Passive Diffusion of Transdermal Glucose: Noninvasive Glucose Sensing Using a Fluorescent Glucose Binding Protein.

The motivation for this study was to determine if a statistically significant correlation exists between blood glucose (BG) and transdermal glucose (TG) collected by passive diffusion. A positive outcome will indicate that noninvasive passive TG diffusion is a painless alternative to collecting blood through a break on the skin. Sampling involves placing a small volume of buffer solution on the surface of membrane or skin for 5 minutes. The sample is then assayed with fluorescent GBP. In vitro testing was done on regenerated cellulose and a porcine skin model to determine diffusion of standard glucose solutions. In vivo testing was done on a healthy subject and a subject with type 2 diabetes. Glucose diffused readily through the regenerated cellulose membrane with good correlation between surface and internal glucose concentrations (R 2 = .997). But the porcine skin model required a surface prewash to achieve the same good correlation R 2 = .943). Based on this, an optimum prewash step was determined for the in vivo studies. The resulting correlation coefficients between TG and BG after a 15-minute prewash in a healthy subject and type 2 subject were .87 and .93, respectively. Removal of the extraneous glucose in the skin by prewashing was an important step in achieving good correlation between TG and BG. The results suggest that passive collection of TG is a noninvasive alternative to current practice of breaking the skin. Further studies are under way to determine the lag time between TG and BG and for the sampling protocol to be more amenable to point-of-care application.

Transdermal flux predictions for selected selective oestrogen receptor modulators (SERMs): comparison with experimental results.

The aim of this work was to evaluate the feasibility of delivering transdermally a series of highly lipophilic compounds (log P ~4-7), comprising several selective oestrogen receptor modulators and a modified testosterone (danazol). The maximum fluxes of the drugs were predicted theoretically using the modified Potts & Guy algorithm (to determine the permeability coefficient (kp) from water) and the calculated aqueous solubilities. The correction provided by Cleek & Bunge took into account the contribution of the viable epidermal barrier to the skin permeation of highly lipophilic compounds. Experimental measurements of drug fluxes from saturated hydroalcoholic solutions were determined in vitro through excised pig skin. Overall, the predicted fluxes were in good general agreement (within a factor of 10) with the experimental results. Most of the experimental fluxes were greater than those predicted theoretically suggesting that the 70:30 v/v ethanol-water vehicle employed may have had a modest skin penetration enhancement effect. This investigation shows that the transdermal fluxes of highly lipophilic compounds can be reasonably predicted from first principles provided that the viable epidermis, underlying the stratum corneum, is included as a potentially important contributor to the skin's overall barrier function. Furthermore, the absolute values of the measured fluxes, when considered in parallel with previous clinical studies, indicate that it might be feasible to topically deliver a therapeutically useful amount of some of the compounds considered to treat cancerous breast tissue.

Correlation between sweat glucose and blood glucose in subjects with diabetes.

BACKGROUND: Sweat contains glucose that can accurately reflect blood glucose. However, skin surface glucose can confound these measurements. METHODS: A perfusion method was used to rapidly harvest sweat from forearm sites on human subjects. The sweat samples were analyzed for glucose by high-performance liquid chromatography methods and compared with the results obtained with a blood glucose meter. RESULTS: The results of 23 different studies of seven individual subjects with diabetes show a strong correlation between sweat glucose and blood glucose. CONCLUSION: Sweat glucose, when properly harvested to prevent contamination from other sources on the skin's surface, can accurately reflect blood glucose levels.

Transdermal drug delivery: clinical considerations for the obstetrician-gynecologist.

INTRODUCTION: The first transdermal drug delivery system was introduced in the United States over 20 years ago. Created as an alternative route of administration to improve patient compliance as well as to reduce side effects, the transdermal delivery of drugs now represents a $1.5 to $2 billion market and is growing rapidly. DATA SOURCES: The medical literature from 1980 to 2005 was searched using the PubMed search engine. The search term was "transdermal," limited to human clinical trials. Abstracts were used to identify clinical trials that compared transdermal preparations and their oral counterparts in the same study. TABULATION, INTEGRATION, AND RESULTS: In this article, we review the rationale for the transdermal administration of drugs; discuss aspects of the anatomy and physiology of the skin relevant to drug transport; examine the qualities required for a drug to be a good candidate for transdermal delivery; and consider key principles for the evaluation of the relative benefits of transdermal delivery, using studies of hormone replacement therapy and oral contraceptive as examples. CONCLUSION: The data reviewed here suggest that certain clinical situations support the use of the transdermal administration of drugs over their oral counterparts.

Physiological differences between interstitial glucose and blood glucose measured in human subjects.

OBJECTIVE: This study investigated whether glucose readings from a sensor sampling in interstitial fluid differ substantially from blood glucose (BG) values measured at the same time. RESEARCH DESIGN AND METHODS: We have evaluated the relationship between BG and glucose extracted from interstitial fluid using the GlucoWatch (Cygnus, Redwood City, CA) biographer, a device that collects glucose from subcutaneous interstitial space through intact skin by application of a low electric current. We evaluated the relative change in the interstitial glucose (IG) signal (IGS) as measured by the biographer versus BG using a normalized two-point sensitivity index (NSI). RESULTS: The results show that biographer measures of IG differ in time and magnitude from the corresponding BG values. In particular, the biographer values were shifted in time due to instrumental and physiological lag. Results show an average total lag of 17.2 +/- 7.2 min for all subjects evaluated. The instrumental lag was 13.5 min, suggesting that physiological lag is approximately 5 min. In addition, when glucose was increasing, the change in IGS was less than that in BG, while when BG was decreasing, the change in IGS was greater than that in BG. CONCLUSIONS: Similar results have been reported for other measures of IG, suggesting that differences reflect physiological variation in glucose uptake, utilization, and elimination in blood and interstitial space. This further evidence of the difference between IG and BG should be considered when interpreting glucose measurements from devices that sample interstitial fluid.

Frequency and thermal effects on the enhancement of transdermal transport by sonophoresis.

The aims of this work were: (i) to examine the role of ultrasound (US) frequency and intensity on the transport of glucose and mannitol across porcine skin in vitro, (ii) to quantify the energy delivered to the skin during application of low-frequency sonophoresis, and (iii) to 'deconvolute' the thermal effect, induced by US application to the skin, to the enhanced permeability of the cutaneous barrier. Low- (20 kHz) and high-frequency (10 MHz) sonophoresis were first compared. Only low frequency US resulted in significantly increased permeation. Low-frequency, US-induced enhancement of mannitol transport was symmetric; that is, mannitol flux was the same when 'delivered' or 'extracted' from a donor solution (in both cases, the US probe was present on the surface side of the skin). Calorimetry was used to quantify the US energy delivered by the sonicator. Subsequently, the US-enhanced transdermal transport of mannitol, during which a significant (and US intensity-dependent) temperature increase occurred, was compared to that provoked, in the absence of sonophoresis, by a comparable thermal effect. Only 25% of this enhancement was attributable to the increased temperature induced by US. It follows that another mechanism, most probably cavitation, is principally responsible for the lowered skin barrier function observed.

Glucose monitoring by reverse iontophoresis.

Glucose can be extracted through intact skin by electro-osmotic flow (a process called 'reverse iontophoresis') upon the application of a low-level electrical current. Recently we have combined iontophoretic extraction with an in situ glucose sensor in a device called the GlucoWatch biographer. Clinical results with this device show close tracking of blood glucose over a range of 2.2 to 22.2 mmol/l for up to 12 h using a single blood glucose value as calibration. The biographer readings lag behind blood glucose values by an average of 18 min. An analysis of data from 92 diabetic subjects in a controlled clinical setting shows a linear relationship (r=0.88) between GlucoWatch biographer readings and blood glucose. The mean absolute relative difference between the two measurements was 15.6% and more than 96% of the data fell in the (A+B) regions of the Clarke error grid. Similar results have been obtained from subjects using the GlucoWatch biographer in an uncontrolled home environment. The automatic, frequent, and non-invasive measurements obtained with the GlucoWatch biographer provide substantially more information about glucose levels than do the current fingerstick methods. This information can be used for improved decisions about all aspects of diabetes management.