Iontophoresis for enhancing penetration of dermatologic and antiviral drugs.

Iontophoresis is the process of introducing ionic drugs into the body for therapeutic purposes. Although iontophoresis has the potential for systemic therapy, it has mainly been used for local therapy at body surfaces. Many ionic drugs are available including lidocaine, epinephrine, methylprednisolone succinate, dexamethasone phosphate, several antivirals, various antibiotics, and other specific drugs. The use of an indicated ionic drug by iontophoresis offers a broad potential for promoting the development of more effective therapies in dermatology. Iontophoresis of ionized drugs provided a 20-60 fold increase in penetration over topical application. Iontophoresis for dermatological use requires that: a) a charged drug be placed at an electrode having a polarity the same charge as the drug, b) the condition or disease under treatment be at or near the body surface, and c) a modern, sophisticated source of direct current, with appropriate accessories, be used. The current source must have features that make it not only effective, but also safe for application to the patient. Modern systems for application of drugs by iontophoresis have features that make the process simple and efficient for use in practice. Iontophoresis has a long history of use, having been suggested for various therapies for many years in medicine, physical therapy and dentistry. Pilocarpine iontophoresis is a preferred method for cystic fibrosis detection. Also, lidocaine iontophoresis has been advocated to anesthetize the tympanic membrane before myringotomy. Anesthesia of the skin to a depth of 1.0 cm or more has been reported in double-blind studies of human volunteers. Local anesthesia by iontophoresis was reported to be effective for: 1) cutaneous cutdowns in patients requiring kidney dialysis, 2) delicate eyelid surgery, as the sole anesthetic, 3) preinjection topical anesthesia, and 4) shave biopsies of skin lesions. The use of iontophoresis for treating difficult cases of hyperhydrosis is quite popular among dermatologists. The present report emphasizes uses of iontophoresis in dermatology and is divided into discussion of studies using iontophoresis for postherpetic neuralgia, local anesthesia, antiviral therapy, and for corticosteroid therapy of nonspecific inflammatory lesions. Over 1250 patients have been treated for postherpetic neuralgia by corticosteroid iontophoresis at 6 medical centers with 60-80% of patients showing a major therapeutic response with return to a tolerable pain level. Double-blind studies of varicella zoster (active and postherpetic) and herpes simplex have proven that iontophoresis is a valuable modality for treating viral diseases of the skin. Many other uses for iontophoresis have been proposed in the literature that involve several hundred research papers, several textbooks and many book chapters. Review of the literature supports the concept that iontophoresis provides an optimal method for drug application in therapy of surface tissues.

Electrophoretic evaluation of the mobility of drugs suitable for iontophoresis.

Iontophoresis is the process of increasing the penetration of drugs for therapeutic purposes using DC electricity. The most important factor for iontophoresis is the formation of drug ions in solution. On this basis, the penetration of any drug applied by iontophoresis might be maximized at an optimal pH. Seven medications were investigated: acyclovir, methylprednisolone sodium succinate, metronidazole, dexamethasone sodium phosphate, minoxidil, lidocaine hydrochloride, and adenine arabinoside monophosphate. Using techniques of paper electrophoresis, we evaluated the influence of pH on the mobility (mu) of the drugs in phosphate buffers at pH 5, 7, and 9. The mu-values were calculated after detecting the drugs on paper with ultraviolet light. The results indicate that the seven drugs had higher mu-values usually at one, but sometimes at two, of the pH values studied. This study suggests that a variation in pH might alter the maximum ionization, and therefore, the optimal mobility for these seven drugs, as well as other drugs, suited to iontophoresis.

Current strategies for dentist-applied treatment in the management of hypersensitive dentine.

Few of the many dentist-applied treatments for dentine hypersensitivity meet the requirements of an ideal desensitizing agent'. This paper, although not exhaustive, covers methods that may be classified from simplest to most complex. Topical methods are simple, but they are often uncomfortable and the effects usually quite short-lasting, and many fall short of the 'ideal'. Fluorides and oxalates appear to be the best topical methods. Iontophoresis of fluoride represents an intermediate stage of complexity and it meets most of the criteria of an ideal desensitizing agent. Newer restorative materials, such as glass-ionomer cements and dentine bonding agents, are the most complex. These are still under investigation, but when the tooth needs recontouring, or in difficult cases that do not respond to other treatments, the dentist may choose to use a restorative material. Resin primers alone could be promising but the effects are not permanent and investigation into their use is still under way. Finally, laser treatment has been espoused for dentine desensitization. This requires extremely expensive equipment, must be dentist applied, and might produce pulpal irritation. Much more study is needed on restorative treatments and lasers before they can be considered as effective desensitizing agents. Until that research is completed, the dentist must choose one or more of the available methods in order to have a clinical therapy that is likely to relieve the symptoms of hypersensitive dentine.

Pharmacologic management of temporomandibular joint disorders and chronic head and neck pain.

One goal of pharmacology is to break a cycle of pain and spasms. In this cycle, pain leads to muscle spasms, and spasms lead to pain with no physiologic feedback control occurring. A second goal is to break another interacting cycle of pain and inflammation. In this cycle, pain mediators can lead to inflammation and the inflammation itself can contribute to pain. The two cycles perpetuate each other because they have many interacting factors in common. Drugs are useful either alone or to supplement other forms of therapy that can break the pain/spasm cycle, as well as the pain/inflammation cycle. This article discusses the many types of drugs available to the clinician today. Although the original version of this article was published by the first author in 1973, the number of new drugs (including some new classes of agents) and newer concepts of pain that have been introduced have required further updating.

Iontophoresis: an effective modality for the treatment of inflammatory disorders of the temporomandibular joint and myofascial pain.

The use of the iontophoresis modality for driving medications through the skin for treatment of certain TM dysfunction and myofascial pain dysfunction syndrome was first suggested by Gangarosa and Mahan in 1982. This paper introduces the iontophoresis technique for treatment of inflammatory and myofascial disorders of the craniomandibular system. The historical aspects of iontophoresis in medicine and dentistry is reviewed. As an aid to understanding the clinical applications of this method, a review of diagnostic classification of temporomandibular disorders and an in-depth review of the role of the inflammatory process are provided. The effect of inflammation on the synovial/lymphatic system is detailed. Reference is made to the advantages of iontophoresis over hypodermic injection. The basis materials and methods of use of the modality are shown along with a protocol for patient treatment. Several case studies are discussed with clinical observations given.

Use of verbal descriptors, thermal scores and electrical pulp testing as predictors of tooth pain before and after application of benzocaine gels into cavities of teeth with pulpitis.

A double-blind pilot study was conducted on 27 consenting human volunteers who had irreversible pulpitis associated with persistent toothache pain from open carious lesions. Formulations tested contained either 0, 10%, or 20% benzocaine and were identified only by a numbered code. Before the experiment started, a small amount of a known 5% benzocaine gel was placed for 1 minute on the tongue of each patient to assure a sensation of numbness within the oral cavity. Then the test tooth was washed with a gentle stream of warm water and dried with gauze. A randomly selected test medication was placed into the open cavity and around the gingival margins for 5 minutes. Pre- and posttreatment tests were conducted at the following timed intervals: 0, 5, 15, 30, 45, 60, 75 and 90 minutes. The tests included degree of pain (rated: 0 = none, 1 = mild, 2 = moderate, 3 = severe); electrical pulp testing (EPT) by a modified, voltage-ramping instrument; and ice water testing (0.5 mL directed quickly onto sound enamel of the tooth and rated: 0 to 4, with 4 being intolerable). After testing, or when pain returned to baseline, endodontic procedures were performed. There was a significant increase (p < 0.032, Fisher exact test) in subjects obtaining pain relief, rated by verbal descriptors, from the benzocaine gels (14 out of 18 improved) compared to placebo (3 out of 9 improved). It was concluded that: 1) benzocaine gels are effective formulations for temporary relief of toothache pain, 2) there were no statistical differences in EPT scores between teeth having pulpitis and control teeth, 3) there were no correlations between direction of EPT scores and pain relief, 4) cold water testing was a good predictor of whether or not a tooth had pulpitis, and 5) changes in cold water testing scores after treatment could not be correlated to relief of pain according to verbal descriptors. The effectiveness of benzocaine in relieving toothache pain verifies previous studies; however, a difference between 10% and 20% benzocaine could not be demonstrated probably because of two factors: 1) the present experiment had a small sample size, and 2) there was no direct measurement of duration of local anesthesia.

Iontophoretic treatment of herpetic whitlow.

Herpetic whitlow can be a vector for spread of infection, especially among health care professionals. Until now, treatment has been inadequate. In two patients with documented herpetic infections of the finger, the antiviral drug idoxuridine was applied to the lesions by cathodal iontophoresis. Results were characterized by rapid relief of discomfort and swelling, rapid appearance and coalescence of vesicles, and rapid healing, with reduced pain and little or no paresthesia. No recurrences have been noted in the two patients after 42 and 38 months. The positive beneficial results indicate that aggressive iontophoretic treatment for herpetic whitlow is useful and justified.

Iontophoresis of vidarabine monophosphate for herpes orolabialis.

The cutaneous application of antiviral agents was studied by iontophoresis, a process that increases penetration of most drugs 20- to 60-fold. Twenty-seven subjects with vesicular orolabial herpes were treated one time in a double-blind, placebo-controlled clinical study: nine received vidarabine monophosphate (ara-AMP), nine received acyclovir (ACV), and nine received NaCl. Ara-AMP-treated lesions yielded lower titers of virus after 24 hr compared with lesions treated with NaCl or ACV (P less than .05). Ara-AMP significantly decreased the duration of shedding of virus (P less than .05) and time to dry crust (P less than .05) compared with the other two agents. There was a trend toward decreased healing time after ara-AMP treatment.

Adrenergic induction of HSV-1 ocular shedding in rabbits.

Four groups of latently infected rabbits were induced to shed HSV-1 into the tear film by a one-time ocular iontophoresis of 6-hydroxydopamine (6-HD) followed 3 days later by five consecutive days of twice daily topical epinephrine (Epi). Groups 1 and 4 had both eyes inoculated and Groups 2 and 3 had only one eye inoculated. Groups 1 and 2 had eyes swabbed to detect HSV-1, and Groups 3 and 4 had eyes washed. Group 1 was iontophoresed with 1.0% 6-HD at 0.5 mAmp for 5 min, and Groups 2, 3 and 4 were iontophoresed with 0.1% 6-HD at 0.75 mAmp for 5 min. Group 1 received topical 2.0% Epi, and Groups 2, 3, and 4 received topical 1.0% Epi. Inoculated eyes in all groups shed HSV-1 during the induction period. The peak of HSV-1 shedding occurred on the last day of Epi application for Groups 1 and 2, and on the day after the last Epi application for Groups 3 and 4. The ratio of total positive tear film samples to total samples for inoculated eyes that received 6-HD and Epi were 53/119 (45%), 38/87 (44%), 24/66 (36%), and 14/33 (42%) for Groups 1, 2, 3, and 4, respectively. Therefore, even reduced concentrations of 6-HD and Epi, as well as beginning Epi 3 days after 6-HD, induced HSV-1 ocular shedding.

Iontophoresis of epinephrine isomers to rabbit eyes induced HSV-1 ocular shedding.

Iontophoresis of 0.01% levo(-) epinephrine for 8 min at 0.8 mAmp once daily for 3 consecutive days induces ocular shedding of herpes simplex virus type 1 (HSV-1) in latently infected rabbits. In the present experiment, we tested dextro(+) and levo(-) epinephrine for their comparative effects on induced HSV-1 ocular shedding. One hundred percent of the eyes shed virus after either 0.01% dextro(+) or levo(-) epinephrine iontophoresis (8 min, 0.8 mAmp). However, the shedding frequency caused by 0.005% levo(-) epinephrine was significantly higher (P less than 0.05) than that by 0.005% dextro(+) epinephrine when the iontophoresis was conducted at 0.4 mAmp for 4 min. Iontophoresis of 0.001% levo(-) epinephrine for 8 min at 0.8 mAmp once daily for 3 consecutive days and iontophoresis of 0.001% dextro(+) epinephrine for 8 min at 0.8 mAmp once daily for 3 consecutive days did not induce HSV-1 ocular shedding in latently infected rabbits. The data suggest that the mechanism of induction of HSV-1 ocular shedding by epinephrine is correlated to the receptor potency of levo(-) epinephrine.

HSV-1 quantitation from rabbit neural tissues after epinephrine-induced reactivation.

Epinephrine iontophoresis into the eye can induce ocular herpes simplex virus type-1 (HSV-1) shedding with a high frequency from latently infected rabbits. The present study was designed to qualify and quantify infectious HSV-1 from neural tissues of latently infected rabbits after ocular epinephrine iontophoresis. Epinephrine iontophoresis was performed daily for 3 consecutive days on selected days during 220-227 days postinoculation. The induced ocular shedding was detected in the tear film with a frequency of 83% (10/12) within 72 hr after the initial iontophoresis. The rabbits were killed 24 hr after the last iontophoretic treatment, and the corneas and neural tissues were homogenized immediately. The cell-free supernatants were inoculated on primary rabbit kidney cell monolayers for qualitative assays of infectious virus and later titrated on CV-1 monolayers. The frequencies of the recovery of infectious HSV-1 from the cell-free homogenates were 0% of the corneas (0/12), 83% (10/12) from the superior cervical ganglion (SCG), 100% (12/12) from the trigeminal ganglion (TG), 42% (5/12) from the ophthalmic branch of the trigeminal nerve (TN), 8% (1/12) from the root entry zone of the trigeminal nerve into the brain-stem (REZ), and 0% (0/12) from the cerebellum. The authors conclude that epinephrine iontophoresis can reactivate the latent HSV-1 in neural tissues and infectious virus can be quantified from the cell-free homogenates. To the best of our knowledge, this is the first report to quantify HSV-1 with a high frequency from neural tissues following induced reactivation.

Antibody-dependent cellular cytotoxicity mediated by polymorphonuclear leukocytes and mononuclear cells against HSV-1 infected primary cultures of rabbit corneal epithelium.

The roles of rabbit polymorphonuclear leukocytes (PMNL) and mononuclear cells (MC) for the regulation of ocular herpes simplex virus-1 (HSV-1) infection were studied. The antibody-dependent cellular cytotoxicity (ADCC) mediated by PMNL and MC from normal rabbit peripheral blood was assessed kinetically employing a specific 51Cr release assay. The HSV-1 infected primary cultures of rabbit corneal epithelium (PRCE) were used as the target cells to obtain a homologous assay system. The PRCE was prepared by an epithelium outgrowth technique and identified by electron microscopy. The expression of the surface HSV-1 antigens on PRCE was examined by indirect immunofluorescent staining; the cell population stained by fluorescein increased from 40% at 3 hr postinfection (PI) to 100% at 8 hr PI. To determine how early the cytotoxicity occurs, PRCE were infected with HSV-1 for 2 hrs. After 2 hrs, the ADCC was checked every 10 min for the first 40 min and then at 1, 2 and 4 hr of incubation. The cytotoxicity was apparent at 10 min postincubation and reached 46% by PMNL and 40% by MC at 4 hr postincubation (6 hr PI). Significant cytotoxic effect (26% by PMNL and 16% by MC) occurred as early as 3 hr PI. When the one-step growth cycle of HSV-1 was studied in the PRCE, HSV-1 had an eclipse period of 4 hr and a rise period of 8 hr. This suggests that rabbit PMNL and MC have the potential to eliminate the HSV-1 infected rabbit corneal epithelium before HSV matures in the cells.

Fluoride levels in dentin after iontophoresis of 2% NaF.

The fluoride in successive layers of dentin (from 3-6 micron were removed per etch) has been measured following topical or iontophoretic application of 2% aqueous sodium fluoride to coronal exposed dentin of freshly extracted human third molar teeth. The fluoride contents of the topical and iontophoresed first etches were, respectively, 12 and 22-31 times greater than that of control (untreated) teeth. Similarly, the fourth etches were 12 and 50-70 times greater, and the seventh (last sampled) etches were 5 and 28-41 times greater. There was no apparent change in acid solubility of the dentin as its fluoride content varied under the conditions of this study. This is the first report studying the fluoride content of extremely thin layers of dentin successively removed by acid etch and relating topical to iontophoretic uptake.