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PubMed1985

Effects of intracellular sodium and potassium iontophoresis on membrane potentials and resistances in toad urinary bladder.

Glass microelectrodes were used to measure membrane potentials and the ratio of apical to basolateral membrane resistances before and after the passage of current from the potential-recording microelectrode to ground, in toad urinary bladder epithelium, in order to iontophorese cations into the cell. After application of the current, there was a transient change in the tip potential of the microelectrode. This artifact was measured with the microelectrode in the mucosal medium and was subtracted from the potential recorded in the cell. The serosal medium was bathed by Ringer's solution containing 51.5 mM K+ to minimize any current-induced increase of K+ in the unstirred layer. Under those conditions, both Na+ and K+ iontophoresis caused a significant hyperpolarization of basolateral membrane potential (Vcs) and a significant increase in the ratio of apical to basolateral membrane resistances (Ra/Rb). When bladders were exposed to amiloride in the mucosal solution, Na+ iontophoresis caused the basolateral membrane to hyperpolarize, but no significant changes were observed in Ra/Rb. When Na+ was injected in the presence of serosal ouabain, Vcs depolarized and Ra/Rb increased. K+ iontophoresis caused the basolateral membrane potential to hyperpolarize in the presence of ouabain but Ra/Rb did not change significantly. These results indicate that the Na+ pump in toad bladder is rheogenic, that apical Na+ conductance is sensitive to the cell levels of Na+ and K+ and that the basolateral membrane is K+ permeable.

Amiloride↗

PubMed2003

Transcutaneous iontophoresis of methadone provokes local flushing and thermal hyperalgesia.

OBJECTIVE: To investigate whether the introduction of methadone into the skin of the human forearm produces wheals, cutaneous vasodilatation or thermal hyperalgesia and, if so, to determine whether these responses are mediated by opioid receptors. SUBJECTS: Healthy adults. METHODS AND RESULTS: In Experiment 1 (N = 11), the increase in local blood flow (monitored with a laser Doppler flowmeter) was greater after the iontophoresis of methadone than saline (mean increase +/- S.D. 12.6 +/- 8.8 versus 2.2 +/- 1.9 times greater than baseline, p < 0.01). Flushing did not spread into surrounding skin and wheals did not form. In Experiment 2, pre-treatment with naloxone (N = 12) prevented increases in blood flow to methadone whereas saline pre-treatment (N = 14) did not. The heat pain threshold was lower at the site of methadone administration than at an untreated site (42.8 +/- 2.3 degrees C versus 44.6 +/- 1.7 degrees C, p < 0.001), and this effect was inhibited by naloxone pre-treatment. However, naloxone pre-treatment also antagonized an inhibitory effect of methadone on the pain generated by a 7-second pulse of 45 degrees C heat. In Experiment 3 (N = 11), the iontophoresis of methadone was repeated after an interval of 1.5 h. Vasodilatation to methadone persisted after the second iontophoresis, and sensitivity to heat was greater at a site of methadone administration than at a site of saline administration or an untreated control site. CONCLUSIONS: Stimulation of mu-opioid receptors dilated cutaneous blood vessels, and evoked local thermal analgesia and hyperalgesia at different stimulus intensities. However, stimulation of mu-opioid receptors did not produce wheals or flares.

Administration, Cutaneous↗

PubMed1993

Extracellular H+ iontophoresis modifies responses to gamma-aminobutyric acid and cyanide of reticulospinal vasomotor neurons in rats.

Responses of reticulospinal vasomotor neurons, recorded in the rostral ventrolateral reticular nucleus of the medulla oblongata, to gamma-aminobutyric acid (GABA) and cyanide microiontophoreses were examined during H+ iontophoresis in anesthetized rats. Extracellular H+ iontophoresis attenuated GABA-evoked decreases and enhanced cyanide-induced increases in the neuronal activity, but had no effect on the neuronal activity when applied alone. Opposite responses were produced during OH- iontophoresis. Similar effects were also observed on the glycine-evoked inhibition of these neurons during H+ and OH- iontophoreses, suggesting that H+ modulation of the GABA-evoked inhibition may not result from a specific action at the GABA receptor-channel complex. It is concluded that extracellular H+ ions exert a modulatory action on responses of the reticulospinal vasomotor neurons to other neuro-active substances and may significantly contribute to hypoxic-ischemic cardiovascular regulation.

Animals↗

PubMed1993

Glutamate iontophoresis induces long-term potentiation in the absence of evoked presynaptic activity.

Protocols that induce long-term potentiation (LTP) typically involve afferent stimulation. We tested the hypothesis that LTP induction does not require presynaptic activity. The significance of this hypothesis is underscored by results suggesting that LTP expression may involve activity-dependent presynaptic changes. An induction protocol using glutamate iontophoresis was developed that reliably induced LTP in hippocampal slices without afferent stimulation. Iontophoresis LTP was Ca2+ dependent, was blocked by MK-801, and occluded tetanus-induced LTP. Iontophoresis LTP was induced when excitatory postsynaptic potentials were completely blocked by adenosine plus tetrodotoxin. Our results suggest constraints on the involvement of presynaptic mechanisms and putative retrograde messengers in LTP induction and expression; namely, these processes must function without many forms of activity-dependent presynaptic processes.

Action Potentials↗

PubMed2006

Effect of DC/mDC iontophoresis and terpenes on transdermal permeation of methotrexate: in vitro study.

The systemic toxicity caused by methotrexate limits its use and transdermal delivery would be a possible alternative. Transdermal permeation of methotrexate loaded into polyacrylamide-based hydrogel patch, across mice skin was studied in vitro after pretreatment with terpenes and ethanol, alone or in combination with iontophoresis (DC/mDC). Polyacrylamide patches gave the maximum flux as compared to the copolymers of acrylamide and acrylic acid. Of the terpenes used, pure menthol showed maximum enhancement (38%), whereas pure limonene elicited a minimum of 9.9% enhancement. Binary combination of menthol and ethanol increased the permeation to 54.9%, which was further enhanced to 93.69% and 117% when used in combination with DC and square wave (mDC) iontophoresis, respectively. ATR-FTIR of the stratum corneum treated with terpenes showed a split in the asymmetric C-H stretching vibrations along with decrease in peak heights and areas of asymmetric, symmetric C-H stretching, C=O stretching and amide bands. A split in amide II band was observed with iontophoresis. ATR-FTIR studies suggest conformational changes in the lipid-protein domains thereby increasing permeation. Histopathological studies on treated skin samples, gave an insight about the anatomical changes brought by the application of various enhancers. Binary mixture of menthol and ethanol in combination with square wave gave best results.

Acrylic Resins↗

PubMed2004

Evaluation of forearm microvascular blood flow regulation by laser Doppler flowmetry, iontophoresis, and curve analysis: contribution of axon reflex.

The relative contribution of vasodilating factors to the control of blood flow in the forearm cutaneous microcirculation is not well defined. Therefore, a mathematical transformation is introduced to decompose the superimposed signal and to investigate the involved mechanisms separately. Transdermal iontophoresis was used for the delivery of acetylcholine (ACh) or sodium nitroprusside (SNP) into the forearm, and cutaneous perfusion was measured using a laser Doppler flowmeter (LDF). The curve fitting procedure used in this study indicates that the LDF signal in response to ACh iontophoresis can be described by the superposition of two independent hyperbolic response curves. Obviously, each component of LDF signal indicates the existence of a separate mechanism, with corresponding rate constant k, latency T, and the saturation level Fmax. Blockade of C-fiber function (axon reflex) with topical anesthesia removes one of the two components of this response and allows the precise quantification of its contribution. SNP-evoked response also has two components, but their parameters were different from those of ACh. Therefore, ACh and SNP cause vasodilation in the skin microcirculation through different pathways. These findings have implications for clinical studies that use the iontophoresis technique for assessing vascular function and comparing responses to ACh and SNP to evaluate endothelial dysfunction.

Acetylcholine↗

PubMed2002

Down-regulation of NOSII gene expression by iontophoresis of anti-sense oligonucleotide in endotoxin-induced uveitis.

Transcorneoscleral iontophoresis was used to enhance ocular penetration of a 21-bp NH(2) protected anti-NOSII oligonucleotides (ODNs) (fluorescein or infrared-41 labeled) in Lewis rats. Both histochemical localization and acrylamide sequencing gels were used. To evaluate the potential to down-regulate NOSII expression in the rat model of endotoxin-induced uveitis (EIU), anti-sense NOSII ODN, scrambled ODN or saline were iontophorezed into these animals' eyes. Iontophoresis facilitated the penetration of intact ODNs into the intraocular tissues of the rat eye and only the eyes receiving ODNs and electrical current demonstrated intact ODNs within the ocular tissues of both segments of the eye. Iontophoresis of anti-NOSII ODN significantly down-regulated the expression of NOSII expression in iris/ciliary body compared to the saline or scrambled ODN treated eyes. Nitrite production was also significantly reduced in the anti-NOSII applied eyes compared to those treated with saline. Using this system, intraocular delivery of ODNs can be significantly enhanced increasing the potential for successful gene therapy for human eye diseases.

Animals↗

PubMed2003

Regulation of human cutaneous circulation evaluated by laser Doppler flowmetry, iontophoresis, and spectral analysis: importance of nitric oxide and prostaglandines.

Nitric oxide (NO) and prostaglandines (PGs) are important in regulation of vascular tone and blood flow. Their contribution in human cutaneous circulation is still uncertain. We inhibited NO synthesis by infusing N(G)-monomethyl-L-arginine (L-NMMA) in the brachial artery (16 micromol/min for 5 min) and reversed it by intraarterial infusion of L-arginine (40 micromol/min for 7.5 min). PG synthesis was inhibited by the cyclooxygenase inhibitor aspirin (600 mg over 5 min intravenously). Basal cutaneous perfusion and perfusion responses during iontophoresis with the endothelium-dependent vasodilator acetylcholine (ACh) and the endothelium-independent vasodilator sodium nitroprusside (SNP) were recorded by laser Doppler flowmetry (LDF). We performed wavelet transforms of the measured signals. Mean spectral amplitude within the frequency interval from 0.0095 to 1.6 Hz and mean and normalized amplitudes of five intervals around 1, 0.3, 0.1, 0.04, and 0.01 Hz were analysed. The oscillations with frequencies around 1, 0.3, 0.1, and 0.04 Hz are influenced by the heartbeat, the respiration, the intrinsic myogenic activity of vascular smooth muscle, and the neurogenic activity of the vessel wall, respectively. We have previously shown that the oscillation with a frequency around 0.01 Hz is modulated by the vascular endothelium. L-NMMA reduced mean value of the LDF signal by approximately 20% (P = 0.0067). This reduction was reversed by L-arginine. Mean value of the LDF signals during ACh and SNP iontophoresis did not change after infusion of L-NMMA. Aspirin did not affect mean value of the LDF signal or the LDF signal during ACh or SNP iontophoresis. Before interventions the only significant difference between the effects of ACh and SNP was observed in the frequency around 0.01 Hz, where ACh increased normalized amplitude to a greater extent than SNP. L-NMMA abolished this difference, whereas it reappeared after infusion of L-arginine (P = 0.0084). Aspirin did not affect this difference (P = 0.006). We conclude that basal cutaneous blood flow and the endothelial dependency of the oscillation around 0.01 Hz are partly mediated by NO, but not by endogenous PGs. Other aspects of human cutaneous circulation studied are not regulated by NO or PGs.

Acetylcholine↗

PubMed2004

Evaluation of a low-dose lidocaine iontophoresis system for topical anesthesia in adults and children: a randomized, controlled trial.

BACKGROUND: Commonly used classes of topical anesthetics require 30 to 60 minutes to provide effective anesthesia. A new low-dose lidocaine iontophoresis system (LDLIS) may provide topical anesthesia in 10 minutes at a lower dose than previous systems, thereby limiting adverse events. METHODS: This was a prospective, randomized, multicenter, double-blind, placebo-controlled, clinical trial. Adults and children aged 5 to 17 years (inclusive) received a 10-minute ionntophoretic treatment with either lidocaine or a saline placebo before venipuncture or venous cannulation. Intensity of pain associated with venipuncture or venous cannulation was assessed using either a 10-cm Visual Analog Scale (VAS) for adults and children aged 12 to 17 years or the Facial Affective Scale (FAS) for all children enrolled. RESULTS: Five hundred forty-eight patients (276 adults, 272 children) participated. Mean (SD) VAS pain scores were lower in adults who received iontophoresis with lidocaine rather than with placebo (0.77 [1.49] vs 2.52 [2.30], P < 0.001) and in children aged 12 to 17 years (1.50 [1.87] vs 2.58 [2.26], P = 0.001). FAS pain scores were lower among children who received iontophoresis with lidocaine rather than with placebo (0.36 [0.26] vs 0.51 [0.27], P < 0.001). Similar results were found for children stratified by age group (5-7 years: 0.40 [0.30] vs 0.60 [0.31], P = 0.011; 8-11 years: 0.35 [0.27] vs 0.48 [0.27], P = 0.021; 12-17 years: 0.33 [0.21] vs 0.48 [0.24], P = 0.001). Mean (SD) parental ratings of pain on the FAS for children aged 5 to 11 years were also lower for the lidocaine group (0.45 [0.28] vs 0.55 [0.25], P = 0.018). Adverse events were similar between groups and included skin erythema and edema. One patient in the study experienced a partial-thickness burn. CONCLUSION: In this study of adults and children, the LDLIS provided effective topical anesthesia for venipuncture and venous cannulation within 10 minutes.

Adolescent↗

PubMed1986

Transscleral iontophoresis of cefazolin, ticarcillin, and gentamicin in the rabbit.

Corneal iontophoresis produces high concentrations of drugs in the anterior segment but not in the vitreous humor of the phakic eye, presumably because transport is impeded by the lens-iris barrier. We have used two modifications to produce high levels of commonly used antibiotics in the vitreous humor of the phakic rabbit eye: the device is placed over the pars plana, circumventing the lens-iris barrier; the contact area of the column of fluid is kept small (less than or equal to 1 mm diameter) so as to provide a high current density. Applying 2 mAmp for 10 minutes, we were able to achieve mean vitreal concentrations of cefazolin, ticarcillin, and gentamicin of 94-207 micrograms/ml in the normal rabbit eye. Drug penetration showed a correlation with strength of current (0.1-2 mAmp) and with duration of iontophoresis (1-10 minutes) but not with concentration of the drug solution. Transscleral iontophoresis is a promising noninvasive technique to achieve high vitreal levels of charged solutes.

Animals↗

PubMed2003

Optimization of aminolevulinic acid delivery by iontophoresis.

UNLABELLED: The objective was to optimize aminolevulinic acid (ALA) electrotransport into and through the skin by adjustment of formulation composition and ionic strength. ALA delivery was investigated as a function of the polarity and concentrations of drug and background electrolyte in the donor solution. The anodal iontophoretic flux of ALA from a 10% solution was compared with the drug's passive flux from the same formulation to which 5% dimethyl sulphoxide (DMSO) had been added. Iontophoresis of the predominantly zwitterionic ALA from the anode is more efficient than that from the cathode. It was possible, though, to increase the electrotransport of ALA by simultaneously delivering the drug from both anode and cathode. Reduction of NaCl concentration in the anode led to a 3- to 4-fold increase in ALA flux. Transport of ALA across the skin and the amount of prodrug delivered into the skin (SC and [epidermis+dermis]) were approximately 4-fold greater with iontophoresis as compared to the passive application of the DMSO formulation. IN CONCLUSION: (a) electroosmosis from the anode is enhanced when the background electrolyte concentration is lowered; and (b) low-level iontophoresis enhances ALA transport across and, more importantly, into the [epidermis+dermis] than a simple formulation incorporating DMSO.

Aminolevulinic Acid↗

PubMed2003

Transdermal iontophoresis of insulin. V. Effect of terpenes.

To increase the skin permeation of large peptides like insulin, it is necessary to utilize a combination of enhancement strategies. In this regard, this study investigated the effect of terpenes/EtOH combination in comparison to EtOH and neat terpene on transdermal iontophoretic permeation of insulin. Ex-vivo experiments were conducted using full thickness rat skin after pre-treatment for 2 h with 5% of menthol, menthone, cineole and pulegone in EtOH; EtOH alone; neat menthone with and without iontophoresis (0.5 mA/cm(2); 6 h). FT-IR studies were carried out using rat epidermal sheets after pre-treatment with enhancer solution for 2 h and tritiated water permeation studies was used to investigate the alteration in skin barrier property after enhancer or current treatment. The lag time was significantly reduced (P<0.05) with terpene/EtOH pre-treatment in comparison to passive control and EtOH pre-treatment, although there was no significant difference (P>0.05) among the terpenes. Synergistic enhancement in flux was observed with terpene/EtOH, and menthone/EtOH showed highest enhancement among the terpene/EtOH combinations. On the other hand, enhancement with neat menthone was higher than with menthone/EtOH. FT-IR studies showed that terpene/EtOH, EtOH and neat terpene act at the intercellular lipids. The skin barrier property was significantly (P<0.05) compromised with neat menthone treatment. Iontophoresis had a lesser effect on skin barrier property compared to chemical enhancer pre-treatment. Terpene/EtOH caused synergistic enhancement of insulin permeation when combined with iontophoresis and was influenced by the type and concentration of terpene.

Administration, Cutaneous↗

PubMed1998

In vitro acyclovir distribution in human skin layers after transdermal iontophoresis.

The purpose of the present work was to study the in vitro distribution of acyclovir in human skin layers after iontophoresis, applied in order to increase the amount of drug in the basal epidermis, site of Herpes simplex infections. Experiments were done with Franz diffusion cells applying, as donor, acyclovir solutions (pH values: 3.0 and 7.4) or a commercial cream. Quantification of drug at different skin depths was performed by horizontal slicing of frozen skin, and drug extraction and analysis by high-performance liquid chromatography. Seven h of transdermal iontophoresis (0.5 mA cm-2 induced an accumulation of acyclovir in epidermis and dermis ranging from 80 to 150 micrograms cm-3, characterized by homogeneous distribution of the drug in skin layers. After short current application time (30 min) however, the concentration profile of drug in skin was not significantly different from the obtained after seven h of passive diffusion, employing pH 3.0 donor solution. After 30 min of iontophoresis, the acyclovir reservoir on the skin was maintained for up to five h producing a dramatic increase of drug concentration in skin, evening out over 80 micrograms cm-3 until a depth of 300 micrograms. Acyclovir can be accumulated at target site more quickly and maintained at higher level through application of a iontophoretic pulse and by keeping the drug reservoir on skin.

Acyclovir↗

PubMed1998

Iontophoresis of monomeric insulin analogues in vitro: effects of insulin charge and skin pretreatment.

The aim of this study was to investigate the influence of association state and net charge of human insulin analogues on the rate of iontophoretic transport across hairless mouse skin, and the effect of different skin pretreatments on said transport. No insulin flux was observed with anodal delivery probably because of degradation at the Ag/AgCl anode. The flux during cathodal iontophoresis through intact skin was insignificant for human hexameric insulin, and only low and variable fluxes were observed for monomeric insulins. Using stripped skin on the other hand, the fluxes of monomeric insulins with two extra negative charges were 50-100 times higher than that of hexameric human insulin. Introducing three additional charges led to a further 2-3-fold increase in flux. Wiping the skin gently with absolute alcohol prior to iontophoresis resulted in a 1000-fold increase in transdermal transport of insulin relative to that across untreated skin, i.e. to almost the same level as stripping the skin. The alcohol pretreatment reduced the electrical resistance of the skin, presumably by lipid extraction. In conclusion, monomeric insulin analogues with at least two extra negative charges can be iontophoretically delivered across hairless mouse skin, whereas insignificant flux is observed with human, hexameric insulin. Wiping the skin with absolute alcohol prior to iontophoresis gave substantially improved transdermal transport of monomeric insulins resulting in clinically relevant delivery rates for basal treatment.

2-Propanol↗

PubMed2001

The role of electroosmotic flow in transdermal iontophoresis.

Iontophoresis enhances transdermal drug delivery by three mechanisms: (a) the ion-electric field interaction provides an additional force which drives ions through the skin; (b) flow of electric current increases permeability of skin; and (c) electroosmosis produces bulk motion of the solvent itself that carries ions or neutral species, with the solvent 'stream'. The relative importance of electroosmotic flow is the subject of this review. Experimental observations and theoretical concepts are reviewed to clarify the nature of electroosmotic flow and to define the conditions under which electroosmotic flow is an important effect in transdermal iontophoresis. Electroosmotic flow is bulk fluid flow which occurs when a voltage difference is imposed across a charged membrane. Electroosmotic flow occurs in a wide variety of membranes, is always in the same direction as flow of counterions and may either assist or hinder drug transport. Since both human skin and hairless mouse skin are negatively charged above about pH 4, counterions are positive ions and electroosmotic flow occurs from anode to cathode. Thus, anodic delivery is assisted by electroosmosis, but cathodic delivery is retarded. Water carried by ions as 'hydration water' does not contribute significantly to electroosmotic flow. Rather electroosmotic flow is caused by an electrical volume force acting on the mobile counterions. The simple 'limiting law' theory commonly given in textbooks and some research articles is a very poor approximation for transdermal systems. However, several extensions of the limiting law are compatible with each other and with the available experimental data. One of these theories, the Manning theory, has been incorporated into a theory for the effect of electroosmotic flow on iontophoresis, the latter theory being in good agreement with experiment. Both theory and experimental data indicate that electroosmotic flow increases in importance as the size of the drug ion increases. The 'ionic' or Nernst-Planck effect is the largest contributor to flux enhancement for small ions. Increased skin permeability or the skin 'damage effect', is a significant factor for both large and small ions, particularly for experiments at high current density. For monovalent ions with Stokes radii larger than about 1 nm, electroosmotic flow is the dominant flow mechanism. Because of electroosmotic flow, transdermal delivery of a large anion (or negatively charged protein) from the anode compartment can be more effective than delivery from the cathode compartment.

Administration, Cutaneous↗

PubMed1986

Iontophoresis in dermatology. A review.

Iontophoresis, the process of increasing the penetration of drugs into surface tissues by the application of an electric current, has been applied to a great many disease conditions over its 200-year history. Although its greatest success has been in the treatment of hyperhidrosis, it is steadily finding new applications. Many aspects of the mechanisms of iontophoresis have yet to be studied before the technic is both fully understood and maximally utilized. In this article we review the literature on iontophoresis as it pertains to dermatology, including the basic principles, engineering aspects.

Administration, Topical↗

PubMed1996

Physical enhancement of dermatologic drug delivery: iontophoresis and phonophoresis.

Iontophoresis and phonophoresis are emerging technologies capable of enhancing drug penetration through the stratum corneum, the principal barrier to percutaneous absorption. With utilization of applied electric current or ultrasonic waves, respectively, iontophoresis and phonophoresis have shown efficacy in an increasing number of clinical applications. This article reviews the underlying principles, current status, and potential of iontophoresis and phonophoresis in dermatologic therapy.

Anesthetics, Local↗

PubMed2003

Transtympanic iontophoresis of gadopentetate dimeglumine: Preliminary results.

OBJECTIVE: We sought to demonstrate the feasibility of using iontophoresis to deliver pharmaceutical agents into the middle and inner ear for the treatment of middle and inner ear diseases, which is proved in this study by the successful iontophoresis of the ferromagnetic contrast agent gadopentetate dimeglumine. Study design and setting Eight rabbits were iontophoresed using gadopentetate dimeglumine solution 469 mg/mL. Then, all rabbits underwent magnetic resonance imaging for the detection of gadopentetate dimeglumine in the middle and inner ear structures. The study was conducted in the tertiary referral center the University Hospital of Crete. RESULTS: The high signal intensity of the gadopentetate dimeglumine solution was demonstrated within the middle ear cavity and inner ear structures of all iontophoresed ears and in none of the noniontophoresed ones. CONCLUSIONS: Transtympanic iontophoresis could be an effective method for the passage of pharmaceutical agents into the middle and inner ear for the treatment of middle and inner ear diseases.

Administration, Topical↗