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PubMed2000

ATP in human skin elicits a dose-related pain response which is potentiated under conditions of hyperalgesia.

Despite the considerable interest in the possibility that ATP may function as a peripheral pain mediator, there has been little quantitative study of the pain-producing effects of ATP in humans. Here we have used iontophoresis to deliver ATP to the forearm skin of volunteers who rated the magnitude of the evoked pain on a visual analogue scale. ATP consistently produced a modest burning pain, which began within 20 s of starting iontophoresis and was maintained for several minutes. Persistent iontophoresis of ATP led to desensitization within 12 min but recovery from this was almost complete 1 h later. Different doses of ATP were delivered using different iontophoretic driving currents. Iontophoresis of ATP produced a higher pain rating than saline, indicating that the pain was specifically caused by ATP. The average pain rating for ATP, but not saline, increased with increasing current. Using an 0.8 mA current, subjects reported pain averaging 27.7 +/- 2.8 (maximum possible = 100). Iontophoresis of ATP caused an increase in blood flow, as assessed using a laser Doppler flow meter. The increase in blood flow was significantly greater using ATP than saline in both the iontophoresed skin (P < 0.01) and in the surrounding skin, 3 mm outside the iontophoresed area (P < 0.05). The pain produced by ATP was dependent on capsaicin-sensitive sensory neurons, since in skin treated repeatedly with topical capsaicin pain was reduced to less than 25% of that elicited on normal skin (2.1 +/- 0.4 compared with 9.3 +/- 1.5 on normal skin). Conversely, the pain-producing effects of ATP were greatly potentiated in several models of hyperalgesia. Thus, with acute capsaicin treatment when subjects exhibited touch-evoked hyperalgesia but no ongoing pain, there was a threefold increase in the average pain rating during ATP iontophoresis (22.7 +/- 3.1) compared with pre-capsaicin treatment (7.8 +/- 2.6). Moreover, ATP iontophoresed into skin 24 h after solar simulated radiation (2 x minimal erythymic dose) resulted in double the pain rating of normal skin, increasing from 15.3 +/- 4.1 to 32.7 +/- 4.1. The pain response to saline was not significantly altered after UV irradiation at any time-point studied. We conclude that ATP produces pain by activating capsaicin-sensitive nociceptive afferents when applied to skin. The possibility that ATP activates nociceptors indirectly via its degradation products cannot be ruled out. The effects of ATP are dose-dependent and responses desensitize only slowly. In inflammatory conditions, ATP may be a potent activator of nociceptors and an endogenous mediator of pain.

Adenosine Triphosphate↗

PubMed2000

Reproducibility of laser Doppler imaging of skin blood flow as a tool to assess endothelial function.

Endothelial dysfunction might be an important and early event in the pathogenesis of major cardiovascular diseases. Therefore, the evaluation of endothelial function in humans may be of great clinical relevance. Usual methods for that purpose are either invasive and/or technically demanding. In the dermal microcirculation, endothelial function may be assessed noninvasively from the laser Doppler measurement of increases in blood flow after either the transdermal application of acetylcholine by iontophoresis, or the release of transient arterial occlusion (reactive hyperemia). An endothelium-independent response may be provided by the iontophoresis of sodium nitroprusside. This approach is notable for technical simplicity, but of uncertain reproducibility. Sixteen young, healthy, nonsmoking males were examined in the fasting state. Changes in skin blood flow were measured with a laser Doppler imager during the iontophoresis of acetylcholine and sodium nitroprusside, as well as during reactive hyperemia, on two different days, at each of two different sites on the volar face of the forearm. Nonspecific effects related to the stimulation of terminal nerve fibers by the iontophoretic current were suppressed by prior surface anesthesia. The iontophoresis of acetylcholine and sodium nitroprusside induced a seven- to eightfold increase in dermal blood flow. The corresponding figure for peak reactive hyperemia was approximately fourfold. The mean coefficients of variation of responses recorded on different days, on the same site, in the same individual were <10% for iontophoresis of acetylcholine and for peak reactive hyperemia, and between 10 and 20% for iontophoresis of sodium nitroprusside. This day-to-day variation was significantly smaller than the site-to-site variation (p < 0.01 for all three responses). Endothelium-dependent and -independent responses of dermal blood flow evaluated with laser Doppler imaging are highly reproducible from day to day, at least in healthy nonsmoking young male subjects, and provided some simple precautions are observed, foremost among which is the strict standardization of the recording site. These observations may have implications for the testing of endothelial function in clinical studies.

Acetylcholine↗

PubMed2004

Investigation into the mechanisms by which nedocromil sodium, frusemide and bumetanide inhibit the histamine-induced itch and flare response in human skin in vivo.

BACKGROUND: In a previous study, iontophoresis of nedocromil sodium into human skin in vivo was shown to reduce histamine-induced itch and flare. In asthma, the Na+/K+/2Cl- cotransporter inhibitors, frusemide and bumetanide, have been reported to have many similar actions to nedocromil sodium. OBJECTIVE: To compare the effects of these drugs in the histamine-induced itch, flare and weal response in human skin in vivo and elucidate their site of action. METHODS: Nedocromil sodium, frusemide bumetanide and reversed osmosis water (control), were introduced by iontophoresis into the forearm skin of 10 volunteers in each of two single-blind studies. In study 1, histamine (20 microL of 100 microM) or vehicle was injected into the area of iontophoresis 10 min later. In study 2, histamine or vehicle was injected 5 mm outside the area of iontophoresis so the flare developed over the area of iontophoresis. Itch was scored on a visual analogue scale every 20 s for 5 min, flare areas were assessed using scanning laser Doppler imaging up to 10 min and weal was assessed by planimetry at 10 min. RESULTS: In study 1, nedocromil sodium, frusemide and bumetanide reduced itch scores by 36%, 48% and 34%, respectively, and flare areas by 17%, 26% and 15% respectively (all P<0.05). Weal areas and blood flux in the flare were unaffected. In study 2, itch scores, flare areas and weal areas were not inhibited. Also, blood flux values in areas of drug and water iontophoresis were not different. CONCLUSION: This study has provided evidence to support the hypothesis that nedocromil sodium, frusemide and bumetanide inhibit sensory nerve activation to reduce the itch and flare responses induced by histamine in human skin in vivo. It is likely that inhibition of a Na+/K+/2Cl- cotransporter in the sensory nerve membrane is a possible mechanism of action.

Adult↗

PubMed2005

Determination of sensitive electrophysiologic parameters at follow-up of different steroid treatments of carpal tunnel syndrome.

Nonsurgical treatment for carpal tunnel syndrome (CTS) is frequently offered to those with mild to moderate symptoms. However, the most sensitive electrophysiological parameters at follow-up, and most effective type of different methods of steroid treatment for CTS, remain unknown. The aim of this study was to compare the efficacy of local corticosteroid injection, phonophoresis, and iontophoresis for the treatment of CTS, and to evaluate the most sensitive electrophysiologic parameters at the follow-up visit. Different conservative treatments were applied in this prospective study. Fifty-six hands of 31 patients were randomly treated with local steroid injection, iontophoresis, or phonophoresis with 2- and 4-month follow-up visits. Conventional and new neurophysiologic sensorimotor nerve conduction parameters for CTS diagnosis were performed on the initial visit and at 2 and 4 months after treatment. The local steroid injection group showed a significant improvement in the mean nerve conduction parameters after the second and fourth months when compared with basal values, whereas no significant changes except the difference between the median and ulnar distal latency to the fourth digit (D4M-D4U), difference between sensory median distal latency to second digit and ulnar distal latency to the fifth digit (D2M-D5U), and median motor distal latency were observed in the iontophoresis and phonophoresis groups. At the end of follow-up period, the most sensitive parameters were D4M-D4U and D2M-D5U; the D4M-D4U was improved 60% in the injection group, 33% in iontophoresis group, and 39% in phonophoresis group, and the improvement of the D2M-D5U was 70%, 28%, and 28%, respectively, in the injection, iontophoresis, and phonophoresis groups. These findings show that steroid injection is superior to iontophoresis and phonophoresis in the treatment of CTS, and that the most sensitive neurophysiologic parameters in follow-up are D4M-D4U and D2M-D5U, being the objective measures of the outcome of CTS treatment.

Adrenal Cortex Hormones↗

PubMed1987

Timolol induces HSV-1 ocular shedding in the latently infected rabbit.

Timolol iontophoresis into the eye can induce herpes simplex virus type 1 (HSV-1) shedding in rabbits latently infected with HSV-1 strain McKrae. Anodal iontophoresis of 0.01% timolol was done at 0.8 mAmp for 8 min once a day for 3 consecutive days. Viral shedding was determined by the presence of HSV-1 in the preocular tear film obtained by eye swabs. In two experiments, iontophoresis of 0.01% timolol resulted in all eyes (18/18) shedding HSV-1 for an average duration of 4.3 days. When 5.0% timolol was applied topically to rabbit eyes supersensitized by iontophoresis of 6-hydroxydopamine (6-HD), all eyes (10/10) shed virus for an average duration of 2.9 days. All eyes (12/12) receiving iontophoresis of 6-HD, pre- and posttreatment with topical application of 5.0% timolol, and posttreatment with topical application of 1.0% epinephrine shed virus for an average duration of 3.6 days. Eyes treated with topical application of 5.0% timolol alone showed no difference in HSV-1 ocular shedding, compared with untreated eyes. We concluded that both iontophoresis of 0.01% timolol and topical application of 5.0% timolol to adrenergically supersensitized eyes induced HSV-1 shedding reliably and with a high frequency, and that topically applied timolol does not block the HSV-1 ocular shedding induced by epinephrine in adrenergically supersensitized eyes.

Administration, Topical↗

PubMed1980

Increased penetration of nonelectrolytes into mouse skin during iontophoretic water transport (iontohydrokinesis).

Iontophoresis increases penetration of ionic drugs into surface tissues by repulsion of ions at the active electrode. However, we reported increased penetration of idoxuridine by either anode(+) or cathode(-). Although not highly ionized, idoxuridine forms anions in aqueous solution requiring introduction under the cathode(-). We postulated that increased penetration of idoxuridine after anodal(+)-iontophoresis may result from water movement associated with sodium ion transfer. When water is transported into tissue, nonelectrolytes may also be transported. The term iontohydrokinesis was adopted to describe water transport during iontophoresis, and no specific mechanism is implied by this new term. Iontohydrokinesis was studied after cathodal(-)- and anodal(+)-iontophoresis of dilute NaCl solutions containing [3H]-9-beta-D-arabinofuranosyladenine, (Ara-A), [3H]H2O and [3H]thymidine (dThd). Since Ara-A and dThd are nonconductive, any increase in penetration must be due to water transport by iontohydrokinesis. Anodal iontophoresis resulted in the following statistically significant increases in penetration compared to topical application: [3H]H2O, +155%; [3H]dThd, +429% and [3H]Ara-A, +488%. Cathodal(-)-iontophoresis resulted in statistically significant increases in penetration: [3H]H2O, +78% and [3H]dThd, +286%; the penetration of [3H]Ara-A increased +56% but this was not statistically significant. Electrical current does not change skin permeability.

Adenine↗

PubMed2003

Electronically facilitated transdermal delivery of human parathyroid hormone (1-34).

Electronically facilitated transdermal delivery of human parathyroid hormone (1-34), hPTH (1-34), was investigated in vitro, using dermatomed porcine skin. The effect of iontophoretic current density, electroporative pulse voltages and also electroporation followed by iontophoresis was investigated on the in vitro percutaneous absorption of hPTH (1-34). Iontophoresis at 0.5 mA/cm2 current density significantly enhanced (P<0.05) the flux of hPTH (1-34) in comparison to passive flux. Electroporation pulses of 100, 200 and 300 V significantly increased (P<0.05) the flux of hPTH (1-34) in comparison with the passive as well as iontophoretic flux at 0.5 mA/cm2. The electroporative flux of hPTH (1-34) was found to vary linearly (R2 = 0.97) with the pulse amplitude. The principal barrier of the skin, stratum corneum, was found perturbed following the pulses as evident by light microscopy studies. The application of electroporation pulses followed by iontophoresis further increased the flux by several fold. The flux of hPTH (1-34) with the electroporation pulses of 100 and 300 V followed by iontophoresis at 0.2 mA/cm2 was 10- and 5-fold higher, respectively, in comparison to the flux with corresponding pulses alone. This shows the synergistic effect of iontophoresis in combination with electroporation on skin permeability of hPTH (1-34). The results indicate the possibility of designing controlled transdermal delivery systems for hPTH (1-34) using electroporation followed by iontophoresis.

Administration, Cutaneous↗

PubMed1994

Electrophysiological evidence for a functional interaction between 5-HT1A and 5-HT2A receptors in the rat medial prefrontal cortex: an iontophoretic study.

In this study, we examined the interaction of 5-HT1A and 5-HT2A receptors in the rat medial prefrontal cortex (mPFc) using the techniques of extracellular single unit recording and microiontophoresis. The iontophoresis of the selective 5-HT1A receptor agonist (+-)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT) produced a current-dependent suppression (2.5-20 nA) of the basal firing rate of spontaneously active mPFc cells. The iontophoretic (5-10 nA) and systemic administration (0.1-0.5 mg/kg, i.v.) of the 5-HT2A/5-HT2C receptor antagonist ritanserin and the selective 5-HT2A receptor antagonist MDL 28727 significantly potentiated and prolonged 8-OHDPAT's suppressant action. In addition, the systemic administration of another selective 5-HT2A antagonist MDL 100907, but not its less active enantiomer MDL 100009, also potentiated and prolonged 8-OHDPAT's action. The potentiating effect of the 5-HT2A receptor antagonists on the action of 8-OHDPAT is specific in that neither the iontophoresis of ritanserin nor MDL 28727 altered the suppressant action produced by the iontophoresis of the 5-HT3 receptor agonist 2-methylserotonin onto mPFc cells. Moreover, the suppressant action of 8-OHDPAT was not altered by the systemic administration of the selective 5-HT3 receptor antagonist granisetron (0.1-0.5 mg/kg, i.v.). On the other hand, the iontophoresis of a low current (0.5 nA) of the 5-HT2A,2C receptor agonist (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) potentiated the excitation induced by the iontophoresis of l-glutamate on quiescent mPFc cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamines↗

PubMed1998

Assessing microcirculation in familial dysautonomia by laser Doppler flowmeter.

Microcirculatory vasomotor responses to an alpha-adrenergic agonist and an antagonist were assessed in 11 familial dysautonomia and nine control subjects by laser Doppler flowmetry. Using two iontophoresis machines, blood flow in the midclavicular areas was continuously monitored by two channel laser Doppler flowmeter. Simultaneously, the alpha-antagonist (0.5 mM phentolamine hydrochloride) and a control solution (0.9% saline) were iontophoresed at 200 microA for 15 min. The alpha-agonist (0.5 mM norepinephrine bitartrate) was then iontophoresed (20 microA) to both pretreated areas for progressively longer pulses separated by 3-min observation intervals (15, 30, 60, 90, 120 s). The familial dysautonomia subject group had higher mean baseline perfusion with widely fluctuating baselines, especially on the phentolamine pretreated side (P = 0.03). Saline iontophoresis significantly increased perfusion in the control group, but not in the familial dysautonomia group (ANOVA: P = 0.02 and 0.15, respectively). There was > 100% increase in flow by the end of the saline observation period in seven of nine controls, but in only three of 11 familial dysautonomia subjects. Phentolamine iontophoresis differentiated familial dysautonomia subjects into responders and nonresponders by 7-8 min when all nine control subjects, but only five of 11 familial dysautonomia subjects, had > 200% increase in blood flow. Irrespective of pretreatment type, norepinephrine decreased blood flow in both familial dysautonomia and control groups (ANOVA: P < 0.0001), but the final mean change after saline was greater in the control group, P = 0.02. The final mean changes of flow after phentolamine pretreatment were not different between the two groups and were comparable to the familial dysautonomia group's smaller response after saline pretreatment. Higher baseline perfusion suggests dilation may be intrinsic to familial dysautonomia vasculature. Two populations of familial dysautonomia subjects are noted; those who like controls increase blood flow with iontophoresis of the alpha-antagonist and those who are refractory. In addition, in familial dysautonomia subjects, the microcirculatory constrictive response to alpha-agonist iontophoresis is less than that observed for controls. These data suggest that some familial dysautonomia subjects may have decreased or dysfunctional adrenoceptors as well as decreased innervation.

Adolescent↗

PubMed1996

Adrenergic receptors in the forehead microcirculation.

The presence of alpha- and beta-adrenoceptors in the forehead microcirculation was investigated in 49 healthy subjects. Local vascular responses to noradrenaline, isoprenaline and adrenergic antagonists, administered transcutaneously by iontophoresis, were monitored via laser Doppler flowmetry. Iontophoresis of the alpha-adrenergic antagonist phentolamine induced a persistent increase in skin blood flow, whereas iontophoresis of saline induced a minor increase in skin blood flow which subsided rapidly. Skin blood flow increased moderately after the iontophoresis of the beta-adrenergic antagonist propranolol. Pretreatment of the experimental site with phentolamine blocked the normal vasoconstrictor response to noradrenaline, and unmasked a minor vasodilator component of response in some subjects. Iontophoresis of the beta-adrenergic agonist isoprenaline induced dose-dependent vasodilatation which was antagonised by propranolol. These findings indicate that alpha-adrenoceptors in the forehead microcirculation normally mediate a vasoconstrictor response to iontophoretically-applied noradrenaline. In addition, beta-adrenoceptors appear to mediate a minor vasodilator component of response.

Adolescent↗

PubMed2006

Enhanced transscleral lontophoretic transport with ion-exchange membrane.

PURPOSE: Transscleral iontophoresis has been recently re-examined for drug delivery to the back of the eye. In conventional iontophoresis, due to the relatively high electromobility of the endogenous competing ions (counterions) relative to that of the drug ion in the tissue barrier, the efficiency of iontophoretic drug delivery is generally low. The objective of the present study was to examine ion-exchange membrane-enhanced transscleral iontophoretic transport in which the ion-exchange membrane in series with the sclera can hinder the transport of the competing counterions and selectively allow the transport of the permeant across the sclera. METHODS: The physical properties of the Ionac ion-exchange membrane and excised rabbit sclera were determined in equilibrium uptake experiments and in passive and iontophoretic transport experiments with salicylate, tetraethylammonium, urea, and mannitol. Transscleral experiments with the ion-exchange membrane were conducted with salicylate and excised rabbit sclera in vitro. The contribution of electroosmosis to electrotransport during transscleral iontophoresis was assessed with urea and mannitol. RESULTS: The ion-exchange membrane is highly positively charged and has a small effective pore size. The sclera is relatively porous with a large effective pore size and low pore tortuosity. The sclera is also net negatively charged but this does not significantly affect the transport of small ions. A three-fold steady-state transscleral flux enhancement of salicylate was observed in ion-exchange membrane-enhanced iontophoresis over conventional transscleral iontophoresis without the membrane. Such enhancement was relatively independent of the applied electric current density and the thickness of the studied ion-exchange membrane assembly. Although the ion-exchange membrane altered transscleral electroosmosis, the contribution of electroosmosis to electrotransport was not significant. CONCLUSIONS: The present study has demonstrated the potential of ion-exchange membranes for enhancing iontophoretic transport and drug delivery.

Animals↗

PubMed1982

Acyclovir and vidarabine monophosphate: comparison of iontophoretic and intravenous administration for the treatment of HSV-1 stromal keratitis.

We determined the therapeutic efficacy of iontophoretic application of acyclovir and vidarabine monophosphate (ara-AMP) for the treatment of herpes simplex virus (HSV) type 1-induced stromal keratitis in rabbits. The therapeutic efficacy of intravenous administration of acyclovir was assessed in the same model. Stromal keratitis was produced by intrastromal injection of 10 microliters purified HSV-1, McKrae strain. Treatment began the first day after intrastromal injection. Iontophoresis (0.5 mAmp for four minutes) of 3.4 percent (0.1 M) ara-AMP and 5.0 percent (0.22 M) acyclovir was performed once daily for five consecutive days in two treatment groups. Intravenous administration of 50 mg acyclovir/kg was performed twice daily for eight consecutive days. Intravenous administration of NaCl (0.14 M) and ocular iontophoresis of NaCl (0.14 M) were performed as controls in the two treatment groups. At least two scorers performed a single masked evaluation of the disease severity (lesion scoring) of the conjunctiva, corneal epithelium, stroma, and iris by still lamp examination. The eyes were scored daily for 12 consecutive days, and then every other day up to day 22. Iontophoresis of acyclovir or ara-AMP significantly reduced the course of the disease compared with iontophoresis of NaCl. Intravenous administration of acyclovir significantly reduced the disease compared with intravenous NaCl. This suggests that iontophoresis of acyclovir or ara-AMP either alone or in combination with intravenous administration of acyclovir may be of value in the treatment of HSV-1 stromal keratitis.

Acyclovir↗

PubMed2004

The effect of pretreatment with terpenes on transdermal iontophoretic delivery of arginine vasopressin.

This study investigates the effects of terpenes and iontophoresis on the in vitro permeation of arginine vasopressin (AVP) through rat skin and the biophysical changes induced by the chemical enhancers in the stratum corneum (SC) lipids by FT-IR spectroscopy. Pretreatment with terpenes (e.g. 5% w/v, carvone, pulegone, cineole and menthol in EtOH:W (2:1) system) increased (P < 0.05) the flux of AVP in comparison to control (not pretreated with enhancer) but was not significantly different (P > 0.05) in comparison to iontophoresis. Amongst different terpenes studied maximum enhancement ratio was observed with cineole. In combination, iontophoresis did not further increase (P > 0.05) the permeation of AVP through the enhancer pretreated epidermis in comparison to pretreatment with enhancer or iontophoresis alone. Hence it was concluded that although the combination was effective in flux enhancement compared to control, there was no synergism in action between terpenes and iontophoresis. FT-IR spectroscopic studies revealed that EtOH:W (2:1) system is not effective in lipid extraction. The area under the symmetric and asymmetric stretching peaks at 2850 and 2920 cm(-1) revealed that at the concentration used terpenes did not extract any lipids from the epidermis. The mode of action of terpenes is attributed to the breaking of hydrogen bonds between the ceramide head groups of lipids in the SC leading to greater fluidization of the SC lipids.

Administration, Cutaneous↗

PubMed2003

Combined chemical and electrical enhancement modulates stratum corneum structure.

In a previous in vitro study it has been shown that pretreatment with a water-based surfactant formulation results in a two-fold increase in transdermal iontophoretic transport of R-apomorphine compared to iontophoresis only. The aim of the study presented in this paper was to unravel the mechanisms involved in the increased iontophoretic delivery. Freeze fracture electron microscopy and cryo-scanning electron microscopy were used to visualise the ultrastucture of human stratum corneum after (i) application of the surfactant formulation, (ii) iontophoresis and (iii) application of the surfactant formulation followed by iontophoresis. Non-occlusive application of the surfactant formulation did not exert any detectable changes in the ultrastructure of the stratum corneum, except for swelling of the outermost corneocyte layers. Application of a current density of 0.5 mA/cm(2) for 9 h induced a swelling of the corneocytes and the formation of water pools that were occasionally present in the intercellular regions. Application of the surfactant formulation followed by iontophoresis resulted in a further swelling of the corneocytes and a frequent presence of water pools in the intercellular regions throughout the whole stratum corneum. The observed changes in the ultrastructure of the stratum corneum can explain the increased R-apomorphine transport during iontophoresis.

Administration, Cutaneous↗

PubMed2003

Enhanced iontophoretic delivery of buspirone hydrochloride across human skin using chemical enhancers.

Buspirone hydrochloride (BH) is a structurally and pharmacologically unique anxiolytic that is used to treat a variety of different anxiety conditions. The marketed product is named BuSpar. The in vitro iontophoretic delivery of BH through human skin was investigated in order to evaluate the feasibility of delivering a therapeutic dose of BH by this route. We also examined the influence of co-formulations of chemical enhancers (Azone, oleic acid, menthone, cineole, and terpineol) on BH permeation, both without iontophoresis and with iontophoresis-to look for possible synergistic effects. By applying iontophoresis at 0.5 mA/cm(2), it was possible to achieve a BH steady state flux of approximately 350 microg/cm(2)h, which would be therapeutically effective if clinically duplicated. Importantly, 24 h of iontophoresis at 0.5 mA/cm(2) did not affect skin morphology and after the current was switched off, the skin's permeability to BH rapidly reverted to its pre-iontophoretic level. Without iontophoreis, BH transdermal flux was significantly enhanced by the application of 2.5% (v/v) concentrations of Azone, oleic acid, or menthone but not cineole or terpineol. Furthermore, this paper identified a synergistic transport enhancement effect developing when very low current (0.025 mA/cm(2)) iontophoresis was applied in conjunction with Azone treatment.

Adjuvants, Pharmaceutic↗

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↗

PubMed1995

The electrical characteristics of human skin in vivo.

PURPOSE: The objectives of this study were to investigate the impedance properties of human skin in vivo and to examine the effect of iontophoresis upon them. METHODS: Having established the intra- and inter-individual variation in basal values of skin impedance, the effect of varying iontophoretic current density, ionic strength and counter-ion on the rate of recovery of skin impedance after iontophoresis was investigated. RESULTS: Passage of an iontophoretic current caused a significant reduction in the magnitude of the skin impedance. Increasing the current density caused an even greater reduction in the value of the skin impedance and slowed the rate of recovery. Reduction of the ionic strength resulted in an increase in the rate of recovery following iontophoresis. A significant increase in the rate of recovery was observed when CaCl2 replaced NaCl as the electrolyte. Although visual inspection revealed the presence of greater erythema when CaCl2 was used, there was an absence of the mild sensation experienced by volunteers when using NaCl. The last part of the study established a correlation between transepidermal water loss and impedance analysis as complementary methods for probing skin barrier function in vivo. The data were fitted to an equivalent circuit consisting of a resistor in parallel with a constant-phase element and a mechanistic model proposed to explain the electrical properties of the skin. CONCLUSIONS: The first comprehensive investigation of the effect of iontophoresis on the electrical properties of human skin in vivo has been described. It would appear from the results, and from their interpretation, that impedance spectroscopy may be an effective method to quantify the impact of iontophoresis on the skin, and to determine the extent to which proposed drug delivery regimens will perturb skin barrier function.

Electric Impedance↗

PubMed2003

Transient hyperaemic response to assess vascular reactivity of skin: effect of locally iontophoresed acetylcholine, bradykinin, epinephrine and phenylephrine.

BACKGROUND: Recently, the transient hyperaemic response (THR) to brief compression (20 s) of the brachial artery has been described as a way to assess vascular reactivity of the forearm skin. We studied the effects of locally iontophoresed vasoactive agents on this response in 20 male volunteers. METHODS: An iontophoresis chamber attached to the anterior forearm permitted simultaneous administration of drugs by iontophoresis and measurement of skin blood flow-flux by laser Doppler probe. Three THR tests were performed before and after iontophoresis by compressing the brachial artery with digital pressure for 20 s and then releasing. The following were iontophoresed: saline 0.9% (iontophoresis vehicle control), acetylcholine, bradykinin, epinephrine and phenylephrine. The THR ratio (THRR) was calculated as F2/F1 where F1 was baseline blood flow-flux immediately before compression and F2 was peak blood flow-flux after release. RESULTS: When compared with saline 0.9%, acetylcholine and bradykinin increased median F1 from 9.2 (range 5.2-23.8) to 22.1 (8.7-61.5) and from 4.8 (3.0-23.2) to 15.0 (2.5-31.8), respectively, and reduced THRR from 1.26 (1.07-2.2) to 0.99 (0.93-1.04) and from 1.63 (1.06-2.58) to 1.09 (0.93-1.19), respectively. Epinephrine, but not phenylephrine, caused a significant reduction in F1 from 9.2 (5.2-23.8) to 4.0 (1.5-22.3). Neither epinephrine nor phenylephrine had significant effect on THRR. CONCLUSIONS: Iontophoresed acetylcholine and bradykinin significantly increase the flow-flux and impair THR in forearm skin, further validating the concept that THR represents true vasodilatation during arterial occlusion. In addition, iontophoresis of vasoconstrictors does not appear to have any consistent effect.

Acetylcholine↗