Promoting absorption of drugs in humans using medium-chain fatty acid-based solid dosage forms: GIPET™

One of the most important and challenging goals in drug delivery is overcoming the poor oral absorption of high-value therapeutics that include peptides. Gastrointestinal Permeation Enhancement Technology (GIPET?) attempts to address this question by safely delivering drugs across the small intestine in therapeutically relevant concentrations. GIPET is based primarily on promoting drug absorption through the use of medium-chain fatty acids, medium-chain fatty acid derivatives and microemulsion systems based on medium-chain fatty acid glycerides formulated in enteric-coated tablets or capsules. Importantly, these excipients are generally regarded as safe and the systems are formulated in such a way that there is no change in chemical composition of the active ingredient. More than 300 volunteers have been administered GIPET formulations in 16 Phase I studies of 6 separate drugs comprising both single- and repeat-dosing regimes. Oral bioavailability of alendronate, desmopressin and low-molecular-weight heparin in humans was increased using GIPET formulations compared with unformulated controls. GIPET was well tolerated by human subjects. Using fluxes of markers of epithelial permeability, the effects of GIPET on the human intestine were shown to be rapid, short-lived and reversible in vivo. These data suggest that GIPET formulations have genuine potential as a platform technology for safe and effective oral drug delivery of a wide range of poorly permeable drugs.     

Modeling cumulative incidence function for competing risks data

A frequent occurrence in medical research is that a patient is subject to different causes of failure, where each cause is known as a competing risk. The cumulative incidence curve is a proper summary curve, showing the cumulative failure rates over time due to a particular cause. A common question in medical research is to assess the covariate effects on a cumulative incidence function. The standard approach is to construct regression models for all cause-specific hazard rate functions and then model a covariate-adjusted cumulative incidence curve as a function of all cause-specific hazards for a given set of covariates. New methods have been proposed in recent years, emphasizing direct assessment of covariate effects on cumulative incidence function. Fine and Gray proposed modeling the effects of covariates on a subdistribution hazard function. A different approach is to directly model a covariate-adjusted cumulative incidence function, including a pseudovalue approach by Andersen and Klein and a direct binomial regression by Scheike, Zhang and Gerds. In this paper, we review the standard and new regression methods for modeling a cumulative incidence function, and give the sources of computer packages/programs that implement these regression models. A real bone marrow transplant data set is analyzed to illustrate various regression methods.     

Histologists,Microtomy, Chronic Repetitive Trauma,and Techniques to Avoid Injury: II. A Physical and Rehabilitation Medicine Physician's Perspective

Abstract

In the first of this series of articles, a national survey of histotechnologists revealed an unexpectedly high incidence of cumulative trauma disorders (CTD) or carpal tunnel syndrome (CTS). Previous reports for CTS have shown incidences ranging from 125 to 515 per 100,000 population in random surveys. Using a focused survey of only American Society of Clinical Pathologist registered technologists, an estimated population incidence of 2,200 per 100,000 had medically treated CTS, 6,300 per 100,000 had medically treated CTD and 14,800 per 100,000 had chronic pain symptomatology.

In this article, members of the Department of Physical and Rehabilitation Medicine discuss the etiology and potential remedies for reducing the incidence of CTD or CTS. ( The J Histotechnol 18:327, 1995).     

Oxygen delivery from hyperbarically loaded microtanks extends cell viability in anoxic environments

Oxygen diffusion limitations within nascent tissue engineered (TE) grafts lead to the development of hypoxic regions, cell death, and graft failure. Previous efforts have been made to deliver oxygen within TE scaffolds, including peroxide-doping, perfluorocarbons, and hyperbaric oxygen therapy, to mitigate these effects and help maintain post transplantation cell viability, but these have suffered from significant drawbacks. Here we present a novel approach utilizing polymeric hollow-core microspheres that can be hyperbarically loaded with oxygen and subsequently provide prolonged oxygen delivery. These oxygen carriers are termed, microtanks. With an interest in orthopedic applications, we combined microtanks within polycaprolactone to form solid phase constructs with oxygen delivery capabilities. The mathematical laws governing oxygen delivery from microtank-loaded constructs are developed along with empirical validation. Constructs achieved periods of oxygen delivery out to 6 days, which was shown to prolong the survival of human adipose derived stem cells (hASCs) and human umbilical vein endothelial cells (HUVECs) as well as to enhance their cellular morphology under anoxic conditions. The results of this study suggest the microtank approach may be a feasible means of maintaining cell viability in TE scaffolds during the critical period of vascularization in vivo.     

Skin permeation and metabolism of di(2-ethylhexyl) phthalate (DEHP)

Phthalates are suspected to be endocrine disruptors. Di(2-ethylhexyl) phthalate (DEHP) is assumed to have low dermal absorption; however, previous in vitro skin permeation studies have shown large permeation differences. Our aims were to determine DEHP permeation parameters and assess extent of skin DEHP metabolism among workers highly exposed to these lipophilic, low volatile substances.     

Comparison between a new multiplex electrochemiluminescence assay and the WHO reference enzyme-linked immunosorbent assay to measure serum antibodies against pneumococcal serotype-specific polysaccharides

Background

Two electrochemiluminescence (ECL) assays were developed which, together, can simultaneously measure serum antibodies against pneumococcal capsular polysaccharides (PnPS) for 17 serotypes. The assays were validated for the 13 PnPS included in the 13-valent pneumococcal conjugate vaccine (PCV13). As recommended by the World Health Organization (WHO), we compared the ECL assays with the WHO reference enzyme-linked immunosorbent assay (ELISA) and derived a threshold corresponding to the 0.35?µg/mL threshold established for the WHO reference ELISA for the non-inferiority comparison and licensure of new PCVs against invasive pneumococcal disease.

Dermal safety assessment of Arm & Hammer laundry products formulated for sensitive skin

Context: The prevalence of sensitive skin among the general population in industrialized countries is reported to be over 50%. Sensitive skin subjects often report significant reactions to contact with cosmetics, soaps and other consumer products.

Objective: This paper describes the overall skin compatibility and mildness program for a newly developed, lightly fragranced, colorant free laundry product (i.e. Arm &; Hammer? Sensitive Skin plus Skin-Friendly Fresh Scent), specially formulated for individuals with sensitive skin. The skin mildness of the product was compared to Arm &; Hammer? Free &; Clear liquid laundry detergent with no fragrance or colorant, and an established history of safe use by sensitive skin consumers.

Materials and methods: The test material was a liquid laundry product with a light scent formulated for sensitive skin consumers (Arm &; Hammer? Sensitive Skin plus Skin-Friendly Fresh Scent). The product was compared to commercially marketed products for sensitive skin with a history of skin safety in the marketplace, including: a very similar product formulation (Arm &; Hammer? Free &; Clear with no fragrance), and several selected competitors’ products. Studies were conducted among individuals with self-assessed sensitive skin (based on a questionnaire) using standard protocols for the Human Repeat Insult Patch Test (HRIPT), 10-Day Cumulative Irritation, the Wrist Band Wear test, and the Safety In-Use testing. Responses in all protocols were evaluated by visual scoring of potential dermatologic reactions, and recording any sensory effects at the time of the examination. In addition, sensory effects collected from panelists’ daily diaries were also evaluated.

Results: The HRIPT confirmed that neither the fragrance alone, nor the product formulation with fragrance, induced contact sensitization in sensitive skin subjects. The 10-Day cumulative irritation study conducted using sensitive skin subjects showed highly favorable skin compatibility, and the test product was comparable to the control product (Arm &; Hammer Free &; Clear) and other nonirritant controls. In the Wrist Band Wear test, exposure to laundered fabrics under exaggerated conditions gave similar results for the test and control products, with no objective signs of skin irritation, and no self-reported persistent adverse sensory effects. Very mild, transient and isolated sensory effects were noted in daily diaries by a small proportion of subjects, and were similar for the test and control products. The Safety In-Use tests evaluated 4-week exposure to product and laundered fabrics under realistic use conditions. There were no clinically objective signs of skin irritation, and reports of transitory, mild sensory effects were minimal and similar for the test and controls.

Discussion and conclusion: A comprehensive skin safety program on a lightly scented sensitive skin laundry formulation (i.e. Arm &; Hammer? Sensitive Skin plus Skin-Friendly Fresh Scent) conducted among panels of self-assessed sensitive skin subjects demonstrated that the presence of a light fragrance did not adversely impact skin compatibility in any of the testing protocols when the product was compared to a similar product with no fragrance. The lightly fragranced product demonstrated overall skin compatibility and mildness when tested in a self-assessed sensitive skin population, and compared favorably to currently marketed sensitive skin products.