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lontophoretic Devices for Drug Delivery
Abstract
Transdermal drug delivery of ionized drugs can be enhanced by iontophoresis. Drug in the ionic form, contained in some reservoir, can be "phoresed" through the skin with a small current across two electrodes, one above the reservoir and one at a distal skin location. Positive ions can be introduced from the positive pole, or negative ions from the negative pole. The design and development of iontophoretic devices are rather simple. Some of the principles of operation and the advantages/disadvantages and clinical implications associated with these devices are outlined in this review.
... 14 They found that permeation of these ILs through the membrane depends on the nature of the components, and salts in general are less likely to permeate the skin-mimicking membrane from solution where each ion is individually solvated, in accordance with the observation that water soluble pharmaceuticals in salt form do not permeate these membranes readily. 15 In 2011, Rogers et al. demonstrated that not only salt formation, but also very strong, partially ionized hydrogen bond formation can be the driving force in the liquefaction of solid pharmaceuticals 16 in the form of deep eutectics. 17 For example, lidocaine free base in combination with fatty acids such as decanoic acid or oleic acid produced low viscosity deep eutectics with no observed crystallization events, only glass transition temperatures of ca. ...
... This is in agreement with the general observation that ionic compounds do not cross membranes as readily as neutral compounds. 15 The only slightly enhanced penetration rate of [Eph][Ibu] ( ), as well as its 110 C melting point, suggest this compound is also a salt. ...
Using permeation through a model membrane in a Franz diffusion cell, we have demonstrated that acidic and basic active pharmaceutical ingredients (APIs) in deep eutectic ‘liquid co-crystal’ form can be held tightly together, even in solution, via strong hydrogen bonds or partially ionized interactions, providing simultaneous transport at rates much higher than solutions of their corresponding, commercially available crystalline salts, albeit at rates that are lower than the neutral forms of the individual molecules. It was also shown that the deep eutectic APIs do not have to be premade, but hydrogen-bonded complexes can be formed in situ by mixing the corresponding API–solvent solutions. To understand the behavior, we have extensively studied a range of nonstoichiometric mixtures of lidocaine and ibuprofen spectroscopically and via membrane transport. The data demonstrates the nature of the interactions between the acid and base and provides a route to tune the rate of membrane transport.
... Recently, SB has been utilized as a valuable tool for accurately directing therapeutic treatments in complex biological networks when combined with control theory. While considerable improvements have been achieved in medication delivery to cardiovascular systems [28], blood pressure management [29], tumor chemotherapy [30], anesthetic drug delivery [31], diabetic control [32], Parkinson's tremor [33], and HIV/AIDS control [34,35], there have also been notable setbacks. ...
The p53 pathway has been the focus of many researchers in the last few decades owing to its pivotal role as a frontline cancer suppressant protein. It plays a vital role in maintaining cell cycle checkpoints and cell apoptosis in response to a broken DNA strand. This is why it is found in the mutated form in more than 50% of malignant tumors. To overcome this, various drugs have been proposed to revive the p53 pathway in cancer patients. Small-molecule-based drugs, such as Nutlin 3a, which are capable of performing this stimulation, are at the fore of advanced clinical trials. However, the calculation of their dosage is a challenge. In this work, a method to determine the dosage of Nutlin 3a is investigated. A control-systems-based model is developed to study the response of the wild-type p53 protein to this drug. The proposed strategy regulates the p53 protein along with negative and positive feedback loops mediated by the MDM2 and MDM2 mRNA, respectively, along with the reversible repression of MDM2 caused by Nutlin 3a. For a broader perspective, the reported PBK dynamics of Nutlin 3a are also incorporated. It has been reported that p53 responds to stresses in two ways in terms of concentration to this drug: either it is a sustained (constant) or an oscillatory response. The claimed dosage strategy turned out to be appropriate for sustained p53 response. However, for the induction of oscillations, inhibition of MDM2 is not enough; rather, anti-repression of the p53–MDM2 complex is also needed, which opens new horizons for a new drug design paradigm.
... Transdermal method deliver medication via percutaneous absorption with the aim of gaining systemic levels of drugs in comparison to oral rout of delivery (9,10). Such delivery of ionized drugs can be enhanced by iontophoresis (11). The concept of iontophoresis dates back to 1908, when it was demonstrated that ions could be driven across the skin by means of an electrical current (12). ...
... 43−45 Furthermore, the iontophoresis-induced current flow may have altered the skin barrier function by increasing the permeability. 46,47 Transdermal Delivery of Therapeutic Flu-DNs. In order to assess whether our DNs-embedded electroconductive hydrogel with the RED system is effective in therapeutic drug delivery, we utilized fluconazole as a model drug. ...
We herein developed an iontophoretic transdermal drug delivery system for the effective delivery of electrically mobile drug nanocarriers (DNs). Our system consists of a portable and disposable reverse electrodialysis (RED) battery that generates electric power for iontophoresis through the ionic exchange. In addition, in order to provide a drug reservoir to the RED-driven iontophoretic system, electroconductive hydrogel composed of polypyrrole-incorporated poly(vinyl alcohol) (PYP) hydrogels were used. PYP hydrogel facilitated electron transfer from the RED battery and facilitated the mobility of electrically mobile DNs release from PYP hydrogel. In this study, we showed that fluconazole- or rosiglitazone-loaded DNs could be functionalized with charge inducing agents, and DNs with charge modification resulted in facilitated transdermal transport via repulsive RED-driven iontophoresis. In addition, topical application and RED-driven iontophoresis of rosiglitazone loaded DNs resulted in an effective anti-obese condition displaying decreased bodyweight, reduced glucose level, and increased conversion of white adipose tissues to brown adipose tissues in vivo. Consequently, we highlight that this transdermal drug delivery platform would be extensively utilized for delivering diverse therapeutic agents in a non-invasive way.
... To inhibit NOS, 200 µL of a 20 mM solution of N ω -nitrol-arginine methyl ester (L-NAME), dissolved in nonconducting and nontoxic propylene glycol, was pipetted onto the drug delivery electrode (PF 383, Perimed, Sweden) (Kellogg et al. 1989;Hodges et al. 2017b). In the solution, only L-NAME was a conductant; therefore, the amount of L-NAME delivered was directly proportional to the current applied and the duration of application (Tyle 1986). A 100 μA current (cathode) was used to locally infuse L-NAME to the dermis by iontophoresis (Perimed, Sweden) from a 1.4 cm 2 surface for 10 min (Hodges et al. 2017b). ...
Purpose:
Children thermoregulate effectively during exercise despite sweating rate being consistently lower when compared with adults. The skin blood flow (SkBF) response of children to exercise is inconsistent, when compared with adults. We examined the SkBF response to exercise in children and adults, along with the potential contribution of nitric oxide to the SkBF response.
Methods:
Forearm SkBF during cycling (30 min at 60% [Formula: see text]O2max) was investigated in 12 boys (10 ± 1 years) and 12 men (22 ± 2 years) using laser-Doppler flowmetry and Nω-nitro-L-arginine methyl ester (L-NAME) iontophoresis to inhibit nitric oxide synthase.
Results:
The exercise-induced SkBF increase was similar in boys and men (mean ± SD, 540 ± 127 vs. 536 ± 103% baseline, respectively, p = 0.43, d = 0.01 [- 0.8 to 0.8]). However, the total hyperaemic response to exercise (area-under-the-curve, AUC) indicated that boys had a greater vasodilatory response (cutaneous vascular resistance, CVC) (p < 0.01, d = 0.6 [- 1.2 to 2.8] than the men (134,215 ± 29,207 vs. 107,257 ± 20,320 CVC·s-1). L-NAME blunted the SkBF response more in boys than in men (group-by-treatment interaction, p < 0.001) and resulted in smaller AUC in boys (56,411 ± 23,033 CVC·s-1; p < 0.001, d = 1.4 [- 0.4 to 3.2] compared with men (80,556 ± 28,443 CVC·s-1; p = 0.08, d = 0.8 [0.0-1.6]). Boys had a shorter delay from the onset of exercise to onset of SkBF response compared with men (205 ± 48 and 309 ± 71 s, respectively; p < 0.01, d = 1.7 [0.9-2.8]). L-NAME increased the delay in boys and men (to 268 ± 90 and 376 ± 116 s, respectively; p = 0.01, d = 1.0 [0.4-2.1]) but this delay was not significantly different between the groups (p = 0.85).
Conclusions:
These findings suggest that boys experience greater vasodilation and faster increases in SkBF during exercise compared with men. The contribution of nitric oxide to the SkBF response to exercise appears to be greater in boys than in men.
... Therefore, the concept of epithelial-on cross-linking is more appealing. Iontophoresis has been used for ophthalmological drug administration since 1908 and applied in various medical fields such as transdermal delivery of anti-inflammatory agents, local anesthetics or analgesics, and transmucosal antiviral administration [11][12][13][14][15][16][17] . More recently, it has been found to be efficacious for transcorneal drug delivery [18] . ...
Corneal cross-linking (CXL) is a noninvasive therapeutic procedure for keratoconus that is aimed at improving corneal biomechanical properties by induction of covalent cross-links between stromal proteins. It is accomplished by ultraviolet A (UVA) radiation of the cornea, which is first saturated with photosensitizing riboflavin. It has been shown that standard epithelium-off CXL (S-CXL) is efficacious, and it has been recommended as the standard of care procedure for keratoconus. However, epithelial removal leads to pain, transient vision loss, and a higher risk of corneal infection. To avoid these disadvantages, transepithelial CXL was developed. Recently, iontophoresis has been adopted to increase riboflavin penetration through the epithelium. Several clinical observations have demonstrated the safety and efficacy of iontophoresis-assisted epithelium-on CXL (I-CXL) for keratoconus. This review aimed to provide a comprehensive summary of the published studies regarding I-CXL and a comparison between I-CXL and S-CXL. All articles used in this review were mainly retrieved from the PubMed database. Original articles and reviews were selected if they were related to the I-CXL technique or related to the comparison between I-CXL and S-CXL.
... Iontophoresis is one of the most common physical enhancement technologies with simple design that use of a small electrical current, at a constant pulse, to promote the placement of charged and uncharged species of therapeutic drugs at the skin surface without pain sensation. Nevertheless, this technique requires the previous ionization of drug solution and remains the possibility of burns (Barry, 2001;Tyle, 1986). Electroporation, a versatile methodology that can be applied to several drugs, uses high-voltage shortduration pulses in order to create regions of membrane permeabilization by the production of aqueous pathways in SC with full reversibility within minutes to hours. ...
The limited efficiency of conventional drugs has been instigated the development of new and more effective drug delivery systems (DDS). Transdermal DDS, are associated with numerous advantages such its painless application and less frequent replacement and greater flexibility of dosing, features that triggered the research and development of such devices. Such systems have been produced using either biopolymer; or synthetic polymers. Although the first ones are safer, biocompatible and present a controlled degradation by human enzymes or water, the second ones are the most currently available in the market due to their greater mechanical resistance and flexibility, and non-degradation over time. This review highlights the most recent advances (mainly in the last five years) of patches aimed for transdermal drug delivery, focusing on the different materials (natural, synthetic and blends) and latest designs for the development of such devices, emphasizing also their combination with drug carriers that enable enhanced drug solubility and a more controlled release of the drug over the time. The benefits and limitations of different patches formulations are considered with reference to their appliance to transdermal drug delivery. Furthermore, a record of the currently available patches on the market is given, featuring their most relevant characteristics. Finally, a list of most recent/ongoing clinical trials regarding the use of patches for skin disorders is detailed and critical insights on the current state of patches for transdermal drug delivery are also provided.
... Iontophoresis is mostly used to enhance drug delivery. A low intensity current is applied to the skin to enhance the diffusion of ionic drugs to cross the epidermal barrier into the skin (Tyle, 1986). The most often applied agent in conjunction with skin BF measurements is acetylcholine chloride (ACh) as it induces endothelium-dependent vasodilation. ...
Adequate blood flow within microcirculation and sufficient tissue oxygenation are essential for tissue health. However, the quantitative understanding of dynamics between the microvascular blood flow and oxygenation remains limited. The aim of this study was to explore and interpret simultaneous measurements of skin blood flux (BF) and oxygenation parameters (OXY) recorded from healthy skin.
Measurements were recorded using a recently developed (Moor Instruments Ltd, UK) combined Laser Doppler Flowmetry (LDF) and White Light Spectroscopy (WLS) technique, which offer an easy to perform assessment of skin microcirculation and skin oxygenation. In this thesis, two open studies have been conducted in cohorts of healthy volunteers to evaluate combined LDF-WLS measurements and to study the relationship between skin BF and OXY.
The engineering challenge of this thesis was to apply signal processing methods to analyse BF and OXY parameters and to extract information that reflect the physiological characteristics of the tissue. Signal processing methods such filtering, convolution, Fourier transform and others served as tools to identify different properties of the signals and subsequently describe the biological systems.
The measurements acquired across wide range of values led to mathematical description of the relationship between skin BF and oxygenation and revealed different oscillatory characteristics in BF and OXY signals. The analysis showed resting BF and OXY signals have the highest coherence across low frequency bands. Furthermore, OXY signals are delayed in respect to BF signals. Signal obtained during thermally induced vasodilation showed a shift in signal power to the cardiac frequency band.
In conclusion, simultaneous measurements of skin BF and OXY signals in combination with signal processing techniques offer an extended assessment of microvascular function, which may complement clinical assessment of tissue status. Further work is now required to combine presented in this thesis BF and OXY characteristics with other available analysis into clinically useful assessment.
... Within the last 10 years, the symmetrical nature of iontophoresis (i.e., that the passage of current across the skin causes ions to move into and out of the membrane at the same time) has led to its application as a noninvasive method of extracting endogenous substances. This socalled reverse iontophoresis procedure is exemplified by the Glucowatch Biographer recently approved by the FDA for glucose monitoring [5][6][7][8][9][10][11][12][13][14][15] . ...
... Iontophoresis is the facilitated movement of ions across a membrane under the influence of an externally applied small electrical potential difference (0.5 mA/cm 2 or less), is one of the most promising novel drug delivery system, which has proved to enhance the skin penetration and the release rate of a number of drugs having poor absorption/permeation profile through the skin [60,61] . It is a localized, non-invasive, convenient and rapid method of delivering water soluble, The potential of this technique has been exploited for the transdermal delivery of many drugs with poor penetration properties e.g., high molecular weight electrolytes such as proteins, peptides and oligonucleotides which are normally difficult to administer except through parenteral route. ...
... It can also be define as a means of enhancing the flux of ionic drugs across skin by the application of an electrochemical potential gradient (Kanikkannan N., 2002). Iontophoresis, which is the facilitated movement of ions across a membrane under the influence of an externally applied small electrical potential difference (0.5 mA/cm2 or less), is one of the most promising novel drug delivery system, which has proved to enhance the skin penetration and the release rate of a number of drugs having poor absorption / permeation profile through the skin (Green et al., 1993, Tyle, 1986, Green, 1996and Sage, 1993. Recently, Bos and Meinardi introduced us to the 500 Dalton rule for skin penetration of chemicals and drugs (Jaskari et al., 2001). ...
The goal of delivery system is to get optimal therapeutic management. But, it still remains a challenge in the field of pharmaceuticals for delivery of ionic species and some non ionic. Several transdermal approaches have been used and recently there has been a great attention in using iontophoretic technique for the transdermal drug delivery of medications, both ionic and non ionic. This technique of facilitated movement of ions across a membrane under the influence of an externally applied electric potential difference is one of the most promising physical skin penetrations enhancing method. The payback of using iontophoretic technique includes improved systemic bioavailability ensuing from bypassing the first metabolism. Variables due to oral administration, such as pH, the presence of food or enzymes and transit times can all be eliminated. This article is an overview of the history of iontophoresis, mechanism, principles and factors influencing iontophoresis and its application for various dermatological conditions.
... The Smart Pill[17] Schematic Representation of Iontophoresis Circuit[28] effectiveness of transdermal drug delivery, active devices have been created that utilize iontophoretics (seeFigure 3), chemical enhancers, and ultrasound. MEMS devices have also been used in this respect.Micro needles (seeFigure 4) created by micro fabrication techniques are used to improve the effectiveness of transdermal drug delivery. ...
... Iontophoresis (ITP) has been generally utilized to facilitate the penetration of drugs across the skin by the application of electric current, which mainly offers an electrical driving force for passage of drugs through the stratum corneum together with enhanced skin permeability of drugs. 268,288 ITP is particularly applicable for transdermal delivery of hydrophobic charged small-molecule drugs. However, it is difficult to accomplish similar efficient enhancement in skin permeation of hydrophilic macromolecular proteins like insulin by using ITP alone. ...
Insulin is essential for type 1 and advanced type 2 diabetics to maintain blood glucose levels and prolong lives. The traditional administration requires frequent subcutaneous insulin injections that are associated with poor patient compliance, including pain, local tissue necrosis, infection, and nerve damage. Taking advantage of emerging micro- and nanotechnologies, numerous alternative strategies integrated with chemical approaches for insulin delivery have been investigated. This review outlines recent developments in the controlled delivery of insulin, including oral, nasal, pulmonary, transdermal, subcutaneous and closed-loop insulin delivery. Perspectives from new materials, formulations and devices at the micro- or nano-scales are specifically surveyed. Advantages and limitations of current delivery methods, as well as future opportunities and challenges are also discussed.
... Iontophoresis is defined as a noninvasive technique where a constant electric current is applied to enhance penetration of an ionized substance into a tissue without epithelial removal. 4 It has been used in various fields of medicine, [5][6][7] for example, local transdermal administration of anesthetics, antiinflammatories, or analgesics, as well as transmucosal administration of antivirals. 8 In ophthalmology, the first studies of iontophoresis were performed in the 1940's with the administration of antibiotics for the treatment of bacterial endophthalmitis and keratitis. ...
Purpose:
To assess corneal stiffening with supersonic shear wave imaging (SSI) technology in an experimental model of iontophoresis-assisted transepithelial corneal collagen cross-linking (I-CXL).
Methods:
Six rabbits underwent full, central I-CXL in one eye. The contralateral eye served as control. In vivo iontophoresis was used for 10 minutes to perform transepithelial delivery of riboflavin prior to UV-A irradiation. Accelerated UV-A protocol was applied for 9 minutes with a 10-mW/cm(2) irradiance. Animals were killed and both treated and control corneas were then immediately mounted on a corneal artificial anterior chamber and internal pressure was varied from 15 to 50 mm Hg in 5-mm Hg increments. Swelling was evaluated via central corneal thickness measurements. Ex vivo inflation tests were monitored using SSI technology that provides real-time mapping of the corneal elasticity.
Results:
Corneal yellowing of the central 9-mm diameter area was clearly visible in the iontophoresis area of all treated eyes. Elasticity versus internal pressure revealed significant differences of the change in elasticity coefficient with pressure between I-CXL-treated and control corneas with a mean slope that was 27.1 and 16.9 kPa/mm Hg, respectively (P = 0.029). Differences in elasticity at individual pressure levels between groups were statistically significant above 40 mm Hg (P < 0.05).
Conclusions:
Intraocular pressure variations were the most important limitations for in vivo stiffness monitoring with SSI because stiffness is a function of internal pressure. Supersonic shear wave imaging succeeded in comparing corneas that underwent I-CXL by performing ex vivo inflation tests where pressure was controlled. Iontophoresis-assisted transepithelial corneal collagen cross-linking corneas exhibited increased resistance to pressure rise, indicating stiffening. In vivo I-CXL and ex vivo SSI is an interesting model to evaluate the sole effect of photopolymerization occurring in the CXL process close to physiological conditions.
... Iontophoresis is a process or technique that causes an increased penetration of ionic or charged molecules into tissue using electrical potential or current, in either continuous (Bagniefski and Burnette, 1990) or pulsed mode (Chien, 1993). It is used to enhance the transdermal flux of many compounds (Tyle, 1986;Banga and Chien, 1988) and at present receives considerable attention ...
Optimization via experimentation in iontophoresis was investigated. A response surface method was applied in optimizing the operating conditions in iontophoretic transdermal delivery of pilocarpine. With an objective for a transitory application of pilocarpine, i.e. in diagnosis of cystic fibrosis or in treatment of hyperhydrosis, the best operating condition was achieved via a response surface method by adjusting the pH of the buffer, ionic strength, current amplitude and frequency of pulsed current or active temporal ratio based on unknown structural models with stationary or slowly varying optima in the region of interest. This method was easy to approach and efficient in seeking optimal experimental conditions for multiple variables and an unknown structural system. Satisfactory results in optimizing the operating conditions in iontophoretic transdermal delivery of pilocarpine were thereby achieved.
Objective:
Persons with spinal cord injury (SCI) are unable to efficiently dissipate heat via thermoregulatory vasodilation as efficiently as able-bodied persons during whole body passive heat stress (PHS). Skin blood flow (SkBF) is controlled by dual sympathetic vasomotor systems: noradrenergic vasoconstrictor (VC) nerves and cholinergic vasodilator (VD) nerves. Thus, impaired vasodilation could result from inappropriate increases in noradrenergic VC tone that compete with cholinergic vasodilation or diminished cholinergic tone. To address this issue, we used bretylium (BR) which selectively blocks neural release of norepinephrine, thereby reducing noradrenergic VC tone. If impaired vasodilation during PHS is due to inappropriate increase in VC tone, BR treatment will improve SkBF responses during PHS.
Design:
Prospective interventional trial.
Setting:
laboratory.
Participants:
22 veterans with SCI.
Interventions:
Skin surface areas with previously defined intact vs. impaired thermoregulatory vasodilation were treated with BR iontophoresis with a nearby untreated site serving as control/CON. Participants underwent PHS until core temperature rose 1°C.
Outcome measures:
Laser doppler flowmeters measured SkBF over BR and CON sites in areas with impaired and intact thermoregulatory vasodilation. Cutaneous vascular conductance (CVC) was calculated for all sites. Peak-PHS CVC was normalized to baseline (BL): (CVC peak-PHS/CVC BL) to quantify SkBF change.
Results:
CVC rise in BR sites was significantly less than CON sites in areas with intact (P = 0.03) and impaired (P = 0.04) thermoregulatory vasodilation.
Conclusion:
Cutaneous blockade of neural release of noradrenergic neurotransmitters affecting vasoconstriction did not enhance thermoregulatory vasodilation during PHS in persons with SCI; rather BR attenuated the response. Cutaneous blockade of neural release of noradrenergic neurotransmitters affecting vasoconstriction did not restore cutaneous active vasodilation during PHS in persons with SCI.
Improvisation in the overall therapeutic benefit of the drugs in terms of efficacy and patient compliance has ushered the researchers to develop a novel Drug Delivery Method. The Transdermal Drug Delivery has amassed tectonic scientific interest gratification to its reliability, patient compliance and painless technique of administering drug formulation into the bloodstream through the skin at a predetermined rate. In the present review, we have enumerated the trailblazing knowledge on the development and mechanism of the Transdermal Drug Delivery System. Herein we also have encompassed the essence of the Polymer Microneedles and Polymer Hydrogels in hewing the Transdermal Drug Delivery Technique the most relevant and effective method of administering drugs over the other Drug Delivery Methods. In this review article we have put forth the overall study of the Transdermal Drug Delivery Technique and the advantages of this method over other drug delivery methods which ushers this method to be the Novel Drug Delivery System.
The aim of this research was to improve transdermal delivery and distribution of tetramethylpyrazine (TMP) in the brain, by adding borneol (BN) and iontophoresis (ITP), and using microneedles (MN), to prevent middle cerebral artery occlusion (MCAO). BN was encapsulated into sulfobutylated-β-cyclodextrin (BN-SBE-β-CD), and then dispersed together with TMP. Four delivery groups were tested: passive (with no ITP and MN), ITP, MN, and MN combined with ITP (MN-ITP). In vitro transdermal fluxes of the drugs in those groups and in that corresponding order were 79.12±14.5, 395.43±12.37, 319.16±29.99, and 1018.07±108.92 μg/cm2 (for TMP), and 39.34±1.31, 202.81±53.56, 715.47±75.52, and 1088.60±53.90μg/cm2 (for BN), respectively, which indicated that the use of MN-ITP greatly enhanced transdermal TMP and BN delivery compared to the other groups. The AUC0-t for the combined use of TMP and BN drugs was measured using two in vivo studies, cutaneous microdialysis and pharmacodynamic, yielding increased folds of 3.69 and 1.98 in ITP, 6.05 and 2.73 in MN, and 12.43 and 7.47 in MN-ITP groups, respectively, as compared to those in the passive group. In addition, the combined use of TMP and BN increased TMP distribution in the heart and the brain, indicated by TMP Cmax of 1.76- and 1.59-fold higher (p < 0.05), and TMP AUC0-t of 1.50 times and 1.19-fold higher (p < 0.01), than with administration of TMP in absence of BN, respectively. The brain infarction area and IL-β expression in the MCAO rat were significantly decreased in the MN-ITP group, compared with the control group (p < 0.05). In conclusion, combination of MN and ITP resulted in a synergistic enhancement of transdermal delivery and distribution of TMP in the brain, when in combination with BN, thereby significantly decreasing the infarct volumes and improving the neurological scores of MCAO.
Tranexamic acid cetyl ester hydrochloride (TXC), which is synthesized by chemically modifying the tranexamic acid with the hydrophobic C16-chain, is utilized as an active ingredient in cosmetics. The chemical structure results in the higher hydrophobicity than water-soluble tranexamic acid which accelerate percutaneous absorption through stratum corneum. Although TXC was designed for the sake of the transdermal permeability to enhance bioavailability, we are interested in its structure as cationic amphiphile. Binary mixtures at different compositions showed a variety of self-assembling structures. Comparing with the general cationic surfactant systems, the TXC/water system showed highly organized orientation of liquid crystal, the higher Krafft temperature, and the lower critical micellar concentration due to its strong inter-molecular interaction between cyclohexyl groups which is a rigid six-membered ring conformation in the molecule. Upon addition of a long-chain alcohol, furthermore, α-gel can be formed. We also observed a unique α-gel phase consisting of dual channels in the quaternary water/TXC/cetyl alcohol/batyl alcohol system, named “Bicontinuous Alpha-Gel (BAG)”, which is beneficial for emulsification of various oils. In this review, we interpret the physicochemical properties of TXC and the hierarchical structure of α-gel, and introduce cosmetic performance of the α-gel formulation such as skin permeation of TXC and sensory effect.
La microcirculation cutanée a été proposée comme modèle d’étude de la dysfonction microvasculaire globale dans les maladies cardiovasculaires. Par ailleurs, elle est spécifiquement atteinte dans la sclérodermie systémique (SSc), qui est une maladie dysimmunitaire rare, particulièrement invalidante, caractérisée par une fibrose cutanée et viscérale associée à une atteinte microvasculaire diffuse et la présence d’auto anticorps dirigés contre des antigènes cellulaires. L’exploration de la fonction microvasculaire cutanée suscite donc un réel intérêt, même s’il n’existe pas de technique standardisée pour l’étude de la fonction microvasculaire, en particulier endothéliale.La première partie de ce travail a porté sur l’étude physiologique de la microcirculation cutanée chez le volontaire sain, en utilisant les méthodes les plus récentes adaptées à l’étude fonctionnelle de la microcirculation (tests de réactivité vasculaire couplés à l’enregistrement du flux sanguin cutané par laser speckle contrast imaging). Dans une seconde partie, nous avons étudié la pathologie de la microcirculation cutanée dans la sclérodermie systémique, en utilisant les mêmes d’étude fonctionnelle de la microcirculation. La dernière partie de cette thèse a été consacrée à l’étude d’une nouvelle approche pharmacologique et thérapeutique dans la prise en charge des manifestations vasculaires cutanées périphériques identifiées chez les patients. Nous avons évalué l’effet vasodilatateur du tréprostinil, analogue de la prostacycline, sur le flux sanguin cutané de divers zones anatomiques, chez le volontaire sain, le patient atteint de SSc, le patient diabétique et lors d’un refroidissement local dans la SSc.
Isotope-edited infrared spectroscopy using carboxylic acids selectively labeled with 13C is proposed herein for the efficient discrimination of pharmaceutical salts and cocrystals, whereby proton-transfer probe vibrations are highlighted by isotope shifts. This new technique can accurately discriminate even a confusing salt from a cocrystal for the traditional method, highlighting the diagnostic peaks and providing the OH in-plane bending vibrations corresponding to intermolecular hydrogen bonding at the carbonyl oxygens of the cocrystals. The technique will accelerate the discrimination which is critical process in cocrystal development.
Transdermal drug delivery can offer potential advantages over conventional oral and parenteral drug administration. However, the protective function of skin imposes a physicochemical barrier to the penetration of hydrophilic and large molecules. The skin is permeable to only small lipophilic drugs. Electroporation utilizes high-voltage electric pulses for very short duration (microsecond–millisecond) to permeabilize the skin and enable the transport of various molecules, including large and hydrophilic substances into and across the skin. The efficiency of molecular transport depends on both the electrical parameters of the pulses and the physicochemical characteristics of the permeant. The in vivo electroporation is generally well tolerated, but may sometimes cause itching, pricking, muscle contractions, and pain. These unwanted side effects could be avoided by the selection of proper electrodes and optimization of the electroporation parameters. This chapter presents the mechanism of percutaneous penetration enhancement induced by electroporation, discusses factors influencing percutaneous penetration of drug molecules, addresses effects of electroporation on the skin when used in vivo, and describes the potential use of electroporation for transdermal drug delivery.
The administration of drugs to skin is being practiced for centuries to treat local diseases, but this route is being used recently for systemic delivery of therapeutic agents. This route of administration is of special interest because of the advantages offered over other routes including avoidance of gastric degradation and first-pass metabolism in addition to superior patient compliance. However, the major limitation of this route of drug administration is that the skin is permeable to only small lipophilic drugs and is highly impermeable to hydrophilic and macromolecular drugs. This barrier property is mainly attributed to the largely lipophilic outermost layer of the skin, stratum corneum (SC) [1]. The successful transdermal or topical formulation of a drug depends on the permeation rate of the drug across the skin or into the skin to achieve therapeutic levels. As many of the drugs lack favorable physicochemical properties for percutaneous absorption, percutaneous penetration enhancers are promising in the development of transdermal formulations. An ideal percutaneous penetration enhancer should promote the transport of drugs across or into the skin in a predictable way without any irreversible effects on the skin barrier properties. Several investigations delved into this aspect and studied different enhancement methods including chemical and physical methods to overcome the barrier properties of skin [2-5]. The present chapter focuses on electroporation, an electrical method to enhance the transport of drug molecules across or into the skin by overcoming the barrier of the SC.
By using an intradermal microdialysis technique 22 h after the transdermal iontophoretic delivery of sodium nonivamide acetate (SNA), a synthetic derivative of capsaicin, the amount of SNA in the extracellular space was measured. Transdermal iontophoresis is a process that enhances skin permeation of ionized species by using an electric field as a driving force. Iontophoresis increased the amount of SNA in dialysate compared with passive diffusion in this study. By using various polymers incorporated in formulations, indicated hydrogels showed higher capacity for SNA delivery than solution formulations. This result was possibly attributable to the antinucleant ability of polymers resulting in the increase of thermodynamic activity of SNA in formulations. Pretreatment with isopropyl myristate, a lipophilic penetration enhancer, on rat skin enhanced transdermal delivery of SNA both for passive and iontophoretic penetration, indicating the possibility of reducing the surface area of the administrations site in clinical use. Microscopic examination revealed no or slight changes in the skin after iontophoretic treatment compared with penetration enhancer pretreatment. The histologic results also suggested iontophoretic treatment with 0.5 mA/cm(2) current density of not more than 7-h application duration may be acceptable clinically. (C) 1999 Wiley-Liss, Inc.
Interaction of exogenous molecules with human skin has evoked continuous interest in the scientific community. The concept of topical drug administration on human skin has been prevalent since the rise of early human civilization. In the recent past, however, this concept has been extended beyond delivery of medicaments to localized skin areas. Human skin is now viewed as an interface for systemic delivery of therapeutic molecules. This route, the transdermal drug delivery route, offers several advantages compared to conventional modes of drug delivery such as needles and oral drug delivery. Transdermal delivery offers painless and sustained administration of systemic therapeutics while eliminating first-pass hepatic metabolism and gastrointestinal degradation commonly associated with oral administration. The skin, which has evolved as a natural protective barrier of an organism, strictly regulates the transport of molecules in and out of the body. It is not surprising that most candidate therapeutics find it difficult to overcome this natural barrier to transport. Several physical and chemical methods have been studied to perturb or compromise the skin barrier to promote the flux of therapeutics into or across the skin (1-5). The prime requirements of any such technique should be: sufficient barrier disruption for optimal flux and quick reversibility of physiological functions at the site of disruption after termination of the treatment. Iontophoresis (6-15), sonophoresis (16-24), electroporation (25-31), and microneedles (32-37) are some of the physical techniques used to compromise the barrier function of skin. Chemical penetration enhancers (CPEs) (38-47), liposomes (48-52), ethosomes (53-55), transferosomes (56,57), niosomes (58,59), and emulsions (60-63) are some of the chemical methods used for enhancing transdermal drug delivery.
Historically, the skin was viewed as an impermeable barrier. However, in recent years, it has been increasingly recognized that intact skin can be used as a port for continuous systemic administration of drugs. The first transdermal drug delivery system which has used this new concept is a scopolamine-releasing transdermal therapeutic system (Transderm-Scop® by Ciba) for motion sickness. This was followed by the marketing of several nitroglycerin-releasing systems. Currently, about ten drugs have been either successfully marketed or are under clinical evaluation for transdermal delivery.
The advances in medical technology have been rationalized on the basis of the saving of lives, the improvement in the well-being of individuals, and more recently the reduction in health care costs. Transdermal drug delivery not only is the combination of several technologies but has developed a sound medical rationale. Looking back on how the administration of medication has evolved, we see that issues in drug delivery and technologies outside the field have influenced transdermal drug delivery.
Recently, there has been an increased interest in drug administration via the skin, with regard to both dermatological products (for therapeutic effects on diseased skin) and transdermal products (for systemic drug delivery). Because of this increased activity and difficulties encountered in the development of these products, scientists working on drug delivery are becoming aware of the need to develop them more systematically using scientific principles and criteria. This is particularly the case for dermatological products, which have long been ne-glected. Over the past decade, many seminars, conferences, and workshops have been held in the United States to discuss the underlying issues in these areas of drug delivery.1–10
Background
The application of therapeutic agents to the skin addresses three general objectives: (a) the treatment of a variety of dermatologic diseases; (b) the “targeted” delivery of drugs to deeper subcutaneous tissues, with a concomitant reduction in systemic exposure; and (c) socalled transdermal administration to elicit a systemic pharmacologic effect.
Objective
Recently, significant progress towards all three goals has been recorded and the level of research and development activity remains high. We aim to discuss these advances from mechanistic and clinical standpoints.
Results
For the topical treatment of skin disease, novel vehicles (e.g., stabilized, supersaturated systems and liposomal formulations) have led to dramatic improvements in local drug bioavailability. Transdermal delivery of drugs for systemic effect, though limited in terms of the number of compounds, is perhaps the most commercially successful (in terms of the number of products) of the controlled release technologies. Considerable activity continues to enhance drug delivery (and hence to extend the range of drugs for which transdermal delivery can be used). Existing patches use formulations that contain solvents and adjuvants capable of reducing the barrier function of the skin. Much effort is directed at iontophoresis (electrically enhanced transport), particularly for small peptides that are difficult to administer by other routes. “Reverse iontophoresis” may allow the extraction of glucose (without skin puncture) so that continuous, noninvasive monitoring of blood sugar in diabetics approaches realization.
Conclusion
In the not too distant future, the skin may also play a role not only in drug delivery, but also with respect to measurements in clinical chemistry.
The effects of switching iontophoresis, including the difference in donor solution on rat skin, were investigated regarding the pH alteration in a donor chamber, skin and plasma concentrations, microphotography and histopathological scoring. Although the pH of donor solution was presumed to be changed in case that platinum was used as an electrode, a pH alteration was hardly observed in switching iontophoresis that used buffer solutions as a donor solution. In contrast, the pH alteration was observed in non-switching iontophoresis. The relation between the plasma and skin concentrations depended on the solvent used. The choice of solvent used was important because the effect of switching iontophoresis on skin permeability and skin damage depended on the solvent. Moreover, when the drug solution was used as a donor, skin damage was alleviated as the switching interval became shorter. Skin damage was low when the agar gel containing the drug was used as a donor in comparison with the drug solution, exception made of 5 and 10 min interval switching. Polarity switching was suggested to bring about not only cancellation of skin polarization but also the suppression of pH alteration in the donor chamber. Therefore, switching iontophoresis was more effective for transdermal administration with lower skin damage compared with the non-switching type.
The understanding of ocular physiopathology and pharmacokinetic and pharmacodynamic parameters of ophthalmic drugs has increased and resulted in the development of new drugs and drug delivery systems for the human eye. Veterinary ocular pharmacology is a new field of study and although pertinent information on the effects of ocular drugs and their proper use in small and large animal patients has increased, the veterinary-labeled ophthalmic drugs presently available in most countries consist primarily of topical antibiotics and antibiotic- corticosteroid combinations and there is a limited number of other drug categories for topical use. This chapter provides some comparative anatomical and physiological features of the eye in the species most frequently encountered in veterinary practice and presents their essential ocular diseases and describes the most appropriate medications for such diseases. It also discusses the application of currently available ocular systems to veterinary ophthalmology and recent developments in the field of drug delivery to the human eye and their possible application to veterinary ophthalmology.
In the last three decades, many advances have been made in the field of drug delivery, with resulting enhancements in the safety, efficacy and convenience of treatment for the patient. Some of the more dramatic developments include technologies that allow for the noninvasive transdermal delivery of several drugs. This delivery is accomplished by Iontophoresis, a process by which an electrical current is used to drive charged particles across the skin and is acts as a one of the most promising physical skin penetration enhancing method. In Iontophoresis, the application of constant electrical current enhances the transdermal transport of a charged drug molecule due to electro-repulsion. The electric field imposes a force on the drug molecule, which adds to the pure passive diffusion or the concentration gradient. During Iontophoresis, the skin permeability also increases due to changes in the structure of the skin caused by current flow. This review briefly describes the advantages, limitations of Iontophoretic drug delivery system and summarizes the experimental design along with electodes used for iontophoretic drug delivery system. Present review also provides an insight on iontophoretic electrochemistry. Various parameters which affect the transdermal absorption of drugs through iontophoresis like electrical, physicochemical and operational have also been reviewed in detail.
Hypertension is the most common cardiovascular disease; its prevalence increases with advancing age. Oral route has the drawbacks namely poor bioavailability due to hepatic metabolism (first pass) and the tendency to produce rapid blood level spikes (both high and low), leading to a need for high and/or frequent dosing, which can be both cost prohibitive and inconvenient. Also injectable administration is invasive nature which may painful, requires skill, and may cause infection, therefore injection are not suitable for self or home sitting administration. Propranolol HCl is a nonselective, beta-adrenergic receptor-blocking agent indicated in the management of hypertension Propranolol is highly lipophilic and is almost completely absorbed after oral administration. However, it undergoes high first-pass metabolism by the liver and on average, only about 25% of propranolol reaches the systemic circulation. Gellan gum at concentration 0.6% w/w optimized. This showed a flux value of 32.814 μg/cm2/hour and 3.039 μg/cm2/hr at viscosity of 490.32 ± 6.01 cps. Propranolol HCL permeation through human cadaver skin via iotophoresis and passive application. It was observed that in comparison to passive permeation study, iontophoretic permeation exhibited more flux. Also, various permeation enhancers were combined with the iontophoresis to study the synergistic effect, but no increase in flux was recorded with them. From the results it was concluded that iontophoretic gellan gum based gel of propranolol HCl can be formulated for the management of hypertension.
The goal of delivery system is to get optimal therapeutic management. But, it stillremains a challenge in the field of pharmaceuticals for delivery of ionic species and some nonionic. Several transdermal approaches have been used and recently there has been a great attentionin using iontophoretic technique for the transdermal drug delivery of medications, both ionic and non ionic. This technique of facilitated movement of ions across a membrane under the influence of an externally applied electric potential difference is one of the most promising physical skin penetrations enhancing method. The payback of using iontophoretic technique includes improved systemic bioavailability ensuing from bypassing the first metabolism. Variables due to oral administration, such as pH, the presence of food or enzymes and transit times can all beeliminated. This article is an overview of the history of iontophoresis, mechanism, principles and factors influencing iontophoresis and its application for various dermatological conditions.
Transdermal iontophoresis is the application of a low electrical current to the skin to facilitate the transport of molecules through this otherwise fairly impermeable membrane. The influx or outflux of charged and uncharged compounds can be controlled by manipulating the total charge delivered and certain vehicle parameters. Electromigration and convective flow (or electro-osmosis) are the two main mechanisms of transdermal iontophoretic transport. Visualization techniques indicate the participation of both intercellular and follicular pathways in iontophoresis. Iontophoresis can be used both for controlled drug delivery and as a non-invasive sampling technique.
We have already reported the substantial synergic effects of CaCl2 and electroporation (EP) on in vitro skin permeation of calcein and FITC dextrans. In the present paper, we investigated the mechanisms for these effects by considering changes in lamellar structure and barrier recovery time of the biggest skin barrier, the stratum corneum, by this combined treatment. The change in skin lamellar structure was evaluated by lipid mobility in the stratum corneum using ATR–FTIR, calcein release from stratum corneum-lipid liposomes (SCLL), in vitro skin permeation of calcein and transepidermal water loss (TEWL). The ATR–FTIR measurement, in vitro skin permeation and changes in TEWL were also used for examining the barrier recovery time.The CH stretching band of skin lipids produced with EP was blue-shifted when compared to that without EP. Asymmetric CH stretching was highest with EP in CaCl2 solution. Little release of calcein was observed from SCLL without EP, whereas higher releases were observed after EP with or without NaCl or CaCl2. Particularly high calcein release (>20%) was observed over 60 min with EP in CaCl2 solution. The in vitro permeation study of calcein was conducted through excised hairless rat skin that was pretreated with EP before skin excision. Permeation rate was highest in skin excised immediately after in vivo EP, and this rate decreased with time after EP treatment. TEWL recovered to control levels within 2 h after EP in distilled water or NaCl solution, whereas high TEWL was maintained after EP in CaCl2 solution.These results suggest that at least lamellar destruction of stratum corneum must be related to the enhanced skin permeation of drugs by the combination of CaCl2 and EPF. On the other hand, a prolonged enhancing effect on the skin permeation of calcein by this combination may be due to a high lamellar destruction and/or delayed barrier repair of stratum corneum.
Purpose:
We compared an iontophoresis riboflavin delivery technique for transepithelial corneal collagen crosslinking (I-CXL) with a conventional CXL (C-CXL).
Methods:
We designed three experimental sets using 152 New Zealand rabbits to study riboflavin application by iontophoresis using charged riboflavin solution (Ricrolin+) with a 1-mA current for 5 minutes. The first set was to compare riboflavin concentration measured by HPLC in corneas after iontophoresis or conventional riboflavin application. The second set was to analyze autofluorescence and stromal collagen modification immediately and 14 days after I-CXL or C-CXL, by using nonlinear two-photon microscopy (TP) and second harmonic generation (SHG). In the third set, physical modifications after I-CXL and C-CXL were evaluated by stress-strain measurements and by studying corneal resistance against collagenase digestion.
Results:
Based on HPLC analysis, we found that iontophoresis allowed riboflavin diffusion with 2-fold less riboflavin concentration than conventional application (936.2 ± 312.5 and 1708 ± 908.3 ng/mL, respectively, P < 0.05). Corneal TP and SHG imaging revealed that I-CXL and C-CXL resulted in a comparable increased anterior and median stromal autofluorescence and collagen packing. The stress at 10% strain showed a similar stiffness of corneas treated by I-CXL or C-CXL (631.9 ± 241.5 and 680.3 ± 216.4 kPa, respectively, P = 0.908). Moreover, we observed an increased resistance against corneal collagenase digestion after I-CXL and C-CXL (61.90% ± 5.28% and 72.21% ± 4.32% of remaining surface, respectively, P = 0.154).
Conclusions:
This experimental study suggests that I-CXL is a promising alternative methodology for riboflavin delivery in crosslinking treatments, preserving the epithelium.
Sodium nonivamide acetate (SNA) is a newly designed derivative of capsaicin which reveals marked antinociceptive activity without producing an overt pungent sensation and skin irritation. The following iontophoretic drug delivery issues have been examined in this paper: (1) the competitive ion effect; (2) transdermal iontophoretic delivery from gel base; and (3) maximization of iontophoretic application mode from gel base. According to the theory of molal volume, divalent salt ions show higher buffering capacity on SNA iontophoretic transport than did monovalent salt ions. However, this effect also causes a great reduction of SNA transdermal flux. The experimental result of transdermal iontophoresis of gel indicated the flux of SNA decreased following the increase of viscosity. Using various polymers incorporated in gel formulations, indicated methyl cellulose and hydroxypropyl methyl cellulose showed higher capacity for SNA iontophoretic transport than the other materials. After a series of evaluation and optimization on the iontophoretic delivery of SNA, transdermal iontophoresis has provided a great capacity of enhancing SNA transport across the skin. The result of the present study is particularly helpful in the development of SNA transdermal delivery system and holds promise for the successful clinical development of an antinociceptive therapeutic regimen.
Transdermal iontophoresis is a process which enhances skin permeation of ionized species by an electrical field as driving force. The aim of this present study was to investigate the transdermal iontophoresis of a newly designed capsaicin derivative, sodium nonivamide acetate (SNA). Studies of electrical and physicochemical factors acting on the kinetics of in vitro iontophoresis were performed. Iontophoresis increased the transdermal penetration flux of SNA as compared to the passive diffusion in this study. Several application modes which possessed the same electrical energy had been researched. The iontophoretic flux of SNA increased following the decrease of donor buffer pH values. This trend could be due to the physiological property of skin and electro-osmotic flow presented. Comparing the various application modes, the discontinuous on/off cyclic current mode showed higher penetration capacity than did continuous mode which was due to the intensity of effective current which would not decay for on/off cyclic application of iontophoresis. The result of the present study is particularly helpful in the development of a SNA transdermal iontophoretic delivery system.
Thyrotropin releasing hormone [L-proglutamyL-L-histidyl-L-proline amide (TRH)], a tripeptide with molecular weight of 362 and a pKa of 6.2, was used as a model peptide for in vitro passive and iontophoretic diffusion cell studies using excised dorsal nude mouse skin. The results indicate that both the charged and uncharged TRH fluxes across the excised tissue were greater than those obtained by passive diffusion alone. The steady-state flux of both the uncharged and charged TRH was directly proportional to the applied current density, with flux being greater for the uncharged TRH. Additional studies on the transport of methylene blue indicate that transport may be occurring through pores, and that positive ions are preferentially passed through the skin. These results imply that the steady-state flux of TRH is primarily due to a direct, electrically induced ion motion and convection. A practical implication of these results is that it may be possible to enhance and control the transdermal delivery of peptides.
The beta-blocker, metoprolol, was introduced transdermally into the veins from a small, square electrode pad (50 cm2) on the forearm by a newly developed iontophoretic device without causing any detectable skin damage. The appliance generates a sophisticated pulse of 12 V at 50 kHz with 20% duty (4 μs) followed by an 80% depolarizing period (16 μs) which may avoid skin irritation caused by polarization. The drug concentration in plasma increased quickly to the therapeutic level which was maintained for a longer period within one session compared with conventional oral administrations. A substantial amount of the drug was also detected in the urine during iontophoresis as well as after the cessation of iontophoresis. These results suggest a possible application of the iontophoretic device for the controlled administration of metoprolol and probably other beta-blockers in combination with cardiographic signal-monitoring systems such as Hotler systems (ambulatory electro-cardiographs) or programmes designed for special modes.
In vitro methodology was developed to investigate the iontophoretic transport of select ionic and non-ionic compounds across hairless mouse skin. Using sodium benzoate and a constant current of 0.1 mA, it was observed that alterations in the diffusion cell configuration and/or return electrode placement relative to the membrane had little effect on the transport of benzoate ions, thus permitting the use of a simple experimental design. Increases in applied current (from 0.0 to 0.2 mA) produced a linear increase in observed benzoate flux. The steady-state flux was also slightly increased (apparently linearly) with greater donor concentrations, but was reduced when competitive ions (NaCl) were added to the donor chamber. Employing a direct current of 0.1 mA and identical solutions, the iontophoretic flux enhancement ratios (flux with current/flux without current) were calculated for benzoate (22.61) and the phenethylamine cation (43.32, using reversed electrode polarity). The flux of a non-ionic compound (benzyl alcohol) was not significantly altered during the application of a 0.1 mA direct current. Upon termination of the current in benzoate iontophoresis experiments (0.1 mA × 3 h), subsequent fluxes were observed to be quite inconsistent. Many yielded values fairly close to the average control (no current exposure) flux for the benzoate ion. However, several of the residual fluxes were nearly 10-fold higher than the control, suggesting compromised skin barrier integrity of a variable nature. This occasional alteration in membrane transport resistance was not, however, observed in experiments performed with benzyl alcohol. It is speculated that the diffusional path followed specifically by ionized species undergoes sporadic current-related changes, and that the flux of the uncharged benzyl alcohol is not affected by alterations in this path. These results suggest that iontophoresis may be a convenient means by which to achieve constant and readily controllable transdermal delivery, locally or to the systemic circulation, for ionized drug species (including peptides). Transport rates may be optimized by adjustment of donor ionic composition and utilization of current densities and patterns deemed physiologically appropriate.
Iontophoresis has been reported as a safe method of tympanic membrane anesthesia but data concerning variations and advances in technique are not available. Normal volunteers were used to determine the effects of varying canal preparation, epinephrine concentration, current level and duration. The two optimal techniques were compared in two groups of ten volunteers. A similar duration of anestheia (90 to 115 min.) was found for both techniques.
Clinical application of two techniques for the purpose of myringotomy and/or ventilation tube placement was done in 60 ears of 49 selected private patients with middle ear effusions. Techniques were used at random in the first 23 ears with equal success. The newly developed dry canal preparation method using lower current and longer time was preferred, because of convenience and added safety, in the last 37 procedures. Failure of anesthesia occurred once with acute otitis media and once due to electrode displacement. Fifty-eight procedures resulted in successful myringotomy and/or tube placement.
Proper case selection, prevention of technical problems, advantages, and practical limitations of this anesthesia method are discussed.
The electrical conductivities of drugs were measured in vitro using a conductivity MHO-meter. These experiments indicate that local anesthetics, vasoconstrictors, some corticosteroids, several anticancer drugs, and several antiviral agents are suitable for iontophoresis. The contribution to conductivity of buffers and nonspecific ions in the same solution with the drug also was defined.
These experiments indicate that iontophoresis of IdUrd into neonatal mouse skin may be as effective as ip administration in blocking TdR metabolism including its incorporation into DNA of the skin. Also, IdUrd appeared to be incorporated into DNA. These results suggest that antiviral chemotherapy in surface tissues may be better accomplished by using ionto-phoretic assistance of penetration since the drug is delivered specifically at the desired site and the overall dose to the animal is small compared to systemic administration. We would expect that the drug which is administered by iontophoresis would probably act similarly on active virus-producing cells to prevent viral multiplication.
Previous studies in the mouse and guinea pig have reported little or no colonization of sensory ganglia by strains of herpes simplex type 1 failing to express the enzyme, thymidine kinase (TK). The current study in the rabbit demonstrated trigeminal ganglionic colonization and reactivation of a latent thymidine kinase negative strain of HSV-1 by two independent methods: iontophoresis-induced ocular shedding and co-cultivation. Treatment with topical steroids during the acute infection did not enhance the latency rate. Following reactivation, back mutation with phenotypic reversion to thymidine kinase positive was demonstrated in a few recovered isolates. The current study also emphasized the importance of species differences to explain differing experimental results in studies of HSV-1 TK negative latency.
Cathodal iontophoresis was used to deliver insulin in 23 alloxan-diabetic, male, New Zealand white rabbits. Currents of 0.2-0.8 mA were used to deliver insulin from reservoirs containing insulin concentrations of 10-500 U/ml in aqueous solution. Regardless of the level of current used, within 1 h of turning the current on, blood glucose levels decreased and serum insulin concentrations increased. Moreover, in most cases, blood glucose levels continued to decrease and serum insulin concentrations continued to increase after the current was turned off, suggesting that iontophoresis could be used to accumulate insulin in the skin and subcutaneous tissues. The amount of insulin that was delivered by iontophoresis could be controlled by the level of current used up to 0.4 mA; increasing the current to 0.8 mA did not deliver more insulin. This may have been due to greater production of hydroxide ions at 0.8 mA, which competed with insulin to carry the current, thus slowing the movement of insulin. The amount of insulin delivered could also be controlled by the amount of insulin available for iontophoresis, i.e., as the insulin reservoir concentration increased, more insulin was delivered at the same current level. Finally, skin preparation was also important in controlling insulin delivery. To deliver enough insulin to reduce blood glucose levels, the stratum corneum had to be disrupted or removed by gentle scraping.
The effectiveness of hyaluronidase iontophoresis on joint and massive soft tissue hemorrhages was studied using twenty-one male hemophiliac patients as subjects. Changes in size of treated area, joint range of motion, skin temperature, and subjective pain response were evaluated.
The demonstration of abnormally high concentrations of electrolytes in eccrine sweat is still the only practical laboratory procedure available for diagnosis of cystic fibrosis. Properly performed, the sweat test is very reliable, but there are many published reports that all of the methods in current use frequently generate incorrect diagnoses. Analysis of potential for error in sweat test methods shows that of the three essential phases involved, stimulation, collection, and analysis, the major cause of intrinsic inaccuracy occurs in the collection process. In this case the problem is due to condensate formation, which leads to the subsequent analysis of nonrepresentative sweat. Human error is also an important cause of false results and is a direct function of the number of critical manual operations involved in the technic. This review provides a critical examination of sweat test methods, identifying problem areas and suggesting ways to improve procedures in the interests of clinically reliable laboratory data in support of diagnosis.
Discomfort or frank pain at venipuncture may be a reason for abstaining from giving blood. In an attempt to offer a painless alternative, a method for iontophoretic application of local anaesthetics was developed. Its effectiveness in producing anaesthesia for venipuncture was tested in a double-blind trial in 47 blood donors. A positive result was obtained in 89%, as against 28% in the placebo group.
Repeated iontophoretic administration of the microtubule inhibitors vinblastine or vincristine to the segmentally related dermatomes of patients suffering from postherpetic, trigeminal and other neuralgias permanently alleviates chronic, autochthonous pain. The beneficial effect of this therapy is probably due to transganglionic degenerative atrophy of primary central sensory terminals in the Rolando substance by blockade of retrograde axoplasmic transport in sensory nerves.
In rats, arginine-vasopressin (AVP) iontophoretically applied to lateral septal neurons activated by fimbria stimulation produced a decrease in the amplitude of the fimbria-evoked field response and a decrease in the frequency of fimbria-evoked action potentials. A second group of rats, treated with α-methyl-p-tyrosine, showed a significantly smaller decrease in responses after AVP iontophoresis, suggesting an interaction between catecholamines and AVP at the synaptic level.
A high voltage electrometer is described which incorporates a controlled current source, direct current monitoring, balance bridge, electrode resistance, and capacitance compensation test circuits. This device is suitable for making biophysical measurements and iontophoresing dyes or enzymes through extremely fine micropipettes with impedances an order of magnitude higher than conventional micropipettes. Such electrodes are useful for recording from the small neurons of the central nervous system in vivo.
The American Commercial & Industrial Conference &
- P Tyle
Electric Ions and Their Use in Medicine
- S Leduc
In A Manual of Electrotherapy
- W J Shriber