, nasolabial, inner forearm, dorsal hand, and palm) by noninvasive devices between January 2005 and December 2012. The corresponding climate data were recorded by local Weather Bureau.

Results: TEWL was increased with atmospheric pressure and decreased with temperature, steam pressure, and relative humidity (p?p?Conclusion: Skin biological parameters are associated with climatic factors. Different sites have different sensitivity to climate factors.     

Efficacy and safety of 2% supramolecular salicylic acid compared with 5% benzoyl peroxide/0.1% adapalene in the acne treatment: a randomized,split-face,open-label,single-center study

Background: Topical drugs for mild to moderate acne include adapalene (ADA) and benzoyl peroxide(BPO). Supramolecular salicylic acid (SSA), a modified SA preparation, is considered as a new effective therapeutic scheme.

Objectives: To compare the safety and efficacy of 2% supramolecular SA (2% SSA) with 0.01% adapalene plus 5% benzoyl peroxide (5%BPO +0.1%ADA) for treatment of facial acne.

Materials and methods: This was an open-label, split face, randomized and single-centre clinical trial. Subjects with mild to moderate acne were enrolled. Two percent SSA cream were randomly applied on one side of the face while 5%BPO +0.1%ADA gel was applied on the opposite side for 28?days. The numbers of acne lesions, along with side effects of the targeted area were evaluated by the investigators at day 0, day 14, and day 28. Skin water content, TEWL and skin lightening indexes were measured at the same time.

Results: A total of 31 of acne patients completed the trial. Dates showed that 2% SSA had similar effects to 5%BPO +0.1%ADA in reducing papules/pustules (47.9% vs. 49.8%), non-inflammatory lesions (43.1% vs. 42.7%) and total lesions (44.1% vs. 45.6%; all p?>?0.05) at day 28. The skin barrier (skin hydration value and TEWL value), skin brightness (L* value) and erythema (a* values) indicators showed no statistical differences in the left and right sides of the face (p?>?0.05).

Conclusion: This study demonstrated that 2% SSA has a similar efficacy with 5%BPO +0.1%ADA in mild to moderate acne treatment. This might be a useful pilot study that could be used to support further larger clinical trials.     

Comparative efficacy of olopatadine 0.1% ophthalmic solution versus levocabastine 0.05% ophthalmic suspension using the conjunctival allergen challenge model

SUMMARY

Objective: To compare the efficacy of olopatadine and levocabastine in reducing ocular allergic itching and vascular hyperemia (redness) induced by conjunctival allergen challenge.

Research design and methods: The study was a randomized, double-masked, contralateral study using the conjunctival allergen challenge (CAC) model. At Visit 1, subjects with a positive allergen skin test and a history of allergic conjunctivitis were administered increasing concentrations of allergen until at least a moderate grade 2 ocular itching and conjunctival redness response was obtained in both eyes. Allergic signs were graded on standardized 0–4 scales. Subjects who reacted positively were re-challenged at Visit 2 with the pre-determined concentration of allergen. Subjects who again responded with at least a grade 2 bilateral ocular itching and conjunctival redness score at Visit 2 were eligible for drug evaluation. At Visit 3, subjects received olopatadine in one eye and levocabastine in the contralateral eye according to a computer-generated randomization scheme generated prior to commencement of the study. Ocular discomfort was then graded in both eyes. Subjects were bilaterally challenged with the predetermined concentration of allergen 27?min after topical drug administration, such that the first post-challenge assessment was made 30?min post-drug instillation. Allergic signs and symptoms were evaluated at 3?min, 10?min, and 20?min post-challenge and safety and efficacy analyses were performed.

Results: Sixty-eight subjects received study drug and were included in the safety and efficacy analyses. Ocular itching scores for olopatadine were significantly lower than levocabastine at 3?min and 10?min post-challenge (?p < 0.001). Ocular redness scores for olopatadine were significantly lower than levocabastine at all time points post-challenge (?p < 0.0001). Of all subjects, 4.41% reported ocular discomfort in the olopatadine eye and 26.5% in the levocabastine treated eye.

Conclusion: Olopatadine treated eyes had significantly less itching and redness than levocabastine treated eyes after conjunctival allergen challenge. Olopatadine was also associated with less discomfort upon instillation than levocabastine.     

Short term study of human skin irritation by single application closed patch test: assessment of four multiple emulsion formulations loaded with botanical extracts

Background: Assessment of skin irritation potential is a major concern in safety assessment of cosmetics, when long-term use of these products are expected. Non-invasive bioengineering probes have been used previously to measure skin irritation potential of cosmetic ingredients.

Objectives: Experimentation carried out to weigh up the skin irritation potential of four multiple emulsion formulations via visual and non-invasive measurements. Immediate effects of formulations and comparison of two assessment techniques were also tried to establish.

Methods: Four multiple emulsion formulations one control (without botanical active) and three containing the functional botanical actives plus additives were tested in this study using the following techniques: transepidermal water loss (TEWL), COLIPA visual scoring method (CVSM), Mexameter MPA 5 (Courage + Khazaka, Germany) and capacitance [Corneometer MPA 5 (Courage + Khazaka, Germany)]. Visual examination and non-invasive measurements were performed at baseline and after 24?h. The formulations were applied on the forearm of 12 healthy volunteers of same sexes aged 20–25 years.

Results: We found that none of the formulation produced irritation both on visual and instrumental evaluation. However, formulations MeB and MeC have comparable immediate effects on dryness, erythema, melanin and TEWL. Formulation MeC produced more effective results on different parameters, may be due to synergistic effect of two extracts, while MeA failed to produce any immediate effects on skin parameters. Moreover results of both assessment methods are parallel to each other.

Conclusions: None of the formulation produce irritant effects, barrier impairment effects or immediate effects except for the formulation MeC which produced appreciable results than other formulations but statistically these results were insignificant (p?>?0.05). Based on these results, it could be concluded that formulations may be implied safely as skin rejuvenating candidates.     

Skin sensitivity and intolerance in Shanghai: cumulative influence of different meteorological parameters

Background: Although Sensitive skin (SS) conditions are reported to be affected by climate changes, the correlations with meteorological parameters remain mostly unclear.

Objective: To investigate the changes of facial skin conditions in different seasons in Shanghai, including the speed and severity of the influences imposed by different meteorological parameters.

Methods: Totally eighty-one healthy female volunteers completed the study in both spring (May) and summer (August). Evaluations of facial skin conditions included stimulating sensory test, clinical grading and biophysical measurements. Correlations between the meteorological parameters and ΔTEWL as well as clinical parameters were analyzed.

Results: There was no significant difference between two seasons in lactic acid sting test. The stimulation sensations felt by Vitamin B3 (VB3) containing cream was significantly higher in May than that in August. In accordance, baseline visual scores for erythema and scaliness in May were also significantly higher than those scores in August. The baseline transepidermal water loss (TEWL) value was significantly higher in May than that in August. Positive correlations were detected between ΔTEWL and atmospheric pressure on the test day, adjust 3-day and 7-day mean of daily solar radiation respectively. There were negative correlations between ΔTEWL and temperature outside on the test day, adjust 3-day mean as well as adjust 7-day mean of relative humidity.

Conclusions: Facial skin conditions in summer are better than that in spring in Shanghai. The influences from atmospheric pressure and temperature are relatively quick in speed, while the influences from relative humidity and solar radiation are slow but cumulative.     

Garenoxacin pharmacokinetics in subjects with renal impairment*

ABSTRACT

Objective: This open-label, parallel-group study determined the pharmacokinetics of garenoxacin in subjects with severe renal impairment, including subjects maintained on dialysis.

Research design and methods: Subjects were assigned to one of four groups according to their underlying renal function: creatinine clearance (CL_cr) > 80?mL/min, CL_cr < 30?mL/min, hemodialysis (HD), and continuous ambulatory peritoneal dialysis (CAPD). Subjects received a single oral 600?mg dose of garenoxacin. Administration of garenoxacin to subjects receiving hemodialysis was completed in two phases separated by 14 days: 3?h before HD (phase 1) and immediately after HD (phase 2).

Main outcome measures: Plasma and urine or dialysate samples were analyzed for garenoxacin, and single-dose pharmacokinetic parameters were estimated. Safety was assessed.

Results: Twenty-five subjects received garenoxacin. Compared with healthy controls, garenoxacin area under the concentration–time curve (AUC) and maximum plasma concentration were increased by 51% and lowered by 20%, respectively, in subjects with severe renal impairment. The terminal half-life was prolonged in subjects with severe renal impairment compared with healthy controls (26.5 ± 7?h vs 14.4 ± 3?h, respectively). In subjects receiving HD or CAPD, removal of garenoxacin from systemic circulation was relatively inefficient (HD, 1.5–11.5%; CAPD, 3%), suggesting no need for a supplemental dose of garenoxacin after dialysis. Garenoxacin was well tolerated.

Conclusions: Based on the broad therapeutic index of garenoxacin, the effects of renal impairment on garenoxacin exposure are not considered clinically significant. There was a modest increase in AUC in subjects with severe renal impairment and the magnitude of the changes was not considered clinically relevant.     

Characterization of dry skin associating with type 2 diabetes mellitus using a KK-Ay/TaJcl mouse model

Purpose: Type 2 diabetes mellitus (DM) induces various dermatological conditions that can affect patient quality of life, including increased susceptibility to skin infections and dry skin. While the mechanisms that underlie the causes of dry skin in type 1?DM have been widely studied, how type 2?DM elicits similar effects is unclear. The purpose of this study was therefore to evaluate skin barrier and hydration function using a KK-A^y/TaJcl mouse model of type 2?DM.

Materials and methods: KK-A^y/TaJcl and control mice were housed separately for 4 weeks and then body weight, water intake, urine production, and blood glucose levels were measured. Skin barrier function was estimated by assessing transepidermal water loss (TEWL) and hydration levels of the stratum corneum. The expression levels of various skin biochemical factors were also examined by western blot, including type 1 collagen, mast cell tryptase, hyaluronic acid binding protein (HABP), and fibroblast protein S100A4.

Results: Compared to control mice, there was a marked increase in body weight, water intake, urine production, and blood glucose levels in the KK-A^y/TaJcl mice over the length of the experiment. Hydration levels in the stratum corneum were lower in KK-A^y/TaJcl mice compared to control mice, although TEWL was not significantly different between groups. We also found that hyaluronic acid binding protein expression was higher in KK-A^y/TaJcl mice, although other biochemical factors were the same.

Conclusions: These findings suggest that hyaluronic acid associates with the dry skin caused by type 2?DM. This contributes to understanding this phenomenon and may lead to better treatment options for patients in the future.     

Evolution of the percutaneous penetration and distribution of uranyl nitrate as a function of skin-barrier integrity: an in vitro assessment

As recommended by OECD Guidelines, percutaneous penetration studies consider intact skin, but rarely injured skin. Recent years have witnessed a growing concern for these two types of dermal exposure in the industry, particularly in the nuclear industry. The aim of this study was to show that a method based on an in vitro device can be used to realistically assess how skin-barrier alterations caused by occupational accidents can modify the percutaneous penetration and distribution of radionuclides, particularly uranium. Wounds encountered in the nuclear industry (i.e., nitric acid burns and abrasion) were simulated on hairless rat skin. Skin-barrier alterations were characterized by means of a histological study and by measuring transepidermal water loss (TEWL) and skin thickness. The percutaneous penetration of uranyl nitrate through intact or injured skin biopsies was then measured in vitro. The maximum uranium flux values obtained for intact skin, skin abrasion with stratum corneum removal, and skin exposed to 2 N HNO₃, 5 N HNO₃, and 14 N HNO₃ were, respectively, 0.6?±?0.02, 1.2?±?0.03, 1.2?±?0.04, 42.0?±?1.0, and 174.0?±?8.7?ng.cm^?2.h^?1. These results demonstrated that the percutaneous absorption of uranium increased with the increased impairment of the stratum corneum. TEWL, combined with maximum uranium flux values measured in vitro, yielded a good prediction of the percutaneous penetration of uranium through injured skin, previously observed in vivo. To conclude, this in vitro assay provides a conservative estimate of the percutaneous diffusion of uranium through intact or injured skin, making it a good alternative method for toxicological studies and risk assessments.     

In vivo antibacterial activity of Garcinia mangostana pericarp extract against methicillin-resistant Staphylococcus aureus in a mouse superficial skin infection model

Context: Garcinia mangostana Linn. (Guttiferae) (GM) pericarp has been shown to exhibit good in vitro antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA); however, there is currently no available information regarding its in vivo antibacterial activity.

Objective: To examine in vivo antibacterial activity of G. mangostana extract against MRSA.

Materials and methods: GM pericarp was extracted by ethanol (GM-EtOH) and methanol (GM-MeOH). The crude extracts were examined for in vitro antibacterial activity against MRSA using broth microdilution assay. The in vivo antibacterial activity of 10% GM-EtOH against MRSA was determined in a tape stripping mouse model of superficial skin infection for 9 days by evaluating transepidermal water loss (TEWL) and performing colony counts from cultured swabs.

Results: GM-EtOH showed greater in vitro activity against MRSA than GM-MeOH in broth microdilution assay with minimum inhibitory concentration 17 versus 20?μg/mL and minimum bactericidal concentration 30 versus 35?μg/mL, respectively. The GM-EtOH (13.20?±?0.49%) contained α-mangostin more than the GM-MeOH (9.83?±?0.30%). In the tape stripping mouse model, 10% GM-EtOH reduced the number of MRSA colonies (0–1) recovered from infected wounds (>100 colonies) on the first day of treatment, restored TEWL to normal levels on the fourth day, and had completely healed the wounds by day 9.

Conclusion: GM-EtOH showed promising in vivo antibacterial activity against MRSA in a superficial skin infection model in mice. It is of interest to develop a topical formulation of GM-EtOH to further study its potential as a novel antibacterial agent.     

Assessment of Skin Barrier Function Using Transepidermal Water Loss: Effect of Age

To probe age-related changes in skin barrier function, transepidermal water loss (TEWL) rates have been measured in young (19–42 years) and old (69–85 years) subjects. TEWL was determined at ventral forearm skin sites, which had been occluded for 24 hr with polypropylene chambers. Baseline TEWL rates (J , which showed no dependence on age, were measured for each subject before and after the experiment. Following removal of the occlusive chamber, TEWL was monitored continuously from t = 0.5 min until its return to the baseline (preocclusion) level, which was typically in the range of 2–7 g/m²/hr. Initial TEWL rates (mean ± SD) were found to differ significantly between young (28.6 ± 7.5 g/m²/hr; n = 26) and old (36.9 ± 10.5 g/m²/hr; n = 18) subjects (P < 0.01). Relaxation of TEWL to J was significantly slower in the aged cohort, such that the characteristic time for diffusion of water in the stratum corneum was estimated to be (mean ± SD) 176 ± 59 min for the young subjects, compared to 360 ± 76 min for the old (P < 0.001.). Thus, the initial TEWL value following removal of occlusion is significantly greater, and the excessive stratum corneum hydration produced by occlusion is dissipated more slowly, in old skin than in young. A hypothesis to explain the slower relaxation of perturbed TEWL in old skin is proposed.     

Experimental 70% hydrofluoric acid burns: histological observations in an established human skin explants ex vivo model

Background: Hydrofluoric acid (HF) is particularly dangerous due to the potential for systemic effects and induction of severe skin necrosis through two mechanisms: corrosiveness and local tissue toxicity. In addition, because it is only partially dissociated (pK_a 3.2), it is capable of penetrating deeply into tissues. There is a lack of experimental studies that objectively characterize the behavior of HF diffusion into human skin, specifically the kinetics of tissue penetration resulting in severe cellular lesions.

Methodology/principal findings: We describe the cutaneous effects of HF using an established ex vivo human skin model. The diffusion of 70% HF starts within the first minute of contact at the epidermal surface and after 2?min reaches the basal layer. In the subsequent minute, the epidermis is destroyed and lesions appear in the papillary dermis after 4?min. Soon after, damage appears in the upper reticular dermis. Thus, 70% HF needs only 5?min of contact to completely penetrate human skin explants. This experiment is reproducible and corroborates previous studies and clinical effects reported in accidental HF exposures.

Conclusion/significance: This study shows that the management of HF chemical skin exposure is a question of minutes, especially for initial decontamination. These experimental observations could be useful for objectively comparing skin decontamination methods. Further studies should help to confirm these preliminary results.     

Dimethyl sulfoxide could be a useful probe to evaluate unusual skin angioneurotic reaction and epidermal permeability

Background/objectives: Dimethyl sulfoxide (DMSO) has been suggested as a traditional chemical probe for assessing skin susceptibility and barrier function. The purpose of this study was to determine the role of DMSO test for the evaluation of unusual skin angioneurotic reaction and epidermal permeability.

Methods: Thirty healthy volunteers were exposed to 98% DMSO on the flexor forearm skin for three exposure durations (5?min, 10?min and 15?min). Clinical visual score and biological physical parameters were obtained. The volunteers were divided into two groups according to the clinical visual scoring. The skin parameters were subsequently analyzed.

Results: There was a significant correlation between clinical visual score and biological physical parameters. The skin color parameters (a*, oxyhemoglobin, erythema and melanin index) and blood flow values were significant between two groups regardless of duration of DMSO exposure, and a significant difference between density values could also be detected if we regrouped the volunteers according to the sting-producing score. Our results also suggested there was no correlation between questionnaire score and clinical visual score or other parameters.

Conclusions: Application of 98% DMSO for 10?min combined with a* (at 30?min) and blood flow (at 10?min) values could help us to identify persons with a hyper-angionerotic reaction to chemical stimulus. The penetrative activity of DMSO correlated with the thickness of the individual’s skin.     

Stratum corneum pharmaco­kinetics of the anti-fungal drug,terbinafine, in a novel topical formulation,for single-dose application in dermatophytoses

ABSTRACT

Objective: The stratum corneum (SC) pharmacokinetics of terbinafine following single-dose administration of a novel cutaneous solution (film-forming solution, FFS) containing terbinafine hydrochloride and a film-forming agent, was investigated in three studies. Terbinafine 1% cream (Lamisil) was included as a benchmark in two of these studies.

Research design and methods: Drugs were applied to areas of the back, and skin strips were taken from defined areas at baseline and from 1 to 312?h after application. Samples were analysed using validated liquid chromatography/mass spectrometry.

Results: The residence time of the film on the skin was up to 72?h after application (up to 12?h for the 1% cream). After application of terbinafine FFS, 30% of the total amount of drug delivered into the SC occurred during the first 2?h, 31% from 2–12?h, and 39% thereafter. The C_max was observed as early as 1.5?h (t_max). SC levels were still detected after 13 days (24?ng/cm²) (t_½ was 162?h). Terbinafine 1% cream showed a similar t_max (2?h) with a lower C_max than terbinafine 1% FFS, and mean SC levels after 7 days of treatment were 46?ng/cm² (day 13). The t_½ was 68?h. Washing at 30?min removed 86% of the film still present on the surface; the decrease of terbinafine concentration in the SC was 84%. A later washing at 12?h removed 73% of the film in comparison to non-washed skin and induced a decrease in the terbinafine content in the SC of 27%.

Conclusions: The SC pharmacokinetic profile of terbinafine 1% FFS indicates that this novel formulation is efficient in delivering high amounts of terbinafine to the skin for a prolonged time and supports its use in the treatment of dermatophytoses with a single application.

Introduction     

A dynamic system for delivering controlled bromine and chlorine vapor exposures to weanling swine skin

Context: Assessing the hazards of accidental exposure to toxic industrial chemical (TIC) vapors and evaluating therapeutic compounds or treatment regimens require the development of appropriate animal models.

Objective: The objective of this project was to develop an exposure system for delivering controlled vapor concentrations of TICs to the skin of anesthetized weanling pigs. Injury levels targeted for study were superficial dermal (SD) and deep dermal (DD) skin lesions as defined histopathologically.

Materials and methods: The exposure system was capable of simultaneously delivering chlorine or bromine vapor to four, 3-cm diameter exposure cups placed over skin between the axillary and inguinal areas of the ventral abdomen. Vapor concentrations were generated by mixing saturated bromine or chlorine vapor with either dried dilution air or nitrogen.

Results: Bromine exposure concentrations ranged from 6.5?×?10^?4 to 1.03?g/L, and exposure durations ranged from 1 to 45?min. A 7-min skin exposure to bromine vapors at 0.59?g/L was sufficient to produce SD injuries, while a 17-min exposure produced a DD injury. Chlorine exposure concentrations ranged from 1.0 to 2.9?g/L (saturated vapor concentration) for exposures ranging from 3 to 90?min. Saturated chlorine vapor challenges for up to 30?min did not induce significant dermal injuries, whereas saturated chlorine vapor with wetted material on the skin surface for 30–60?min induced SD injuries. DD chlorine injuries could not be induced with this system.

Conclusion: The vapor exposure system described in this study provides a means for safely regulating, quantifying and delivering TIC vapors to the skin of weanling swine as a model to evaluate therapeutic treatments.     

Neuroprotective effects of oxysophocarpine on neonatal rat primary cultured hippocampal neurons injured by oxygen-glucose deprivation and reperfusion

Context: Oxysophocarpine (OSC), a quinolizidine alkaloid extracted from leguminous plants of the genus Robinia, is traditionally used for various diseases including neuronal disorders.

Objective: This study investigated the protective effects of OSC on neonatal rat primary-cultured hippocampal neurons were injured by oxygen–glucose deprivation and reperfusion (OGD/RP).

Materials and methods: Cultured hippocampal neurons were exposed to OGD for 2?h followed by a 24?h RP. OSC (1, 2, and 5?μmol/L) and nimodipine (Nim) (12?μmol/L) were added to the culture after OGD but before RP. The cultures of the control group were not exposed to OGD/RP. MTT and LDH assay were used to evaluate the protective effects of OSC. The concentration of intracellular-free calcium [Ca²⁺]_i and mitochondrial membrane potential (MMP) were determined to evaluate the degree of neuronal damage. Morphologic changes of neurons following OGD/RP were observed with a microscope. The expression of caspase-3 and caspase-12 mRNA was examined by real-time quantitative PCR.

Results: The IC₅₀ of OSC was found to be 100?μmol/L. Treatment with OSC (1, 2, and 5?μmol/L) attenuated neuronal damage (p?p?p?2+]_i (p?p?p?Discussion and conclusion: The results suggested that OSC has significant neuroprotective effects that can be attributed to inhibiting endoplasmic reticulum (ER) stress-induced apoptosis.     

Effect of brivaracetam on cardiac repolarisation – a thorough QT study*

ABSTRACT

Objectives: To assess the effect on cardiac repolarisation of the investigational synaptic vesicle protein 2A (SV2A) ligand brivaracetam.

Research design and methods: Subjects received double-blind, multiple bid doses of placebo (n?=?53), brivaracetam 75?mg (n?=?39) or brivaracetam 400?mg (n?=?40), or open-label single-dose moxifloxacin 400?mg (positive control, n?=?52). Continuous 12-lead ECG recordings were performed at baseline and after last dosing, using a Mortara Holter device. Plasma samples were obtained before and up to 12?h after last dosing for drug determination. Triplicate ECGs were extracted before each sample, and read centrally in a blinded manner. QT was corrected using a centre- and gender-specific correction (QTc_SS).

Main outcome measures: The primary endpoint was the largest time-matched mean difference of QTc_SS change from baseline between drug and placebo (maximum ΔΔQTc_SS). The same approach was adopted using the Fridericia's correction (QTc_F). The relationships between ΔQTc_SS and plasma concentration of brivaracetam and moxifloxacin were fitted to a straight line using linear least-squares regression.

Results: Mean maximum ΔΔQTc_SS for brivaracetam 75 and 400?mg bid, and moxifloxacin 400?mg was 0.2?ms, ?1.1?ms and 12.4?ms, respectively. The one-sided 95% upper limit for 75?mg and 400?mg brivaracetam was 4.3?ms and 3.0?ms, respectively; the one-sided 95% lower limit for moxifloxacin was 8.6?ms. After brivaracetam no QTc_SS intervals >480?ms or changes from baseline of >60?ms were observed. ΔQTc_SS did not increase with plasma concentration of brivaracetam, whereas there was a statistically significant rise with increasing moxifloxacin concentrations.

Conclusions: The study was found to be valid in terms of assay sensitivity and the results demonstrated the absence of effects of brivaracetam on cardiac repolarisation. These results suggest that no intensive cardiac monitoring is required during the subsequent stages of brivaracetam development.     

Assessment of long-term immunological and pulmonary safety of inhaled human insulin with up to 24 months of continuous therapy

ABSTRACT

Background: This study was performed to characterize the long-term safety and efficacy of inhaled human insulin (EXU; Exubera (insulin human [rDNA origin]) Inhalation Powder).

Scope: Patients with type 1 or type 2 diabetes (N?=?1290) who had successfully completed one of six controlled EXU open-label trials elected to receive open-label treatment with EXU for up to 3 years, after which they were randomized to discontinue EXU or to continue therapy for 6 months, then discontinue. Immunologic safety was assessed by insulin antibody (IAb) binding, and pulmonary safety was assessed by tests for forced expiratory volume in 1 second (FEV₁) and carbon monoxide diffusing capacity (DL_CO). In addition, changes over time in IAbs were compared with changes in FEV₁, DL_CO, hypoglycemia, and efficacy.

Findings: Antibody binding increased in patients with either type 1 or type 2 diabetes after initiation of EXU and plateaued within 6–12 months (increases were higher in patients with type 1 diabetes than in patients with type 2 diabetes). Decreases in FEV₁ occurred primarily during the first 3–6 months of EXU therapy. Among adult patients in the All Subjects set, the mean (±?SE) annualized rate of decline in FEV₁ was ?0.053?±?0.007 liters/year (95% CI, ?0.065, ?0.040) in adult patients with type 1 diabetes, and ?0.076?±?0.005 liters/year (95% CI, ?0.085, ?0.067) in patients with type 2 diabetes. Changes in DL_CO occurred primarily during the first 3–6 months of EXU therapy. Among adult patients, in the All Subjects set, the mean (±?SE) annual decline in DL_CO was ?0.738?±?0.097?mL/min/mmHg/year (95% CI, ?0.927, ?0.548) and ?0.688?±?0.082 mL/min/mmHg/year (95% CI, ?0.849, ?0.527) in patients with type 1 and type 2 diabetes, respectively.

Antibody binding did not correlate with changes in glycemic control, lung function, dose, or hypoglycemia. Following discontinuation of EXU, IAbs decreased to near baseline levels.

Conclusion: These results are consistent with other trials showing long-term maintenance of safety and efficacy of EXU despite insulin antibody formation and small treatment group differences in pulmonary function. A limitation of the study was the lack of a comparator therapy.     

Antimutagenic and antioxidant activity of a protein fraction from aerial parts of Urtica dioica

Abstract

Context: Urtica dioica L. (Urticaceae), stinging nettle, has been employed as a folklore remedy for a wide spectrum of ailments, including urinary disorders, prostatic hyperplasia, and liver diseases. It has been also used traditionally for cancer treatment.

Object: To evaluate the potential chemopreventive properties of a protein fraction from the aerial part of Urtica dioica (namely UDHL₃₀).

Materials and methods: UDHL₃₀ has been tested for the antimutagenic activity in bacteria (50–800?μg/plate; Ames test by the preincubation method) and for the cytotoxicity on human hepatoma HepG2 cells (0.06–2?mg/mL; 24 and 48?h incubation). Moreover, the antioxidant activity of UDHL₃₀ (0.1–1200?μg/mL; ABTS and superoxide-radical scavenger assays) was evaluated as potential protective mechanisms.

Results: UDHL₃₀ was not cytotoxic on HepG2 cells up to 2?mg/mL; conversely, it exhibited a strong antimutagenic activity against the mutagen 2-aminoanthracene (2AA) in all strains tested (maximum inhibition of 56, 78, and 61% in TA98, TA100, and WP2uvrA strains, respectively, at 800?μg/plate). In addition, a remarkable scavenging activity against ABTS radical and superoxide anion (IC₅₀ values of 19.9?±?1.0?μg/mL and 75.3?±?0.9?μg/mL, respectively) was produced.

Discussion and conclusions: UDHL₃₀ possesses antimutagenic and radical scavenging properties. Being 2AA a pro-carcinogenic agent, we hypothesize that the antimutagenicity of UDHL₃₀ can be due to the inhibition of CYP450-isoenzymes, involved in the mutagen bioactivation. The radical scavenger ability could contribute to 2AA-antimutagenicity. These data encourage further studies in order to better define the potential usefulness of UDHL₃₀ in chemoprevention.     

Efficacy and comfort of olopatadine 0.2% versus epinastine 0.05% ophthalmic solution for treating itching and redness induced by conjunctival allergen challenge

ABSTRACT

Background: Olopatadine 0.2% (Pataday, Alcon Laboratories Inc., Fort Worth, Texas, USA) and epinastine 0.05% (Elestat, Inspire Pharmaceuticals, Inc., Durham, NC, USA) are topical ocular anti-allergic agents. Both are H₁ antihistamine/mast cell stabilizers indicated for the treatment of ocular itching associated with allergic conjunctivitis.

Objective: To compare the efficacy and comfort of olopatadine 0.2% with epinastine 0.05%, in the prevention of ocular itching associated with allergic conjunctivitis following conjunctival allergen challenge (CAC).

Research design and methods: This was a 7 week, four visit, double-masked, randomized, placebo-controlled CAC study. Visit 1 screened subjects for positive ocular allergic responses and Visit 2 confirmed those responses. At Visit 3, 92 subjects were randomized into one of four treatment groups to receive one drop of study medication in each eye: (1) olopatadine 0.2%/placebo, (2) epinastine 0.05%/placebo, (3) olopatadine 0.2%/epinastine 0.05%, (4) placebo/placebo. Subjects were challenged 12?h after drop instillation to evaluate duration of action. At Visit 4, subjects were challenged 5?min after drop instillation to evaluate onset of action. Drop comfort was assessed at Visit 4.

Main outcome measures; results: This article focuses on the results of the onset-of-action challenge (Visit 4). At Visit 4, ocular itching was assessed at 3, 5, and 7?min and redness was assessed at 7, 15, and 20?min post-challenge. Drop comfort was assessed upon instillation, at 30?s, and at 1, 2, and 5?min post-instillation. Olopatadine 0.2%-treated eyes exhibited significantly lower mean ocular itching scores versus epinastine 0.05%-treated eyes at 5 (?p = 0.024) and 7?min (?p = 0.003) post-challenge. Olopatadine 0.2%-treated eyes exhibited significantly lower mean redness scores versus epinastine 0.05%-treated eyes at all time points post-challenge (ciliary: p ≤ 0.013, conjunctival: p ≤ 0.015, episcleral: p ≤ 0.006). Olopatadine 0.2% was rated as significantly more comfortable than epinastine 0.05% at 1?min post-drop instillation (?p = 0.003). All adverse events were non-serious and unrelated to study medication. Although the CAC model reproduces allergic responses that are not environmentally-induced, patients experience varying severities of responses as are seen in real-world situations.

Conclusion: Olopatadine 0.2% was superior to epinastine 0.05% in preventing ocular itching and redness at onset when induced by the CAC model.