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Copper iontophoresis in male contraception.

Copper was deposited by iontophoresis into vasa deferentia of animals, using 1 m. amp. current for 30-90 sec. in rat and 3 m. amp. current for 60 sec. in rabbits. The method was effective for a period of 9 months as a contraceptive. The effect of the metal was localised at the site of deposition and there was no effect on other reproductive organs. The mating behaviour and testosterone levels did not change. The utility of the technique in male contraception is discussed.

Animals↗

Iontophoresis of drugs in the bladder wall: equipment and preliminary studies.

Iontophoresis is the active transport of ions into tissues by means of an electric current: Ji = -D(i)delta Ci/delta chi + DizeECi/kT. Where Ji is the total ionic flux, D(i) the diffusion coefficient, Ci the concentration, z the valency, and E the electric field. The first expression on the right side of the equation is Fick's law of diffusion and approaches zero for bladder mucosa, which leads to uncertain results following intravesical administration of various therapeutic agents. The application of an electric field will potentially accelerate drug administration into the bladder wall in a controllable manner. To evaluate this concept, an appropriate source of electric current and electrodes was fabricated; then, studies were conducted in human cadaveric bladders and clinical trials in human subjects. Ionized dyes were applied in duplicate to 10 fresh cadaveric bladders. Electric currents (3.5-5.0 mA) were applied for 20 min to 10 solutions, and no current was used in 10 controls. Twenty-eight patients had 100 ml solutions of 1% mepivacaine or lidocaine with epinephrine infused into their bladders prior to endoscopic resections. Twenty-two patients received currents of 10-20 mA for 10-20 min, and 6 controls had either no drugs or a current of reverse polarity applied. Visually and on microscopy, the 10 control cadaveric bladder surfaces demonstrated only faint staining of the surface mucosa whereas the experimental surfaces showed full-thickness staining of the mucosa extending into the muscularis. The 6 control patients required supplemental anesthesia or abandonment of the operative procedure. Of the 22 experimental subjects, 16 tolerated procedures with up to 25 g of tissue removed by diathermic resection.

Administration, Intravesical↗

Human calcitonin delivery in rats by iontophoresis.

In-vitro ionotophoresis (0.33 mA cm-2) of calcitonin (50 micrograms mL-1, pH 4) was performed with the hairless rat skin model. Direct current was as potent as pulse current (2.5 kHz on/off 1/1) iontophoresis in promoting transdermal permeation of calcitonin. Increase in duration of current application from 20 min to 1 h did not increase calcitonin flux. Results suggest that calcitonin can be blocked in the skin pores through which it travels or can accumulate in the skin and be progressively released from the depot. In-vivo experiments showed that transdermal iontophoretic administration of calcitonin induced a hypocalcaemic effect in rats.

Animals↗

Iontophoresis--recent developments.

This paper addresses the development and optimization of the technology of iontophoresis as a non-invasive approach to transdermal diagnosis and therapy. The rationale for this work is that the skin offers a unique and easily accessible body surface through which drugs can be delivered and general clinical monitoring information can be extracted.

Administration, Cutaneous↗

The activity of identified supraoptic neurones and their response to acetylcholine applied by iontophoresis.

1. In urethane/pentobarbitone anaesthetized male rats, the hypothalamus and pituitary stalk were exposed by a transpharyngeal approach. Cells recorded with glass micro-electrodes from the ventral hypothalamus near the bifurcation of the internal carotid artery were identified as supraoptic neurones only when their antidromic action potential evoked at constant latency by stimulation of the pituitary stalk was cancelled by collision with a spontaneously occurring action potential.2. More than 80% of the identified cells were spontaneously active. The frequency of firing was often slow (under 1 Hz) and rather irregular. More than half the cells, however, had a more distinctive firing pattern which recurred every 1-3 min and consisted of a period of low or absent activity alternating with periods of quite marked discharge which occasionally exceeded 20 Hz. This periodicity was retained when the over-all activity was enhanced by an intracarotid injection of 0.2 ml. 5% (w/v) NaCl.3. Of fifty-two cells tested, thirty-six were excited by acetylcholine applied by iontophoresis from a multibarrelled micropipette with average ejection currents of 35 +/- 5 nA (S.D. of thirty-six observations). Ten of these cells were also excited by nicotine applied with similar currents.

Acetylcholine↗

Relationship between intracellular calcium and its muffling measured by calcium iontophoresis in snail neurones.

1. We have measured intracellular free calcium ion concentration ([Ca2+]i) with fura-2, and intracellular chloride with chloride-sensitive microelectrodes, in voltage-clamped snail neurones. By making iontophoretic injections of CaCl2 we have investigated calcium muffling, the sum of the processes which minimize the calcium transient, at different values of [Ca2+]i. 2. By injection of calcium into cell-sized droplets of buffer we measured the calcium transport index. It was stable over the range pCa 6-7.4 (0.48 +/- 0.06 measured at pCa 6.70 +/- 0.12, n = 5). 3. Measurement of intracellular chloride activity during a series of fura-2-KCl pressure injections revealed a nearly linear relationship between fura-2 Ca(2+)-insensitive fluorescence and the sum of the increments in intracellular chloride. This allowed us to calculate the intracellular fura-2 concentration ([fura-2]i). 4. The rate of recovery of [Ca2+]i following a depolarization-induced load was increased by low [fura-2]i (10-20 microM) but decreased by higher [fura-2]i (40-80 microM). These effects are consistent with the addition of a mobile buffer to the cytoplasm. 5. Iontophoresis of Ca2+ at various membrane potentials allowed us to calculate the intracellular calcium muffling power (the amount of calcium required to cause a transient tenfold increase in [Ca2+]i per unit volume) and calcium muffling ratio (number of Ca2+ ions injected divided by the maximum increase in [Ca2+]i per unit volume) at different values of [Ca2+]i. 6. Calcium muffling power at resting [Ca2+]i was approximately 40 microM Ca2+ (pCa unit)-1, (about 250 times less than for hydrogen ions). It increased linearly about fivefold with [Ca2+]i over the range 20-120 nM (10 cells, 153 measurements) and therefore exponentially with decreasing pCa. 7. The calcium muffling ratio appeared to be constant (361 +/- 14, n = 10 cells, 130 measurements) over the range 20-120 nM Ca2+. 8. In three experiments we modelled the additional calcium buffering power produced by multiple pressure injections of fura-2 into voltage-clamped snail neurones. Back-extrapolation of the increases in calcium buffering power allowed us to calculate the calcium muffling power of the neurones. 9. Small increases in [fura-2]i (approximately 10 microM) significantly increased intracellular calcium muffling power in individual experiments. However, the variability among neurones in intracellular calcium muffling power was large enough to obscure the additional buffering produced by fura-2 in pooled experiments.

Animals↗

Bacterial and fungal killing by iontophoresis with long-lived electrodes.

Iontophoresis with gold, carbon, and platinum electrodes was shown to effectively reduce or eliminate gram-positive, gram-negative, and Candida albicans inocula in synthetic urine. Platinum and gold electrodes were more effective than carbon electrodes, but platinum showed the best longevity and may reduce or eliminate microbial colonization of catheters.

Bacterial Physiological Phenomena↗

Quantitative analysis of extracellular space using the method of TMA+ iontophoresis and the issue of TMA+ uptake.

The tetramethylammonium (TMA+) method for measuring the volume fraction and tortuosity of brain extracellular space is presented in detail. The temporal and spatial distribution of TMA+ in the extracellular space following iontophoresis or pressure microinjection is described by suitable equations and illustrated with graphs. By fitting the equations to the concentration versus time data obtained from measurements with ion-selective micropipettes, the volume fraction and tortuosity can be measured. In addition, the concentration-dependent uptake of TMA+ can be estimated from the given equations. The final section of the paper derives simple numerical estimates of TMA+ loss from the extracellular space by this mechanism.

Animals↗

Selective abolition of adrenergic vasoconstrictor responses in skin by local iontophoresis of bretylium.

Skin blood flow (SkBF) in humans is controlled by a noradrenergic active vasoconstrictor system and an active vasodilator system of an uncertain neurotransmitter. Understanding how these systems interact would be aided if the vasodilator system could be studied in the absence of effects of the vasoconstrictor system. To accomplish this we combined laser-Doppler velocimetry (LDV) with the local iontophoresis of bretylium in 10 studies with eight healthy subjects. Each subject had two forearm sites (0.64 cm2) treated with bretylium to block local norepinephrine release. LDV was monitored at those sites and at two untreated sites during 3-4 min of cold stress, 35-45 min of heat stress, and a final cold stress to verify blockade. In five studies, local temperature was raised to 39 degrees C at the LDV sites before the final cold stress. Whole body skin temperature was controlled by water-perfused suits. Mean arterial pressure (MAP) was measured noninvasively. Heart rate and internal temperature were also recorded. Cutaneous vascular conductance (CVC) was calculated as LDV/MAP. During the initial cold stress, performed 130 min after bretylium treatment, CVC at treated sites fell by an average of 0.3 +/- 3.2% (P greater than 0.10) and at untreated sites by 29.2 +/- 4.1% (P less than 0.001 between sites). During heat stress, CVC at treated sites rose by 419 +/- 66% and at control sites, by 517 +/- 90% (P greater than 0.10 between sites). The internal temperature threshold for cutaneous vasodilation was not statistically different between sites (P greater than 0.10).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Generation and transit pathway of H+ is critical for inhibition of palmar sweating by iontophoresis in water.

Passing galvanic current across the skin (known as "tap water iontophoresis" or TWI) inhibits sweating; however, its mechanism of action is unclear. Using improved methods, we confirmed that anodal current has more of an inhibitory effect than cathodal current, water is superior to saline, and the inhibitory effect is a function of the amperage used. To address the importance of current flowing through the pores, a layer of silicone grease was placed on the skin to reduce the shunt pathway across the epidermis. With silicone, total skin conductance decreased 60% without the sweat pores being occluded, swelling of the stratum corneum and collapse of the poral lumen was prevented, and current-induced inhibition of sweating was enhanced, most likely because of an increase in current density in the pores. The pH of anodal water, but not of saline, dropped to 3, whereas that of cathodal water increased to 10 during passage of current through the skin. Acidified anodal water was superior to alkaline water. Sweat glands isolated from TWI-induced anhidrotic palmar skin responded to methacholine in vitro, but the sweat rate and pharmacological sensitivity were slightly lowered. Thus the strong acidity generated by hydrolysis of water in the anodal bath and the further accumulation of H+ in the sweat duct by anodal current may be responsible for TWI-induced inhibition of sweating due to an unknown lesion(s) in the duct or sweat pore. The secretory coil function may also be altered because of exposure to intense acidity during TWI. The importance of H+ movement into the sweat pore for inhibition of sweating could be further exploited to develop new strategies for the control of sweating.

Adolescent↗

Current-induced vasodilation during water iontophoresis (5 min, 0.10 mA) is delayed from current onset and involves aspirin sensitive mechanisms.

Study of the microcirculation by iontophoresis is potentially confounded by any non-specific effects of current application. Laser Doppler flow (LDF, mean +/- SD; arbitrary units; AU) was recorded on the forearms of healthy volunteers during and 20 min following application of 0.10-mA current for 1, 3 and 5 min, using deionised water as a vehicle. Local heating to 44 degrees C was then applied for 24 min to assess maximal vasodilation. Cathodal current applications resulted in delayed and prolonged vasodilation (peak values: 78 +/- 29, 75 +/- 19, 80 +/- 37 AU) whereas anodal peak LDF was 13 +/- 6, 27 +/- 34 and 72 +/- 40 AU for 1-, 3- and 5-min periods of current applications, respectively. From current onset, inflexion points in the responses to 3- and 5-min anodal current applications occurred at 4.5 and 6.5 min, respectively, and at approximately 1.5 min for all cathodal current applications. For 5-min current applications: a preliminary tourniquet ischaemia neither changed the time course nor the amplitude of the response to current application. In this situation, local anaesthesia abolished the current-induced vasodilation. Chronic capsaicin pretreatment decreased the amplitude of the vasodilation. Pretreatment with 500 mg oral aspirin decreased the cathodal vasodilation and abolished the anodal vasodilation, even in the absence of preliminary ischaemia. We conclude that vasodilation to prolonged application of 0.10-mA continuous monopolar current after transient tourniquet ischaemia cannot be exclusively the result of an axon reflex initiated by current onset. This current-induced vasodilation is at least partly dependent on capsaicin-sensitive afferent fibres and relies on aspirin-sensitive mechanisms at both polarities.

Adult↗

Long-term efficacy and side effects of tap water iontophoresis of palmoplantar hyperhidrosis--the usefulness of home therapy.

Treatment of palmoplantar hyperhidrosis was carried out with a conventional galvanic generator in 40 patients and with a newly developed iontophoresis apparatus, which is suited for home treatment, in 31 patients. The new apparatus is operated by a rechargeable energy source or by batteries and is disconnected from the electrical net during treatment. It conforms to most recent safety regulations as approved by Underwriter's Laboratory. Hyperhidrosis was completely controlled after 10-12 treatments as revealed by quantitative gravimetric measurements of sweat rates and semiquantitative estimation of starch iodine paper imprints. There was no apparent difference in efficacy between the two apparatuses. Not only hyperhidrosis was abolished, but associated symptoms, such as lividity of palms or soles, acral hypothermia and edema of fingers or toes, also subsided. Skin temperature on palms rose from 29.7 +/- 1.8 degrees C before treatment to 32.2 +/- 1.4 degrees C thereafter. Maintenance treatment was continued on an average for 14 months, in 4 patients for more than 3 years. No loss of efficacy was found during that period. Side effects were minimal and depended upon amperage used. Only slight discomfort during treatment and mild short-lasted skin irritation were observed. Long-term side effects did not occur.

Adolescent↗

Iodine distribution in a porcine eye model following iontophoresis.

Iodine distribution was studied in isolated porcine eyes after iontophoresis using 131I-labelled solutions and chemical methods. After a 15-min treatment with a therapeutically used iodine brine, the iodine content in the ocular tissues showed the following rank order: cornea > retina > vitreous body > anterior chamber fluid > lens. Replacement of the brine by 0.15 M NaI increased the uptake values in a different way, but the same rank order was maintained. The increase was highest in the cornea (5.6-fold) and only about 2-fold in the lens, nevertheless approaching now the level of 10(-4) M, a concentration which was regarded as being optimal for the antioxidant effect of I-. Among the other eye components, the relatively high iodine enrichment of the retina was remarkable. The data are discussed with respect to a possible protective, antioxidative and OH-scavenging efficacy of I- and to previous results in the literature concerning iodine uptake in ocular tissues.

Animals↗

Dentin permeability: changes produced by iontophoresis.

Iontophoretic currents (0--1.0 mA) were applied to dentin disks prepared from human third molars. A negative electrode increased 125I-permeation 10X, while a positive electrode increased 14C-lidocaine 8X. Iontophoresis appears promising as a method to increase the permeation of dentin by ionized substances of therapeutic interest.

Carbon Radioisotopes↗

Iontophoresis of morphine into the arcuate nucleus: effects on dopamine concentrations in hypophysial portal plasma and serum prolactin concentrations.

The effects of morphine on the release of dopamine from tuberoinfundibular neurons and the release of PRL from the anterior pituitary gland were studied in diestrous female rats. Morphine ions ejected iontophoretically in minute quantities into the arcuate nuclei (using one electrode per nucleus) were found to reduce markedly the concentration of dopamine in hypophysial portal plasma. Thirty minutes after the iontophoretic ejection of morphine using charges of 3.6 and 6.6 millicoulombs/electrode, the concentrations of dopamine in hypophysial portal plasma were reduced 70% and 83%, respectively, relative to the preiontophoretic values. When morphine was iontophoresed into each arcuate nucleus using a charge of 1.5 millicoulombs/electrode, there was no change in the concentration of dopamine in hypophysial portal plasma. The suppressive effect of morphine on dopamine release was prevented by pretreatment of the animals with naloxone (5 mg/kg, ip). In addition to the reduction of the concentration of dopamine in hypophysial portal plasma, the iontophoresis of morphine into the arcuate nuclei enhanced the serum concentration of PRL. On the basis of the present observations, it is suggested that morphine acts on an opiate receptor within the arcuate nucleus to suppress the secretion of dopamine from tuberoinfundibular neurons into hypophysial portal blood, thereby enhancing pituitary gland secretion of PRL.

Animals↗

Transdermal delivery of sodium nonivamide propionate by iontophoresis.

The aim of this study was to investigate the transdermal iontophoresis of a newly designed capsaicin derivative, sodium nonivamide propionate (SNP). The iontophoretic permeation of SNP from various pH buffers increased following the decrease of pH values. This trend was consistent with that of sodium nonivamide acetate (SNA) which is another synthetic analogue of capsaicin. However, the iontophoretic permeability of SNP was much lower than that of SNA. SNP was also delivered iontophoretically from hydrogel formulations. It is suggested that ionizable polymers should be avoided for iontophoretic delivery to maintain good penetration capacity of drugs. Both nonionic cellulose polymers of methylcellulose (MC) and hydroxypropyl methylcellulose (HPMC) showed higher iontophoretic flux for SNP than the others did. Furthermore, the flux of SNP leveled off with an increase in the amount of polymers in hydrogel, indicating that the viscosity of vehicles plays an important role in the permeation of SNP. Comparing the various iontophoretic application modes, the discontinuous on/off cyclic mode showed higher penetration capacity than did the continuous mode although they possessed the same electrical energy. Moreover, the desorption time of SNP from skin was approximately 20 min which was longer than that of SNA.

Administration, Cutaneous↗

Factors affecting sulfisoxazole transport through excised rat skin during iontophoresis.

Permeation of sulfisoxazole (SIX) across the excised rat skin were studied using two chamber cell with four electrodes, under three successive experimental conditions: without current for 3 h (treatment I), with current for 4 h (treatment II) and without current for 3 h (treatment III). Transport of SIX was significantly increased by iontophoresis. The enhancement ratio of SIX flux were reasonably predicted by Goldman's equation. There was no significant difference (p less than 0.05) between the flux in treatment I and treatment III. On the basis of the flux reversibility, it was concluded that skin alteration did not occur when the applied electric potential was below 5.025 V. Although a prominent current-induced volume flow (from the anodal side to the cathodal side) was observed during current exposure, SIX flux was not influenced by the volume flow. The flux enhancement of SIX was mainly dependent on transdermal potential difference.

Animals↗

Transfer of diclofenac sodium across excised guinea pig skin on high-frequency pulse iontophoresis. I. Equivalent circuit model.

High frequency pulse iontophoresis of diclofenac sodium across excised guinea-pig skin was carried out in vitro. An equivalent circuit model was constructed to simulate the time courses of voltage drop across the donor solution and the skin. Parameter values obtained by the least-squares adaptation of the model to observed data were consistent with expectation and validated the proposed model.

Animals↗