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Biomedical subjects

R O Potts

Publications and source records attributed to R O Potts.

At least 37 records · Page 2Linked to original sources
PubMed1995

Reverse iontophoresis: noninvasive glucose monitoring in vivo in humans.

PURPOSE: To demonstrate that "reverse iontophoresis" can be used to noninvasively obtain information about systemic glucose levels in vivo in humans. METHODS: The passage of current across the skin in vivo drives ions into the tissue, from the electrode chambers positioned on the skin surface, and simultaneously pulls ions from the body in the opposite direction. Because of the net negative charge on the skin, under normal conditions, the membrane is permselective to cations, and a potential gradient also results, therefore, in electroosmotic convection of solvent in the direction of counterion flow (i.e., from anode to cathode). Thus, it is also possible to enhance the transport of polar, yet uncharged, species using iontophoresis. In an earlier study, the in vitro extraction of glucose, by "reverse iontophoresis" was established, and extension of the approach to an in vivo model was indicated. The idea has therefore been further explored in vivo in humans. RESULTS: Using small, simple, prototypical electrode chambers, attached to the ventral forearm surface, direct current iontophoresis at 0.25 mA/cm2 for periods of up to 1 hour, and a sensitive analytical procedure to measure the quantities of glucose extracted, it has been shown that iontophoretic sampling of glucose is feasible. However, the shorter periods (15 minutes or less) of extraction considered yield results which are "contaminated" (it is believed) by glucose that is a product of lipid metabolism within the skin. While this material is expected to complicate the initial calibration of the approach, the problem is effectively resolved within one hour, by which time the glucose arriving in the electrode chambers on the skin surface is expected to directly reflect the subcutaneous tissue concentration. CONCLUSIONS: Based upon these initial observations, further investigation can now be directed towards optimization of electroosmotic flow and sampling time, improved reproducibility and the development of a practical assay methodology.

Blood Glucose↗
PubMed1995

Measurement of glucose in diabetic subjects using noninvasive transdermal extraction.

Results from the Diabetes Care and Complications Trial show that tight blood glucose control significantly reduces the long-term complications of diabetes mellitus. In that study, frequent self-testing of glucose and insulin administration resulted in a significant reduction in long-term complications. This protocol, however, also resulted in a threefold increase in the frequency of hypoglycaemic incidents. Currently, self-testing requires a drop of blood for each measurement. The pain and inconvenience of self-testing, along with the fear and danger of hypoglycaemia has led to poor patient acceptance of a tight control regimen, despite the clear long-term advantages. A continuously worn, noninvasive method to periodically measure glucose would provide a convenient and comfortable means of frequent self-testing. A continuously worn device could also alert the user of low glucose levels, thereby reducing the incidence of hypoglycaemia. Guy et al. demonstrated a noninvasive method to transport glucose through the skin using low-level electrical current. To provide a quantitative measurement, the flux of glucose extracted across the skin must correlate with serum glucose in a predictive manner. The results presented here show a quantitative relationship between serum and transdermally extracted glucose in diabetics.

Adult↗
PubMed1995

Transdermal drug delivery: useful paradigms.

The successful development of transdermal delivery systems requires a systematic evaluation and understanding of a number of complex phenomena. For example, the study of drug transport through skin (and other biomembranes) has lead to a significant advance in our ability to select drugs which are appropriate for transdermal delivery. Drug release from the transdermal system is also crucial to effective drug delivery and provides a clear opportunity for research in adhesion, polymer physical chemistry, mass transport, and film coating, to name a few. The incorporation of several disciplines into transdermal science holds the exciting promise to provide rapid advances in this technology.

Administration, Cutaneous↗
PubMed1994

Fluorescence spectroscopy of 9-anthroyloxy fatty acids in solvents.

A series of anthroyloxy fatty acid (AF) fluorescent probes, with the anthroyloxy group covalently linked at various positions along the alkyl chain, were studied in solvents exhibiting a wide range of polarity and hydrogen-bond donor (Hd) and acceptor (Ha) ability. These probes were sensitive to the solvent polarity as reflected by the Stokes' shift observed in steady state fluorescence. As determined by multi-linear regression analysis of the observed Stokes' shift and solvent parameters, such as orientation polarizability (delta f), Hd and Ha of the solvents, all the probes were sensitive to the Hd of solvents but were not affected by the Ha of solvents except the 2-AF. Due to the proximity of the polar headgroup to the fluorophore, it appears that some intramolecular hydrogen-bonding is present in 2-AF, an interaction that is sensitive to the pH of the solvent, but is less sensitive to the Hd and Ha of the solvents. Fluorescence lifetimes measured by the multi-frequency phase-modulation technique in mixtures of hexane and ethanol reflect a modified Stern-Volmer behavior suggesting the second solvent, ethanol, specifically interacts with the probe, in part through collisional quenching. Also, the lifetime data were sensitive to very low concentrations of the second solvent (0-0.1%, by vol.). The results from this study provide insight into the intrinsic differences between the different AF positions that must be taken into consideration while investigating the dynamics of lipid bilayer systems. Moreover, this study illustrates the utility and resolving power of lifetime based measurements needed for the interpretation of heterogeneous biophysical environments.

Anthracenes↗
PubMed1994

Polymorphism in stratum corneum lipids.

Fourier transform infrared spectroscopy (FTIR) was employed to investigate the thermotropic phase behavior of stratum corneum lipid multilamellae. Stratum corneum (SC), the uppermost layer of mammalian skin, is unusual in many respects. It has been demonstrated that the lipids of the stratum corneum provide the primary electrical and transport resistance in the skin. These lipids are unusual in their composition, structure and localization; they contain only cholesterol, fatty acids and ceramides and they form broad, multi-lamellar sheets which are located extracellularly. The FTIR results from both the symmetric CH2 stretching and the CH2 scissoring vibrations suggest that the SC lipids exhibit polymorphic phase behavior below the main phase transition temperature. The multiple phases are most likely crystalline mixtures of different alkyl chain packings, along with solid-liquid phases. Similarities between the FTIR results reported here for SC lipids and those obtained for cholesterol-containing gel phase phospholipids suggest that the non-uniform distribution of cholesterol occurs in each system.

Animals↗
PubMed1994

Effect of electroporation on transdermal iontophoretic delivery of luteinizing hormone releasing hormone (LHRH) in vitro.

Electroporation, the creation of transient, enhanced membrane permeability using short duration (microseconds to millisecond) electrical pulses, can be used to increase transdermal drug delivery. The effect of an (electroporative) electric pulse (1000 V, tau = 5 msec) on the iontophoretic transport of LHRH through human skin was studied in vitro. Fluxes achieved with and without a pulse under different current densities (0- 4 mA/cm2) were compared. The results indicated that the application of a single pulse prior to iontophoresis consistently yielded higher fluxes (5-10 times the corresponding iontophoretic flux). For example, at 0.5 mA/cm2 fluxes were 0.27 +/- 0.08 and 1.62 +/- 0.05 micrograms/hr/cm2 without and with the pulse, respectively. At each current density studied, the LHRH flux decreased after iontophoresis, approaching pre-treatment values. The results show that electroporation can significantly and reversibly increase the flux of LHRH through human skin. These results also indicate the therapeutic utility of using electroporation for enhanced transdermal transport.

Amino Acid Sequence↗
PubMed1993

Penetration of industrial chemicals across the skin: a predictive model.

The recently reported dermal absorption and toxicity potential of industrial chemicals is reconsidered using an alternative physicochemically based model of skin penetration. In this model, the outermost, and least permeable, component of the skin [namely, the stratum corneum (SC)] is considered to provide only a lipoidal transport pathway into the body for chemicals that come into contact with the skin. The predictive algorithm of the model is biophysically compatible with known SC properties, and is based on experimental determinations of permeability coefficients through human skin in vitro for nearly 100 compounds of widely divergent physicochemical properties. This simpler prediction results in significantly lower estimates of maximum percutaneous penetration fluxes.

Diffusion↗
PubMed1993

Validation of reflectance infrared spectroscopy as a quantitative method to measure percutaneous absorption in vivo.

Attenuated total-reflectance infrared (ATR-IR) spectroscopy has been used to follow the penetration of a model compound (4-cyanophenol; CP) across human stratum corneum (SC) in vivo, in man. CP was administered for periods of 1, 2, or 3 hr, either (a) as a 10% (w/v) solution in propylene glycol or (b) in an identical vehicle which also contained 5% (v/v) oleic (cis-9-octadecenoic) acid. At the end of the treatment periods, SC at the application site was progressively removed by adhesive tape-stripping. Prior to the removal of the first tape-strip, and after each subsequent tape-strip, an ATR-IR spectrum of the treated site was recorded. The presence of CP, as a function of position in the SC, was monitored spectroscopically via the intense C = N stretching absorbance at 2230 cm-1. The absolute amount of CP, as a function of SC depth, was determined by "spiking" the applied solutions with 14C-labeled compound and subsequent liquid scintillation counting of the removed tape-strips. The presence of oleic acid in the applied formulation significantly increased the rate and extent of CP delivery as evaluated by either spectroscopy or radiochemical analysis. Furthermore, the ATR-IR and direct 14C analysis of CP as a function of SC position were highly correlated. These data strongly support, therefore, the validation of ATR-IR as a quantitative tool to assess percutaneous penetration in vivo.

Administration, Cutaneous↗
PubMed1992

Secondary structural analysis of two recombinant murine proteins, interleukins 1 alpha and 1 beta: is infrared spectroscopy sufficient to assign structure?

The secondary structure for two murine recombinant proteins, interleukins 1 alpha and 1 beta (rmIL-1 alpha and -1 beta), has been analyzed by Fourier transform infrared (IR) spectroscopy and then compared to results obtained by X-ray diffraction, circular dichroism (CD), and nuclear magnetic resonance (NMR) spectroscopy. The IR results obtained here for rmIL-1 alpha and -1 beta suggested that their secondary structures consisted predominantly of beta-sheets or strands. However, the analysis also revealed a significant absorption band near 1656 cm-1, which is typically assigned to alpha-helical or random structures. When these same murine polypeptides were analyzed by CD, no evidence of alpha-helical structures was observed. Further, published X-ray diffraction and NMR studies characterizing the human forms of IL-1 alpha and -1 beta indicate the absence of alpha-helices and that the human proteins are composed mainly of beta-strands (i.e., greater than 55%), with approximately 24% of the amino acids involved in large loops connecting the strands. The murine IL-1 proteins, when compared to their respective human counterparts, each show greater than 80% sequence homology. Given this fact, the CD analyses, and the result that this IR band amounted to 21% of the overall integrated area, the absorption peak at 1656 cm-1 was attributed to the presence of large loops rather than to alpha-helical or random structures. Such a structural assignment appears reasonable and is totally consistent with the established existence of large loops in the human forms as well as in other proteins found to fold similarly (viz., human bFGF).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Predicting skin permeability.

Published permeability coefficient (Kp) data for the transport of a large group of compounds through mammalian epidermis were analyzed by a simple model based upon permeant size [molecular volume (MV) or molecular weight (MW)] and octanol/water partition coefficient (Koct). The analysis presented is a facile means to predict the percutaneous flux of pharmacological and toxic compounds solely on the basis of their physiocochemical properties. Furthermore, the derived parameters of the model have assignable biophysical significance, and they provide insight into the mechanism of molecular transport through the stratum corneum (SC). For the very diverse group of chemicals considered, the results demonstrate that SC intercellular lipid properties alone are sufficient to account for the dependence of Kp upon MV (or MW) and Koct. It is found that the existence of an "aqueous-polar (pore) pathway" across the SC is not necessary to explain the Kp values of small, polar nonelectrolytes. Rather, their small size, and consequently high diffusivity, accounts for their apparently larger-than-expected Kp. Finally, despite the size and breadth of the data set (more than 90 compounds with MW ranging from 18 to greater than 750, and log Koct ranging from -3 to +6), the postulated upper limiting value of Kp for permeants of very high lipophilicity cannot be determined. However, the analysis is able to define the physicochemical characteristics of molecules which should exhibit these maximal Kp values.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Transport↗
PubMed1992

Local enhanced topical delivery (LETD) of drugs: does it truly exist?

There is considerable uncertainty over whether and to what extent topically applied drugs can be delivered directly to anatomical sites beneath the skin, without prior entry into the systemic blood circulation. The in vivo studies reported in this work were designed to assess whether local enhanced topical delivery (LETD) can be achieved with piroxicam, a nonsteroidal antiinflammatory drug. Equivalent doses of tritium-labeled drug were administered by the i.v. or topical routes to male rats. The topical plasma profile reveals a maximum concentration (Cpmax) at 12 hr, compared to a typical, multiexponential decline in plasma concentration after i.v. dosing. All four muscles from the topically dosed shoulder exhibit two distinct peaks, the first at 4 hr and a later one at 12 hr (which coincides with the topical Cpmax). The contralateral muscles from the nondosed shoulder, in contrast, produce only a single peak at 12 hr after topical dosing. After the i.v. administration of piroxicam, the concentration-time profiles for each muscle closely parallel that seen for the i.v. plasma. Tissue-to-plasma ratios (T/P) show that the topical nondosed and the i.v. muscles are nearly constant over the entire time course of this study, indicating a pseudo-equilibrium between the plasma and those muscles. However, the early T/P ratios for the topically dosed muscles are markedly elevated and gradually decline to a constant value only after 12 hr, indicating that a similar pseudo-equilibrium is not established in this case. Thus, these results strongly imply that the topical administration of a drug can lead to LETD for tissues subjacent to the skin.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗
PubMed1992

Physical methods for studying stratum corneum lipids.

The skin's barrier to water loss and drug transport is closely related to the biophysical properties of the stratum corneum lipids. A number of in vitro and in vivo methods have been used to evaluate the physical properties of stratum corneum lipids. Two particularly useful techniques, infrared spectroscopy and differential scanning calorimetry, have provided a wealth of information about stratum corneum structure and function. The results of these studies demonstrate that the alteration of stratum corneum lipid packing results in increased skin permeability. Furthermore, the magnitude of increased permeability can be predicted from these physical properties. Therefore, these results provide both insight into the mechanism of transport through the stratum corneum, as well as a useful paradigm for selection of agents that reversibly alter the permeability of the skin.

Animals↗
PubMed1991

Evidence that oleic acid exists in a separate phase within stratum corneum lipids.

Oleic acid is known to be a penetration enhancer for polar to moderately polar molecules. A mechanism related to lipid phase separation has been previously proposed by this laboratory to explain the increases in skin transport. In the studies presented here, Fourier transform infrared spectroscopy (FT-IR) was utilized to investigate whether or not oleic acid exists in a separate phase within stratum corneum (SC) lipids. Per-deuterated oleic acid was employed allowing the conformational phase behavior of the exogenously added fatty acid and the endogenous SC lipids to be monitored independently of each other. The results indicated that oleic acid exerts a significant effect on the SC lipids, lowering the lipid transition temperature (Tm) in addition to increasing the conformational freedom or flexibility of the endogenous lipid alkyl chains above their Tm. At temperatures lower than Tm, however, oleic acid did not significantly change the chain disorder of the SC lipids. Similar results were obtained with lipids isolated from the SC by chloroform:methanol extraction. Oleic acid, itself, was almost fully disordered at temperatures both above and below the endogenous lipid Tm in the intact SC and extracted lipid samples. This finding suggested that oleic acid does exist as a liquid within the SC lipids. The coexistence of fluid oleic acid and ordered SC lipids, at physiological temperatures, is consistent with the previously proposed phase-separation transport mechanism for enhanced diffusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗