Pharmacokinetic assessment of constituents of Boswellia serrata, pine bark extracts, curcumin in combination including methylsulfonylmethane in healthy volunteers.

OBJECTIVES: Dietary supplements are increasingly used by people with osteoarthritis. Boswellia serrata extract, curcumin, pine bark extract and methylsulfonylmethane have been identified as having the largest effects for symptomatic relief in a systematic review. It is important to understand whether any pharmacokinetic interactions are among the major constituents of these supplements so as to provide information when considering the combination use of these supplements. The aim of this study was to investigate the pharmacokinetics of the constituents alone and in combination. METHODS: This study was a randomized, open-label, single-dose, four-treatment, four-period, crossover study with 1-week washout. The pharmacokinetics of the constituents of these supplements when dosed in combination with methylsulfonylmethane were compared to being administered alone. Plasma samples were obtained over 24 h from 16 healthy participants. Eight major constituents were analysed using a validated ultra-high-performance liquid chromatography-tandem mass spectrometry assay. KEY FINDINGS: The pharmacokinetics of each constituent was characterized, and there were no significant differences in the pharmacokinetic profiles of the constituents when administered as a combination, relative to the constituents when administered alone (P > 0.05). CONCLUSIONS: These data suggest that interactions between the major constituents of this supplement combination are unlikely and therefore could be investigated to manage patients with osteoarthritis without significant concerns for possible pharmacokinetic interactions.

Assessment of human placenta as an ex-vivo vascular model for testing of liquid embolic agent injections with adjunctive techniques.

PURPOSE: This project sought to test the utility of post-delivery human placenta (HP) as a vascular model for liquid embolic agent (LEA) simulation, along with adjunctive techniques. MATERIALS AND METHODS: Twelve LEA injections were performed under fluoroscopy in HP with two reflux control methods: dual lumen 'mini' balloon-catheter (n=9); and injection after proximal nBCA plug formation through a second microcatheter ('pressure cooker') (n=3). Measured outcomes included liquid embolic agent (LEA) advancement and reflux. Reflux was categorized into three grades: grade 0=no reflux; grade 1=occlusion of side branches without reflux beyond the balloon or plug; and grade 2=reflux beyond the balloon or plug. RESULTS: Simulation success was greater when a balloon was used rather than with a nBCA plug (89% vs 33%, P=0.054). In eight successful balloon-assisted injections, the reflux grades were: 50% grade 0; 12.5% grade 1; and 37.5% grade 2. The one successful nBCA plug injection had grade 2 reflux. All grade 2 balloon injections occurred when the balloon was positioned across a vessel bifurcation. CONCLUSIONS: HP provides excellent simulation for liquid embolic agents with a dual lumen balloon catheter.

A comparative assessment of preclinical chemotherapeutic response of tumors using quantitative non-Gaussian diffusion MRI.

BACKGROUND: Diffusion-weighted MRI (DWI) signal attenuation is often not mono-exponential (i.e. non-Gaussian diffusion) with stronger diffusion weighting. Several non-Gaussian diffusion models have been developed and may provide new information or higher sensitivity compared with the conventional apparent diffusion coefficient (ADC) method. However the relative merits of these models to detect tumor therapeutic response is not fully clear. METHODS: Conventional ADC, and three widely-used non-Gaussian models, (bi-exponential, stretched exponential, and statistical model), were implemented and compared for assessing SW620 human colon cancer xenografts responding to barasertib, an agent known to induce apoptosis via polyploidy. Bayesian Information Criterion (BIC) was used for model selection among all three non-Gaussian models. RESULTS: All of tumor volume, histology, conventional ADC, and three non-Gaussian DWI models could show significant differences between control and treatment groups after four days of treatment. However, only the non-Gaussian models detected significant changes after two days of treatment. For any treatment or control group, over 65.7% of tumor voxels indicate the bi-exponential model is strongly or very strongly preferred. CONCLUSION: Non-Gaussian DWI model-derived biomarkers are capable of detecting tumor earlier chemotherapeutic response of tumors compared with conventional ADC and tumor volume. The bi-exponential model provides better fitting compared with statistical and stretched exponential models for the tumor and treatment models used in the current work.

A randomized, open-label, multicenter study of the efficacy and safety of intravesical hyaluronic acid and chondroitin sulfate versus dimethyl sulfoxide in women with bladder pain syndrome/interstitial cystitis.

AIMS: Intravesical instillation of hyaluronic acid (HA) plus chondroitin sulfate (CS) in women with bladder pain syndrome/interstitial cystitis (BPS/IC) has shown promising results. This study compared the efficacy, safety, and costs of intravesical HA/CS (Ialuril® , IBSA) to dimethyl sulfoxide (DMSO). METHODS: Randomized, open-label, multicenter study involving 110 women with BPS/IC. The allocation ratio (HA/CS:DMSO) was 2:1. Thirteen weekly instillations of HA (1.6%)/CS (2.0%) or 50% DMSO were given. Patients were evaluated at 3 (end-of-treatment) and 6 months. Primary endpoint was reduction in pain intensity at 6 months by visual analogue scale (VAS) versus baseline. Secondary efficacy measurements were quality of life and economic analyses. RESULTS: A significant reduction in pain intensity was observed at 6 months in both treatment groups versus baseline (P < 0.0001) in the intention-to-treat population. Treatment with HA/CS resulted in a greater reduction in pain intensity at 6 months compared with DMSO for the per-protocol population (mean VAS reduction 44.77 ± 25.07 vs. 28.89 ± 31.14, respectively; P = 0.0186). There were no significant differences between treatment groups in secondary outcomes. At least one adverse event was reported in 14.86% and 30.56% of patients in the HA/CS and DMSO groups, respectively. There were significantly fewer treatment-related adverse events for HA/CS versus DMSO (1.35% vs. 22.22%; P = 0.001). Considering direct healthcare costs, the incremental cost-effectiveness ratio of HA/CS versus DMSO fell between 3735€/quality-adjusted life years (QALY) and 8003€/QALY. CONCLUSIONS: Treatment with HA/CS appears to be as effective as DMSO with a potentially more favorable safety profile. Both treatments increased health-related quality of life, while HA/CS showed a more acceptable cost-effectiveness profile.

Retinoic acid and dimethyl sulfoxide promote efficient delivery of transgenes to mouse skin by topically transdermal penetration.

Simple and efficient gene transfer to the skin would facilitate many local and systemic gene therapy applications. This study reports a novel approach that allows expression of plasmid DNA in epidermis and hair follicle cells with dimethyl sulfoxide (DMSO) after pre-treatment with depilation and retinoic acid (RA) for the purposes of gene therapy. This study investigated the transdermal efficacy of gene to mouse skin when utilizing DMSO after RA pre-treatment. Retinoic acid pre-treatment can increase the efficiency of transfection. This finding indicates that one can more effectively and much less expensively make use of genes therapy to treat diseases of the hair and skin.

Assessment of methylsulfonylmethane as a permeability enhancer for regional EDTA chelation therapy.

Pharmacologic chelators do not effectively penetrate cell membranes and blood-brain barrier. This study assesses methylsulfonylmethane (MSM) as a permeability enhancer and an excipient to facilitate EDTA transport across biologic membranes, and to make possible localized, regional chelation. Topical application of MSM with C(14)EDTA onto the rat cornea led to uptake of the C(14)EDTA in all tested ocular tissues. Without MSM, EDTA did not penetrate the eye. The ability of MSM to deliver EDTA into an eye provides an opportunity for regional chelation therapy. Additionally, these studies suggest that MSM could also be an adjuvant for delivering ciprofloxacin and other chemical compounds to specific, local tissue sites.

Measurement of skin-fold thickness in the guinea pig. Assessment of edema-inducing capacity of cutting fluids, acids, alkalis, formalin and dimethyl sulfoxide.

The rabbit has been used for decades for predictive testing of skin irritancy, but in recent years, the guinea pig has been suggested as an alternative, especially for assessment of one of the components of the irritant reaction: edema (fluid accumulation). A method based on skin-fold measurements with Harpenden calipers has been developed and modified. In previous papers, experience with sodium lauryl sulphate, nonanoic acid and industrial solvents was reported. The present results concern the use of cutting fluids, buffered and unbuffered acid and alkaline solutions, formalin and dimethyl sulfoxide. This inexpensive and comparatively unsophisticated method afforded clear dose-response relationships and good discriminating power. The only exception was the acid and alkaline solutions, where no changes in skin-fold thickness were observed despite their documented irritant potential. The appearance of erythema (visual scoring) and the increase in skin-fold thickness, and their relationship, are discussed with some illustrative examples. The method described is now well standardized and is suited for predictive testing of the edema-inducing capacity of chemicals and products.