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PubMed2002

Transscleral Coulomb-controlled iontophoresis of methylprednisolone into the rabbit eye: influence of duration of treatment, current intensity and drug concentration on ocular tissue and fluid levels.

The major problems associated with the use of corticosteroids for the treatment of ocular diseases are their poor intraocular penetration to the posterior segment when administered locally and their secondary side effects when given systemically. To circumvent these problems more efficient methods and techniques of local delivery are being developed. The purposes of this study were: (1) to investigate the pharmacokinetics of intraocular penetration of hemisuccinate methyl prednisolone (HMP) after its delivery using the transscleral Coulomb controlled iontophoresis (CCI) system applied to the eye or after intravenous (i.v.) injection in the rabbit, (2) to test the safety of the CCI system for the treated eyes and (3) to compare the pharmacokinetic profiles of HMP intraocular distribution after CCI delivery to i.v. injection. For each parameter evaluated, six rabbit eyes were used. For the CCI system, two concentrations of HMP (62.5 and 150mg ml(-1)), various intensities of current and duration of treatment were analyzed. In rabbits serving as controls the HMP was infused in the CCI device but without applied electric current. For the i.v. delivery, HMP at 10mg kg(-1)as a 62.5mg ml(-1)solution was used. The rabbits were observed clinically for evidence of ocular toxicity. At various time points after the administration of drug, rabbits were killed and intraocular fluids and tissues were sampled for methylprednisolone (MP) concentrations by high pressure liquid chromatography (HPLC). Histology examinations were performed on six eyes of each group. Among groups that received CCI, the concentrations of MP increased in all ocular tissues and fluids in relation to the intensities of current used (0.4, 1.0 and 2.0mA/0.5cm(2)) and its duration (4 and 10min). Sustained and highest levels of MP were achieved in the choroid and the retina of rabbit eyes treated with the highest current and 10min duration of CCI. No clinical toxicity or histological lesions were observed following CCI. Negligible amounts of MP were found in ocular tissues in the CCI control group without application of current. Compared to i.v. administration, CCI achieved higher and more sustained tissue concentrations with negligible systemic absorption. These data demonstrate that high levels of MP can be safely achieved in intraocular tissues and fluids of the rabbit eye, using CCI. With this system, intraocular tissues levels of MP are higher than those achieved after i.v. injection. Furthermore, if needed, the drug levels achieved with CCI can be modulated as a function of current intensity and duration of treatment. CCI could therefore be used as an alternative method for the delivery of high levels of MP to the intraocular tissues of both the anterior and posterior segments.

Animals↗
PubMed1994

[Modification and optimization of tap water iontophoresis].

Tap water iontophoresis is the therapy of choice in hyperhidrosis palmoplantaris. Therapeutic regimens, however, vary greatly. The aim of the present study was to develop an optimized therapeutic scheme. The main methodologic parameters subjected to systematic experimental study included the effects of current polarity, the duration of a single treatment session, the addition of electrolytes to the tap water and the treatment interval during maintenance therapy. The following procedure is proposed. During the initial phase, treatments are carried out three times weekly for 10 min each time. The anode is kept on one extremity until normhidrosis is reached on this extremity. Then, polarity is changed until sweating is reduced to normal on the other extremity (constant polarity). In the subsequent maintenance phase, patients are treated at intervals of 6-8 days for 10 min each time. Polarity is switched from treatment to treatment (alternating polarity). Plain tap water is used without additives.

Adolescent↗
PubMed2005

Effect of charge and molecular weight on transdermal peptide delivery by iontophoresis.

PURPOSE: The study was conducted to investigate the impact of charge and molecular weight (MW) on the iontophoretic delivery of a series of dipeptides. METHODS: Constant current iontophoresis of lysine and 10 variously charged lysine- and tyrosine-containing dipeptides was performed in vitro. RESULTS: Increasing MW was compensated by additional charge; for example, Lys (MW = 147 Da, +1) and H-Lys-Lys-OH (MW = 275 Da, +2) had equivalent steady-state fluxes of 225 +/- 48 and 218 +/- 40 nmol cm(-2) h(-1), respectively. For peptides with similar MW, e.g., H-Tyr-D-Arg-OH (MW = 337 Da, +1) and H-Tyr-D-Arg-NH(2) (MW = 336 Da, +2), the higher valence ion displayed greater flux (150 +/- 26 vs. 237 +/- 35 nmol cm(-2) h(-1)). Hydrolysis of dipeptides with unblocked N-terminal residues, after passage through the stratum corneum, suggested the involvement of aminopeptidases. The iontophoretic flux of zwitterionic dipeptides was less than that of acetaminophen and dependent on pH. CONCLUSIONS: For the series of dipeptides studied, flux is linearly correlated to the charge/MW ratio. Data for zwitterionic peptides indicate that they do not behave as neutral ("charge-less") molecules, but that their iontophoretic transport is dependent on the relative extents of ionization of the constituent ionizable groups, which may also be affected by neighboring amino acids.

Acetaminophen↗
PubMed1979

Effects on pulp and dentin of iontophoresis of sodium fluoride on exposed roots in dogs.

Experiments were performed on young permanent teeth in which there was demonstrable active dentin formation. Following surgical exposure of roots and removal of cementum with scalers, 1 percent sodium fluoride in aqueous solution was applied either topically or with direct-current iontophoresis. Two levels of current, therapeutic or five times therapeutic, were used. Observation periods were 7 and 80 days. There were no demonstrable histologic or ultrastructural alterations of the underlying pulp; nor was there a resultant change in the rate of dentin formation. While exposure of root surface dentin alone (negative control) produced no alterations, grinding the surface (positive control) caused noticeable changes in dentin, odontoblasts, and pulp.

Animals↗
PubMed1995

Theoretical model of iontophoresis utilized in transdermal drug delivery.

A theoretical model of in vitro iontophoresis that utilizes radial mass transport is presented. The applicability of radial transport to the skin morphology of different species is determined by the density of low-resistance pores, which represents the density of skin appendages such as hair follicles or sweat glands. Radial transport is expected to dominate in the case where appendage density is low, in contrast to the linear transport mechanism that would dominate in the case of skin with high appendage density. Parameters such as the effective surface area of highly conductive pores and boundary-layer thickness are defined for the radial and linear transport limits and evaluated for the iontophoretic flux of pindolol hydrochloride through porcine skin. Based upon a decrease in the calculated boundary-layer thickness and an increase in drug flux with current density to a limiting value, it is concluded that radial mass transport is the dominant mechanism of iontophoretic transport under the experimental conditions described.

Administration, Cutaneous↗
PubMed1989

Constant current source for iontophoresis.

A simple, battery-powered current source is described that is suitable for the iontophoresis of axonal tracing substances, such as Phaseolus vulgaris leucoagglutinin. Unlike the previous designs that form the basis of most commonly used iontophoretic devices, this circuit does not use operational amplifiers to provide controlled current. Instead, a pair of bipolar transistors that can be selected to provide a compliance of many hundreds of volts form the regulating circuitry.

Amplifiers, Electronic↗
PubMed1990

Multibarreled glass-coated tungsten microelectrode for both neuronal activity recording and iontophoresis in monkeys.

A multibarreled glass-coated tungsten microelectrode suitable for single-unit recording and iontophoresis in chronically behaving animals is described. The microelectrode was stiff enough to pass through the dura matter of behaving monkeys, and can be applied as a microiontophoretic electrode. The electrode is easy to build and usable in stabilized conditions after repeated penetrations.

Animals↗
PubMed1990

A new strategy of iontophoresis for hyperhidrosis.

We used a modified iontophoretic method with an anticholinergic agent and aluminum chloride to treat hyperhidrosis. The strategy behind this combination was to shift gradually from inhibition of sweat gland secretion to blockage of the sweat duct. In a double-blind study in which we compared our method with tap water iontophoresis, the results were comparable. A second study revealed an 87% response rate, with an average remission period of 32 days. Our data indicate that patients who were older at onset, had a family history negative for the disorder, had an early response, or underwent treatment in cool weather had the most favorable results.

Aluminum↗
PubMed1991

Extracellular alkaline-acid pH shifts evoked by iontophoresis of glutamate and aspartate in turtle cerebellum.

The effect of glutamate and aspartate iontophoresis on extracellular pH was investigated in the turtle cerebellum in vitro. Both amino acids produced a rapid alkaline transient, typically followed by a prolonged acidification. These responses could be evoked in all layers of the cerebellum. Transition from bicarbonate to N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid-buffered media amplified the pH shifts. Similar alkaline-acid transients could be evoked in the molecular layer by electrical stimulation of the parallel fibers or the ipsilateral peduncle, or by superfusion of glutamate or aspartate. However, no alkaline shifts were evoked in the granular layer by either parallel fiber or peduncle stimulation. In contrast, the iontophoretically induced alkaline shifts were largest in the granular layer. Compared with the stimulus-evoked alkalinizations, the iontophoretic alkaline shifts were relatively insensitive to Mn2+ or Cd2+. These data suggest that the activity-dependent alkalinization of brain extracellular space is generated by a bicarbonate-independent mechanism related to excitatory synaptic transmission. The results are consistent with a flux of hydrogen ions through cationic channels, but do not support a direct role for voltage-dependent Ca2+ channels. In view of the sensitivity of ion channels to changes in external pH, and the magnitude of the amino acid-induced pH shifts, these results indicate that extracellular pH could play an important modulatory role in excitatory synaptic transmission.

Animals↗
PubMed1993

Changes of D1 and D2 receptors in adult rat neostriatum after neonatal dopamine denervation: quantitative data from ligand binding, in situ hybridization and iontophoresis.

The specific binding of [3H]SCH23390 to D1 and of [3H]raclopride to D2 dopamine receptors was measured by autoradiography in the rostral and caudal halves of neostriatum and in the substantia nigra of adult rats subjected to near total destruction of nigrostriatal dopamine neurons by intraventricular 6-hydroxydopamine soon after birth. Three months after this lesion, [3H]SCH23390 binding (D1 receptors) was slightly but significantly decreased in the rostral neostriatum (22%), but unchanged in its caudal half and in the substantia nigra. In contrast, [3H]raclopride binding (D2 receptors) was considerably increased throughout the neostriatum (10-40%), while markedly decreased in the substantia nigra (80%). In the rostral neostriatum, there were no parallel changes in D2 receptor messenger RNA levels, as measured by in situ hybridization on adjacent sections. Caudally, however, slight but significant increases in D2 messenger RNA could be observed (10-20%). As assessed by quantitative iontophoresis, there was a marked enhancement (63%) of the inhibitory responsiveness of spontaneously firing units in the rostral neostriatum to dopamine and the D1 agonist, SKF38393, in neonatally lesioned compared to control rats. On the other hand, responsiveness to PPHT, a potent D2 agonist, appeared to be unchanged. Such opposite changes in the number of D1 and D2 binding sites, dissociated from the expression of D2 receptor messenger RNA and from the sensitivity to dopamine and D1 and D2 agonists, suggested independent adaptations of these various parameters following the neonatal dopamine denervation of neostriatum. They also provided further evidence for mechanisms other than the dopamine innervation in the control of the expression of neostriatal D2 receptor messenger RNA during ontogenesis, and emphasized that the effects of dopamine and its D1 and D2 agonists in neostriatum do not depend strictly on the number of D1 and D2 primary ligand recognition sites.

Animals↗
PubMed1995

Iontophoresis in the neostriatum of awake, unrestrained rats: differential effects of dopamine, glutamate and ascorbate on motor- and nonmotor-related neurons.

The neostriatum and its major afferent transmitters, dopamine and glutamate, play a critical role in behavior, but relatively little information is available on their postsynaptic effects in behaving animals. As a first step in addressing this shortcoming, single-unit electrophysiology was combined with iontophoresis in the neostriatum of awake, unrestrained rats. Relative to periods of quiet rest, most neurons (58 of 77) changed discharge rate in close temporal association with movement, while the remainder showed no such relationship. When animals resumed a resting posture, iontophoretic current-response curves were established for dopamine and glutamate as well as for ascorbate, a modulator of neostriatal function released from glutamatergic terminals. Application of either glutamate or ascorbate produced current-dependent increases in activity in all neurons, although this effect was somewhat less pronounced for nonmotor cells. In both types of neurons, the excitatory effect of ascorbate either diminished or shifted to an inhibition at high ejection currents. Dopamine, on the other hand, routinely excited motor-related, but inhibited nonmotor-related neurons. Further assessment of motor-related neurons revealed that in most cases the excitatory effects of either glutamate or dopamine alone were supra-additive when these compounds were either administered together or co-administered with ascorbate. Our results suggest that the response of neostriatal neurons to glutamate or dopamine depends, at least in part, on the motor responsiveness of these cells. Motor-related neurons, moreover, respond to the co-administration of glutamate and dopamine with synergistic increases in firing rate. Ascorbate also influences neostriatal activity, but the postsynaptic action of this substance cannot be explained as a simple interaction with either glutamatergic or dopaminergic mechanisms.

Animals↗
PubMed1993

Non-invasive sampling of lactic acid ions by iontophoresis using chloride ion in the body as an internal standard.

Non-invasive sampling of lactic acid, as a model endogenous compound, through hairless rat skin by iontophoresis was investigated using a two-chamber iontophoretic diffusion cell equipped with platinum electrodes and a pulse depolarization iontophoretic system. Chloride ion in the body was used as an internal standard. First, an in vitro experiment on the permeation of lactate and chloride ions through hairless rat skin was carried out to determine the flux ratio of these ions. The cathode side of the cell (dermis side) was filled with physiological saline containing lactic acid (0.5556, 1.111, 1.667 or 2.222 mmol cm-3) and the anode side (epidermis side) with phosphate buffer (pH 7.4). The amount of lactate and chloride ion permeated from the dermis side to the epidermis side through the skin at a constant current of 3.0 mA was determined using an automatic lactic acid analyser and high-performance ion chromatography, respectively. For construction of a calibration curve of lactic acid in the dermis side, the ionic mobility ratio of lactic acid/chloride ion (UCl/Ulac) was determined using a computer simulation program from the flux ratio of lactic acid and chloride ion and the applied concentration of lactic acid in the dermis side. Second, an in vitro non-invasive sampling experiment of lactic acid through rat skin was carried out at a constant current of 2.0 or 3.0 mA and 2.222 or 1.111 mmol cm-3 of lactic acid in the dermis side, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Recent progress in ocular drug delivery for posterior segment disease: emphasis on transscleral iontophoresis.

Age-related macular degeneration, diabetic retinopathy, posterior uveitis, and retinitis due to glaucoma are leading causes of vision loss in the United States and other developed countries. Because these diseases are located in the posterior segment of the eye, topical application of ophthalmic medicines is of limited benefit, since topically applied drugs rarely reach therapeutic levels in the affected posterior tissues such as the choroid and retina. Intravitreal injections can deliver drugs to the posterior segment without the side effects associated with systemic administration. However, the repeated and long-term injections often needed may cause complications, such as vitreous hemorrhage, retinal detachment, or endophthalmitis. Recent advances in ocular drug delivery methods and the development of novel biopharmaceutical agents could lead to new regimens for the treatment of disease of the posterior retina, choroids, and macula. This review will summarize recent literature concerning ocular drug delivery of bioactive compounds to the posterior segment of the eye with emphasis on transscleral iontophoresis.

Animals↗
PubMed2005

Transdermal iontophoresis of the dopamine agonist 5-OH-DPAT in human skin in vitro.

The feasibility of transdermal iontophoretic delivery of a potent dopamine agonist 5-OH-DPAT was studied in vitro in side by side diffusion cells across human stratum corneum (HSC) and dermatomed human skin (DHS) according to the following protocol: 6 h of passive diffusion, 9 h of iontophoresis and 5 h of passive diffusion. The influences of the following parameters on the flux were studied: donor solution pH, NaCl concentration, drug donor concentration, current density and skin type. A current density of 0.5 mA cm(-2) was used, except for one series of experiments to study the current density effect. Probably due to the influence of the skin perm-selectivity and the competition with H(+), increase in pH from 3 to 5 resulted in a significant increase in flux. Further increase in pH to 6 did not further increase the flux. The iontophoretic transport was found to increase linearly with concentration and current density, providing a convenient way to manage dose titration for Parkinson's disease therapy. Increase in concentration of NaCl dramatically reduced the flux of 5-OH-DPAT as a result of ion competition to the transport. When DHS was used, the iontophoretic transport was less. Also, with DHS the response in flux profile, by switching the current on and off, was shallower than that with HSC. With the optimum condition, a delivery of 104 microg of 5-OH-DPAT per cm(2) patch per hour is feasible, indicating that the therapeutic level could be achieved with a smaller patch size than required in case of rotigotine. Thus, based on this in vitro study, transdermal iontophoretic delivery of 5-OH-DPAT is very promising.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2005

Contributions of electromigration and electroosmosis to peptide iontophoresis across intact and impaired skin.

d-(Arg)-Kyotorphin iontophoresis was investigated across intact and impaired skins in vitro. Iontophoretic flux increased from 68+/-12 to 538+/-116 nmol cm(-2) h(-1) when the peptide concentration in the anodal compartment was raised from 5 to 40 mM. Electromigration was the principal transport mechanism, accounting for approximately 70% of total peptide delivery. Reducing the number of competing ions in the formulation significantly increased iontophoretic flux but did not affect convective solvent flow. The latter was independent of peptide concentration indicating that skin permselectivity was not modified by kyotorphin transport. Total iontophoretic flux was unaffected when the stratum corneum was removed by tape-stripping (146+/-34 versus 150+/-26 nmol cm(-2) h(-1)). However, the contributions of the different transport mechanisms were significantly altered: (i) electromigration decreased, as more of the charge was carried by anions from the sub-dermal milieu; (ii) electroosmosis was absent; and (iii) passive permeation increased significantly. Transport rates across intact and impaired skin barriers were statistically indistinguishable when the donor electrolyte composition was modified; increased competition from anions was mitigated by the decreased Na+ levels in the formulation. Removal of Cl- ions from the receiver phase further increased peptide delivery, and also increased anodal electroosmosis.

Acetaminophen↗
PubMed1997

Acetic acid iontophoresis and ultrasound for the treatment of calcifying tendinitis of the shoulder: a randomized control trial.

OBJECTIVE: To assess the effects of acetic acid iontophoresis (AAI) and ultrasound on calcifying tendinitis of the shoulder, and to determine the relation between changes in the radiological measures of calcium deposit (CD) and shoulder function. DESIGN: Randomized control trial. SETTING: General community, private practice. PATIENTS: Twenty-two adults (7 men, 15 women) with a calcifying tendinitis of the shoulder, without associated conditions, stratified according to the type of lesions (X-ray: type I, fleecy appearance: type II, homogeneous), were randomly allocated to an experimental (EXP, n = 11) or to a control (CTL, n = 10) group. INTERVENTIONS: CTL group, no treatment; EXP group, nine treatments including AAI (5% acetic acid solution via the negative electrode, 5mA galvanic current, 20 minutes) followed by continuous ultrasound (0.8w/cm2, 1MHz, 5 minutes). MAIN OUTCOME MEASURES: Area and density of the CD, passive shoulder abduction (range of motion [ROM]), pain intensity. RESULTS: Significant reduction in the area and density of CD (ANCOVA, p = .01 and .03) over time in the EXP and CTL groups, but no significant difference between groups for any of the variables measured. The decrease in the area of CD in type I lesions (n = 5) was larger (Mann-Whitney U test, p < .01) than in type II (n = 16) lesions. The relation was stronger (rs = .90) between changes in area and density of CD than between ROM and pain (rs = -.67). Correlations were weak (rs = .21 to .41) between radiological and functional changes. CONCLUSION: The reduction in CD area and density likely results from a natural process rather than treatment (AAI and ultrasound); type I lesions (resorptive phase) are more likely to display resorption of the CD than type II lesions (formative phase). Reduction of the CD area does not necessary result in a functional improvement.

Acetic Acid↗
PubMed1995

Interaction between diffusion and Michaelis-Menten uptake of dopamine after iontophoresis in striatum.

A quantitative description of the behavior of a neurotransmitter in the brain extracellular microenvironment requires an understanding of the relative importance of diffusion versus uptake processes. This paper models the behavior of dopamine released from a small iontophoresis electrode and its voltammetric detection by a carbon fiber sensor 100 microns away as a basis for developing a new paradigm for measuring dopamine kinetics in intact rat neostriatum. The diffusion equation incorporating uptake, characterized by a maximum velocity Vmax and a Michaelis-Menten constant Km, was transformed to an integral equation and solved numerically for the dopamine concentration, C. Analytical solutions were derived for limiting cases of a steady-state free-boundary problem when C >> Km and the linear time-dependent problem when C << Km. These solutions were compared with complete numerical solutions, both for normal uptake (Vmax = 0.2 or 0.8 microM s-1; Km = 0.15 microM), and in the presence of the uptake blocker nomifensine (Km = 6 microM). The results suggest that an experimental strategy for the quantitative analysis of dopamine, and other compounds, in living tissue is to fit a family of concentration versus time curves generated with different iontophoretic current strengths and recorded with a microsensor, to the numerical solution of the diffusion-uptake equation.

Animals↗