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PubMed1997

Iontophoretic delivery across the skin: electroosmosis and its modulation by drug substances.

PURPOSE: The long-term objective of this research is to understand how the efficiency of iontophoresis depends upon the structural and physicochemical properties of the administered drug. Specifically, the ability of certain drug species to alter the permselective properties of the skin was examined. METHODS: Using conventional in vitro methodology, the inhibition of electroosmotic flow induced by the iontophoresis of five different beta-blockers (of varying lipophilicity) was examined. The concomitant electrotransport of the most lipophilic species (propranolol) and the convective movement of solvent in the anode-to-cathode direction were measured. In addition, the possibility that electroosmosis might be augmented by the delivery of anionic drugs was also considered. RESULTS: Iontophoresis of lipophilic, cationic beta-blockers caused a concentration-dependent inhibition of conventional electroosmosis. The most hydrophilic analogs elicited no effect. As a result of this charge neutralization phenomenon, the optimal concentration for propranolol iontophoresis was significantly less than the maximum achievable in aqueous solution. Only a very modest improvement in convective solvent flow was induced by the cathodal iontophoresis of anionic compounds. CONCLUSIONS: The permselectivity of the skin can be altered by drugs which are positively charged and which possess a significant, adjacent hydrophobic surface. The latter seems able to "anchor" the molecule in the skin and the counter charge to the membrane's negative character ensures a tight association. Both lipophilicity and a positive charge are essential-without either, the phenomenon is not observed. The conformational flexibility of the drugs studied to-date, however, prevents unambiguous conclusions about the three-dimensional nature of the putative "binding site".

Adrenergic beta-Antagonists↗
PubMed1990

Transport mechanisms in iontophoresis. III. An experimental study of the contributions of electroosmotic flow and permeability change in transport of low and high molecular weight solutes.

The objective of this research was to provide in vitro transport data designed to clarify the relative importance of permeability increase and electroosmotic flow in flux enhancement via iontophoresis. Iontophoretic fluxes were measured with both anode and cathode donor cells, and passive fluxes were measured both before iontophoresis (Passive 1) and after iontophoresis (Passive 2). Data were generated for three uncharged low molecular weight solutes (glycine, glucose, and tyrosine) and two high molecular weight anionic species (carboxy inulin and bovine serum albumin). Flux enhancement is greater for anodic delivery than for cathodic delivery, even for the negatively charged molecules, and anodic flux of glucose decreases as the concentration of NaCl increases. Both observations are consistent with a mass transfer mechanism strongly dependent on electroosmotic flow. Steady-state anodic flux at 0.32 mA/cm2, expressed as equivalent donor solution flux (in microliters/hr cm2), ranged from 6.1 for glycine to about 2 for the large anions. As expected, iontophoretic flux is higher at 3.2 mA/cm2 than at 0.32 mA/cm2, and passive flux measured after iontophoresis is about a factor of 10 greater than the corresponding flux measured before the skin was exposed to electric current. There are two mechanisms for flux enhancement relative to passive flux on "fresh" hairless mouse skin: (1) the effect of the voltage in increasing mass transfer over the passive diffusion level, the effect of electroosmotic flow dominating this contribution in the systems studied in this report; and (2) the effect of prior current flow in increasing the "intrinsic permeability" of the skin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Iontophoretic delivery of a series of tripeptides across the skin in vitro.

The iontophoresis of eight tripeptides, of the general structure alanine-X-alanine, has been measured across hairless mouse skin in vitro. The peptides were blocked (a) at the carboxyl terminus using the mixed anhydride reaction with t-butylamine and (b) at the amino terminus by acetylation with 14C-acetic anhydride. The nature of the central residue (X) was varied by selecting one of five neutral amino acids, two negatively chargeable moieties (aspartic and glutamic acids), and a positively chargeable species (histidine). Constant current iontophoresis at 0.36 mA/cm2, using Ag/AgCl electrodes, was performed for 24 hr in diffusion cells, which allowed both anode and cathode to be situated on the same (epidermal) side of a single piece of skin. Due to a combination of osmotic and electroosmotic forces, the anodal iontophoretic flux of neutral peptides was significantly greater than passive transport. Steady-state fluxes were not achieved, however, suggesting that time-dependent changes in the properties of the skin barrier may be occurring. Limited, further experiments confirmed that, on a 24-hr time scale, these changes were not fully reversible. The cathodal delivery of anionic permeants was well controlled at a steady and highly enhanced rate by the current flow. This behavior closely paralleled earlier work using simple negatively charged amino acids and N-acetylated amino acid derivatives. It appears that the normalized iontophoretic flux of these anionic species is independent of lipophilicity but may be inversely related to molecular weight. The positively charged peptide, Ac-Ala-His-Ala-NH(But), showed greater anodal iontophoretic enhancement when delivered from a donor solution at pH 4.0 than from a solution at pH 7.4.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMed1991

Iontophoretic delivery of amino acids and amino acid derivatives across the skin in vitro.

The effects of penetrant properties (lipophilicity and charge) and of vehicle pH on the iontophoretically enhanced delivery of amino acids and their N-acetylated derivatives have been examined in vitro. The penetrants were nine amino acids (five were zwitterionic, two positively charged, and two negatively charged) and four N-acetylated amino acids, which carry a net negative charge at pH 7.4. Iontophoresis at constant current (0.36 mA/cm2), using Ag/AgCl electrodes, was conducted across freshly excised hairless mouse skin. Iontophoretic flux of the zwitterions was significantly greater than passive transport. Delivery from the anode was greater than from the cathode for all zwitterions. The level of enhancement was inversely proportional to permeant octanol/pH 7.4 buffer distribution coefficient. Cathodal iontophoresis of the negatively charged amino acids and of the N-acetylated derivatives produced degrees of enhancement which were significantly greater than those measured for the "neutral" zwitterions. Furthermore, the enhanced flux reached a steady-state level within a few hours for the negatively charged species, whereas the transport of the zwitterions continued to increase with time. Anodal iontophoresis of histidine and lysine, the two positively charged amino acids studied, induced substantial enhancement which was sensitive to the pH of the delivery vehicle. For example, the flux of histidine from an applied solution at pH 4 (where the amino acid carries a net positive charge) was significantly greater than that from a vehicle at pH 7.4 (where histidine is essentially neutral). The behavior of lysine was more complex and suggested a certain degree of neutralization of the skin's net negative charge.

Administration, Cutaneous↗
PubMed1994

Characterization of convective solvent flow during iontophoresis.

During iontophoresis under neutral pH conditions, there is a net convective flow of volume (electroosmosis) from anode to cathode leading to the enhanced transport of dissolved polar (but uncharged) solutes in the same direction. The objective of this study was to address the following unresolved questions with respect to electroosmotic transport: [1] Whether the efficiency of electroosmotic transport is solute size-dependent and, if so, how severe is this dependence? [2] Is electroosmosis linearly related to current density in the same way that the iontophoretic flux of charged species appears to be? [3] Are positively charged permeants able to influence their own electrotransport across the skin (by modifying the net charge on the membrane and altering, as a result, the permselectivity) and, if so, why and to what extent? Electroosmosis was assessed from the iontophoreically driven fluxes of mannitol, sucrose and lactose across hairless mouse skin in vitro. It was found that:- (a) The electroosmotic transport rate of mannitol is similar to that of the disaccharides, sucrose and lactose, when examined under identical conditions. The dependence of electroosmotic flux upon molecular size requires study of solutes having a wider range of MW than those considered here. (b) Electroosmotic flow from anode-to-cathode increases with applied current density; similarly, convective flow in the opposite direction diminishes with increasing current density. Apparently, there is correlation between the net movement of solvent and the total flux of ions across the skin. (c) The permselectivity of skin can be 'neutralized' by driving, iontophoretically, a cationic, lipophilic peptide (specifically the leutinizing hormone releasing hormone (LHRH) analog, Nafarelin) into the membrane.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Reverse iontophoresis: development of a noninvasive approach for glucose monitoring.

Solvent flow generated during iontophoresis can be used to convect neutral molecules through the skin, thereby greatly enhancing their flux. This concept was exploited to realize noninvasive glucose measurement by its iontophoretic extraction from the subcutaneous tissue. The hypothesis was tested in vitro using hairless mouse skin. The dermal surface was bathed with a glucose solution; chambers on the epidermal surface housed the current delivery electrodes. Iontophoresis (at 0.36 mA/cm2) was performed for 2 hr, at the end of which the solutions in contact with the electrodes were analyzed. The amount extracted was proportional to the glucose solution concentration bathing the dermis. Higher radioactivity levels were found at the anode than at the cathode, possibly because of glucose metabolism during its outward transport across the skin. Glucose biotransformation results in negatively charged metabolites which migrate to the anode. Two sensitive glucose sensors were developed; one was selective for glucose, the other for glucose and related compounds. Both sensors indicated the presence of glucose at the cathode but an abnormally high value was also recorded at the anode. This signal, however, was not due to glucose but rather to electroactive ascorbate withdrawn from the skin. Finally, a system has been developed with which glucose can be extracted noninvasively from the subcutaneous tissue and unambiguously measured. Whether iontophoretic glucose sampling in vivo will be equally successful remains to be answered.

Animals↗
PubMed1993

Convective solvent flow across the skin during iontophoresis.

Enhanced flux of neutral solutes during transdermal iontophoresis is attributed largely to electroosmotic volume flow. In this study, the iontophoretic fluxes of tritiated water (3H2O) and 14C-labeled mannitol through hairless mouse skin (HMS) were determined. The following questions were addressed: (i) What is the variability of water flux during iontophoresis? (ii) To what extent is the iontophoretic flux of a neutral solute correlated with water flux? (iii) Does the intrinsic permeability of the skin to neutral solutes change following iontophoresis? (iv) What is the effect of low pH on electroosmotic volume flow? and (v) Does the skin remain permselective after removal of the stratum corneum? Transport of both water and mannitol reached steady-state levels during 10 hr of constant-current iontophoresis (0.36 mA/cm2). Anodal fluxes exceeded cathodal values. Cathodal mannitol flux was retarded, relative to passive transport, by net volume flow in the opposite direction, such that transport of this molecule increased significantly after the termination of current passage. Anodal equivalent volume flows for water and mannitol, respectively, were 2.7 (+/- 1.3) and 1.23 (+/- 0.59) microL/hr cm2, indicating that only approximately 50% of the water flux participated in the electroosmosis of mannitol. The passive permeability of water and mannitol after 10 hr of iontophoresis was, respectively, 6 and 30 times greater than the pretreatment values. At pH 7, the cationic permselectivity of HMS was marginal [the Na+ transport number (tNa+) was determined to be 0.46] and less than that reported for human skin.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMed2004

Brain pathways and behavioral responses to weak electric fields in parasitic sea lampreys (Petromyzon marinus).

The authors characterized the behavioral and brain responses of parasitic sea lampreys (Petromyzon marinus) to weak electric fields. Lampreys showed preferences for the cathodal end of the testing aquarium after electric stimulation. Within a range of cathodal fields (-0.1 to -30.0 mu-V/cm), lampreys exhibited increased active behaviors. In contrast, anodal fields decreased most active behaviors below baseline. Exposure to electric fields resulted in changes in Western blot patterns for the neuronal activity markers Fos, Fos-B. and Jun in whole-brain homogenate. Electric stimulation also increased Fos-B immunoreactivity in the octavolateral and the habenula-fasciculus retroflexus-interpeduncular systems. These results confirm that the octavolateral system is associated with electroreception and suggest that the habenula-fasciculus retroflexus-interpeduncular system may be pan of the electroreceptive network.

Animals↗
PubMed1977

Gastric pathology and feeding deficits induced by hypothalamic damage in rats: effects of lesion type, size, and placement.

Three doses each of cathodal or anodal direct current were delivered to coagulate lateral hypothalamic tissue bilaterally in rats. Increases in hypothalamic tissue damage were associated with more instances of aphagia, greater amounts of glandular, but not rumenal, gastric pathology, and greater weight loss. Both anodal and cathodal lesions produced aphagia and similar amounts of gastric pathology, but anodal lesions also appeared to facilitate weight loss independently of the tissue damage. Extensive chromatolysis surrounding anodal lesion cavities may be importantly related to the postoperative effects. In additional experiments, anodal electrolytic lesions or cortical suction ablations were used to vary the location of neural damage. Fedding deficits and gastric pathology resulted from the destruction of several brain areas. In particular, eating of dry food in the presence of high gastric pathology was observed in rats with lesions ventral and medial to an area in the dorsolateral hypothalamus that was associated with aphagia. When aphagia was accompained by severe gastric pathology, the brain lesions typically encroached extensively on more ventromedial areas. Moreover, aphagia sometimes was observed with only negligible gastric pathology. It is suggested that gastric pathology is not primary to the expression of the aphagia that follows lateral hypothalamic damage.

Animals↗
PubMedDate not supplied

Changes in cell shape and actin distribution induced by constant electric fields.

The development of motility in cultured cells is usually associated with a polarization of the cell shape. In particular, the leading edge of the cell is extended into a lamella which acts as a locus for the elaboration of cell processes and for the formation of cell-substrate contacts and, at the opposite end, retraction fibres often extend beyond the trailing edge of the cell. The alignment of microfilament bundles (stress fibres) along the direction of migration and the presence of a band of actin at the leading edge of the cell suggest an involvement of this protein in the motile process. The direction of growth and orientation of various cell types in tissue culture can be influenced by externally applied d.c. electric fields but the effect of the field on cellular motile activities is unknown. Here we describe a galvanotropic response of cultured Xenopus epithelial cells. At a field strength of 5 V cm-1 these cells elongate perpendicularly with respect to the field. The anodal side of the cell retracts and both the ends and cathodal edge become active in the extension of ruffling lamellipodia. In parallel with the change in the cell axis, stress fibres are oriented perpendicularly to the field, and a band of actin is associated with the lamellae at the cathodal edge and at the ends of the cell.

Actins↗
PubMed2000

Prototype systems for rechargeable magnesium batteries.

The thermodynamic properties of magnesium make it a natural choice for use as an anode material in rechargeable batteries, because it may provide a considerably higher energy density than the commonly used lead-acid and nickel-cadmium systems. Moreover, in contrast to lead and cadmium, magnesium is inexpensive, environmentally friendly and safe to handle. But the development of Mg batteries has been hindered by two problems. First, owing to the chemical activity of Mg, only solutions that neither donate nor accept protons are suitable as electrolytes; but most of these solutions allow the growth of passivating surface films, which inhibit any electrochemical reaction. Second, the choice of cathode materials has been limited by the difficulty of intercalating Mg ions in many hosts. Following previous studies of the electrochemistry of Mg electrodes in various non-aqueous solutions, and of a variety of intercalation electrodes, we have now developed rechargeable Mg battery systems that show promise for applications. The systems comprise electrolyte solutions based on Mg organohaloaluminate salts, and Mg(x)Mo3S4 cathodes, into which Mg ions can be intercalated reversibly, and with relatively fast kinetics. We expect that further improvements in the energy density will make these batteries a viable alternative to existing systems.

Journal Article↗
PubMed1995

Low-level direct electrical current therapy for hepatic metastases. I. Preclinical studies on normal liver.

Low-level direct electrical current has shown promise as a potential therapeutic modality (direct current therapy; DCT) in the treatment of malignant disease, including metastases, but to date much experimental work has been empirical and has added little to our knowledge of the mechanisms involved. As a prerequisite to a clinical trial for metastases in the liver, we have employed an in vivo liver model to examine the quantitative and qualitative relationships between electrode polarity, charge and tissue necrosis. Two distinct regions of necrosis were induced, distinguishable histologically and by magnetic resonance imaging: (i) a cylindrical region of primary necrosis centred on the electrode, its volume directly proportional to the charge passed, but greater at the anode than cathode; and (ii) a wedge-shaped infarct, apex at the electrode and base extending to the liver edge. The extent of this infarct was again greater at the anode than the cathode, but showed a sigmoidal relationship with charge. Results indicate pH changes at the electrodes as likely mediators of tissue injury, but show also that significant distant ischaemic injury can occur as a consequence of primary damage. These findings should be considered when selecting tumours for possible direct current therapy and when determining the sites of electrode placement.

Animals↗
PubMed2006

A class of non-precious metal composite catalysts for fuel cells.

Fuel cells, as devices for direct conversion of the chemical energy of a fuel into electricity by electrochemical reactions, are among the key enabling technologies for the transition to a hydrogen-based economy. Of several different types of fuel cells under development today, polymer electrolyte fuel cells (PEFCs) have been recognized as a potential future power source for zero-emission vehicles. However, to become commercially viable, PEFCs have to overcome the barrier of high catalyst cost caused by the exclusive use of platinum and platinum-based catalysts in the fuel-cell electrodes. Here we demonstrate a new class of low-cost (non-precious metal)/(heteroatomic polymer) nanocomposite catalysts for the PEFC cathode, capable of combining high oxygen-reduction activity with good performance durability. Without any optimization, the cobalt-polypyrrole composite catalyst enables power densities of about 0.15 W cm(-2) in H2-O2 fuel cells and displays no signs of performance degradation for more than 100 hours. The results of this study show that heteroatomic polymers can be used not only to stabilize the non-precious metal in the acidic environment of the PEFC cathode but also to generate active sites for oxygen reduction reaction.

Journal Article↗
PubMed2002

Effect of acetone feeding on alcohol dehydrogenase activity in the olive fruit fly, Bactrocera oleae.

The purpose of this study is to demonstrate a clear connection between the presence of acetone in larval diet and alcohol dehydrogenase (ADH) activity in laboratory raised populations of Bactrocera oleae. ADH activity of B. oleae is depressed in acetone-impregnated diets. At the same time the change of activity is accompanied by a change in the relative proportions of the multiple forms of ADH. The bulk of activity in the most cathodally migrating form is lost, and all the activity becomes localized in the less cathodally migrating forms of the enzyme. Moreover, ADH activity, expressed in vivo, appears to drop after exposure to acetone, as shown by the fact that larvae become less sensitive to pentenol poisoning. Our results show clear selective differences imposed by acetone on three homozygous genotypes involving the ADH alleles F, S and I in B. oleae. The directions of these differences were found to vary with the fitness component under test. Acetone treatment seems to affect developmental time and larva's viability as well as allele frequencies of ADH under artificial rearing. The effect of acetone on the maintenance of ADH polymorphism in artificially reared populations of B. oleae is further discussed.

Acetone↗
PubMed2000

Epidural electric stimulation of posterior structures of the human lumbar spinal cord: 1. muscle twitches - a functional method to define the site of stimulation.

OBJECTIVES: To describe an electrophysiological method for determining the relation between lumbar cord dorsal roots and cathode of epidural electrode for spinal cord stimulation (SCS). MATERIALS AND METHODS: Data has been collected from 13 subjects who have been under evaluation of effectiveness of SCS for control of spasticity. Induced muscle twitches from both quadriceps (Q), adductors (A), hamstrings (H), tibial anterior muscles (TA) and triceps surae muscles (TS) were simultaneously recorded with surface-electrode polyelectromyography (pEMG) and analyzed for amplitudes, latency times and recruitment order. RESULTS: Stimulation of dorsal lumbar cord structures evoked characteristic EMG events during muscle twitch responses. Their amplitudes varied with stimulus strength. Latency times were rather invariable regardless of stimulus strength. Two distinct recruitment orders were demonstrated depending on whether the stimulating cathode was placed over the upper (=response from quadriceps and/or adductor muscles) or the lower (=response from tibialis anterior and triceps surae) lumbar cord segments. The chances to stimulate upper lumbar cord segments are best around the 12th thoracic vertebra. CONCLUSIONS: pEMG recording of muscle twitches enables us to accurately differentiate between upper and lower lumbar cord segments. Furthermore, our findings regarding amplitude, latency and recruitment order strongly suggest that we stimulate posterior roots not posterior columns of the lumbar spinal cord.

Adolescent↗
PubMed2002

Influence of room lighting on grey-scale perception with a CRT-and a TFT monitor display.

OBJECTIVES: To determine the influence of ambient lighting on grey-scale perception using a cathode-ray tube (CRT) and a thin film transistor (TFT) computer display. METHODS: A cathode ray tube (Nokia XS 446) and a liquid crystal display (Panasonic LC 50S) were used at reduced room lighting (70 lux) and under conditions recommended for a dental operatory (1000 lux). Twenty-seven observers examined twice a modified SMPTE test pattern [0 to 255; 255 to 0] grey-scale values. The corresponding contrast differences were allocated to four ranges of grey levels (I: 0-63; II: 64-127; III: 128-191; IV: 192-255). The influences of monitor type, grey-scale range and illumination were evaluated by means of repeated measures analysis of variance. RESULTS: Detection of differences in monochromatic intensity was significantly earlier with reduced lighting (P<0.0001). When full ambient lighting was used, the TFT display was superior compared to the CRT monitor in ranges II and III (P<0.0001), whereas no differences could be detected for grey intensities between 0 and 63 (P=0.71) and between 192 and 255 (P=0.36). CONCLUSIONS: Background lighting hampers grey-scale perception on computer displays. In this study of one TFT and one CRT monitor, the TFT in full ambient lighting was associated with earlier detection of grey scale differences than CRT.

Adult↗
PubMed2004

On-chip cell lysis by local hydroxide generation.

We present a novel method for on-chip cell lysis based on local hydroxide electro-generation. Hydroxide ions porate the cell membrane, leading to cell lysis. After lysis occurs, hydrogen ions, also generated on chip, react with excess hydroxide, creating a neutral pH lysate and eliminating the need for a wash step. Three different cell types are shown to be effectively lysed by this method: red blood cells, HeLa (human tumor line) and Chinese Hamster Ovary (CHO) cell lines. The release of cytoplasmic molecules from HeLa and CHO cells is demonstrated by monitoring the escape of a membrane impermeant dye from the cytoplasm. In the vicinity of the cathode, the hydroxide concentration is predicted by finite element simulations and shown to fit the lysis rates at different distances from the generating cathode. For flow-through experiments, a second device integrating a mechanical filter with hydroxide generation is fabricated and tested. The purpose of the filter is to trap whole cells and only allow lysate to pass through. The flow rate dependence of hydroxide concentration at the lysis filter is modeled and lysis efficiency is experimentally determined to be proportional to the hydroxide concentration for flow rates from 15 to 30 microl min(-1).

Animals↗
PubMed2006

A passive microfluidic hydrogen-air fuel cell with exceptional stability and high performance.

We describe an advanced microfluidic hydrogen-air fuel cell (FC) that exhibits exceptional durability and high performance, most notably yielding stable output power (>100 days) without the use of an anode-cathode separator membrane. This FC embraces an entirely passive device architecture and, unlike conventional microfluidic designs that exploit laminar hydrodynamics, no external pumps are used to sustain or localize the reagent flow fields. The devices incorporate high surface area/porous metal and metal alloy electrodes that are embedded and fully immersed in liquid electrolyte confined in the channels of a poly(dimethylsiloxane) (PDMS)-based microfluidic network. The polymeric network also serves as a self-supporting membrane through which oxygen and hydrogen are supplied to the cathode and alloy anode, respectively, by permeation. The operational stability of the device and its performance is strongly dependent on the nature of the electrolyte used (5 M H2SO4 or 2.5 M NaOH) and composition of the anode material. The latter choice is optimized to decrease the sensitivity of the system to oxygen cross-over while still maintaining high activity towards the hydrogen oxidation reaction (HOR). Three types of high surface area anodes were tested in this work. These include: high-surface area electrodeposited Pt (Pt); high-surface area electrodeposited Pd (Pd); and thin palladium adlayers supported on a "porous" Pt electrode (Pd/Pt). The FCs display their best performance in 5 M H2SO4 using the Pd/Pt anode. This exceptional stability and performance was ascribed to several factors, namely: the high permeabilities of O2, H2, and CO2 in PDMS; the inhibition of the formation of insoluble carbonate species due to the presence of a highly acidic electrolyte; and the selectivity of the Pd/Pt anode toward the HOR. The stability of the device for long-term operation was modeled using a stack of three FCs as a power supply for a portable display that otherwise uses a 3 V battery.

Air↗