Transtympanic iontophoresis of gadopentetate dimeglumine: Preliminary results

Share Embed


Descrição do Produto

Transtympanic iontophoresis of gadopentetate dimeglumine: Preliminary results PANAGIOTIS CHRISTODOULOU, MD, PANAGIOTIS G. DOXAS, MD, CHARITON E. PAPADAKIS, THOMAS MARIS, PHD, and EMMANUEL S. HELIDONIS, MD, Heraklion, Greece

OBJECTIVE: We sought to demonstrate the feasibility of using iontophoresis to deliver pharmaceutical agents into the middle and inner ear for the treatment of middle and inner ear diseases, which is proved in this study by the successful iontophoresis of the ferromagnetic contrast agent gadopentetate dimeglumine. STUDY DESIGN AND SETTING: Eight rabbits were iontophoresed using gadopentetate dimeglumine solution 469 mg/mL. Then, all rabbits underwent magnetic resonance imaging for the detection of gadopentetate dimeglumine in the middle and inner ear structures. The study was conducted in the tertiary referral center the University Hospital of Crete. RESULTS: The high signal intensity of the gadopentetate dimeglumine solution was demonstrated within the middle ear cavity and inner ear structures of all iontophoresed ears and in none of the noniontophoresed ones. CONCLUSIONS: Transtympanic iontophoresis could be an effective method for the passage of pharmaceutical agents into the middle and inner ear for the treatment of middle and inner ear diseases. (Otolaryngol Head Neck Surg 2003;129:408-13.)

I n 1984, Passali et al

1

reported that transtympanic iontophoresis of a mycolytic agent (N-acetylcysteine) or an anti-inflammatory agent (benzydamine) was effective for the treatment of otitis media with effusion and stressed that this technique was superior to oral administration in terms of faster reaction, less systemic toxic reactions, and a higher concentration of the drug in the middle ear.

From the Departments of Otolaryngology (Drs Christodoulou, Doxas, Papadakis, and Helidonis), Radiology (Dr Prassopoulos), and Medical Physics (Dr Maris), University of Crete School of Medicine. Reprint requests: C. E. Papadakis, MD, Psaron 7 Street, Heraklion, Crete 71307, Greece; e-mail, [email protected]. Copyright © 2003 by the American Academy of Otolaryngology–Head and Neck Surgery Foundation, Inc. 0194-5998/2003/$30.00 ⫹ 0 doi:10.1016/S0194-5998(02)00713-7 408

MD,

PANOS PRASSOPOULOS,

MD,

Sato et al2 used iontophoresis of an anti-inflammatory agent (corticosteroid) and antibiotic for the treatment of otitis media with effusion in children, and their results showed that this treatment was useful in controlling the inflammation and infection in the middle ear that are considered to be important pathogenetic factors. Gillespie et al3 iontophoresed with lidocaine 8 rabbits, followed by diagnostic vestibulotomies. Significant amounts of perilymph lidocaine were found in both the intact and perforated tympanic membrane groups. In the perforated tympanic membrane group, the perilymph lidocaine level was 8 times that of the intact tympanic membrane group. Iontophoresis has been also used to introduce lidocaine ions into the inner ear for the treatment of tinnitus.4 The initial results indicated that approximately 60% of patients reported a reduction in tinnitus intensity.5 Succeeding studies demonstrated that a few patients experienced slight improvement, although the tinnitus persisted in its annoyance and the majority did not notice any difference in their tinnitus during and/or after treatment 6,7 In the present study, we sought to demonstrate the middle ear cavity and the inner ear structures by means of transtympanic iontophoresis of the ferromagnetic contrast agent gadopentetate dimeglumine. MATERIALS AND METHODS After the approval of the University Hospital of Crete animal review committee, 8 rabbits, weighing 1.4 to 1.8 kg, were anesthetized with subcutaneous injection of ketamine HCl 30 mg/kg and promazine HCl 50 mg/kg. All external auditory canals were thoroughly cleaned for better visualization and then filled with the iontophoretic solution. All tympanic membranes were intact. One ear of each rabbit was used for the iontophoresis, and the other was used as a control. We used an

Otolaryngology– Head and Neck Surgery Volume 129 Number 4

iontophoretic applicator (Iontophor-PM model 6111; Life-Tech, Inc, Stafford, TX). The ferromagnetic contrast agent used was gadopentetate dimeglumine solution 469 mg/mL. The signal intensity of the undiluted contrast agent is low on T1-weighted images used in this study and thus not appropriate for our application. Twelve different dilutions of contrast agent with normal saline were tested to select the one rendering the highest signal intensity on the T1-weighted image parameters used in the present study. The different dilutions within 12 vials were positioned in the magnet. The highest signal was shown by dilution of 6 mL in 1000 mL of normal saline (ie, 2.81 mg/mL), and this dilution was used in the present study. The 8 rabbits were randomly divided into 2 groups of 4 rabbits each. One external auditory canal of each rabbit was filled with the final dilution of gadopentetate dimeglumine. The anode (positive electrode) was placed into the external auditory canal, coming into contact with the dilution of gadopentetate dimeglumine and without touching the skin, and the cathode (negative electrode) was placed in the contralateral area of the neck. In the first group the direct current (1 mA) was applied for 15 minutes, whereas in the second group the direct current (1 mA) was applied for 20 minutes. The contralateral (control) ear of each rabbit remained filled with the final dilution of gadopentetate dimeglumine, for the same time, without being iontophoresed. At the end of the procedure, all external auditory canals were irrigated with 50 mL normal saline to wash out the solution, and the rabbits underwent magnetic resonance imaging (MRI). The 8 rabbits were scanned using a 1.5-T whole body superconducting imager (MAGNETOM Vision Plus, Siemens). Standard quadrature radiofrequency (RF) body coil (64-cm diameter) was used for signal excitation, and a small circular loop RF coil (3 cm diameter) operating only as receiver was used for signal detection. Appropriate coil loading for RF transmission was ensured for body coil in each experiment using a Plexiglas tube (body coil phantom loader) filled with conductive paramagnetic solution and positioned around each rabbit.

CHRISTODOULOU et al 409

During the experiment, the rabbits were placed in the prone position with their longest anatomic axis (head-feet axis) parallel to the magnet’s principal axis and their heads overextending toward the coronal plane. A small circular loop coil was positioned above the rabbit’s head with its principal axis parallel to rabbit’s transverse anatomic direction. Using this configuration, axial T1weighted images were obtained to demonstrate the overall anatomy using a single-echo multislice gradient echo (GE) 2-dimensional flash sequence (TR, 15 milliseconds; TE, 6 milliseconds; flip angle, 70°; 5 slices; slice thickness, 8 mm; interslice gap, 2 mm; field-of-view [FOV], 150 ⫻ 150 mm2; reconstruction matrix, 128 ⫻ 256 pixels; and 1 excitation). Consequently, 3 series of images were acquired, with each depicting different details of the anatomic structures. The first series of images consisted of 9 coronal 2-mm slices obtained using a T1-weighted single-echo multislice spin echo (SE) 2-dimensional standard sequence (TR, 400 milliseconds; TE, 14 milliseconds; flip angle, 90°). Slices were almost parallel to rabbit’s external ear canals, thus depicting anatomy of outer, middle, and inner ear structures. Gradient strength used in this sequence (23 mT/m) was compromising for a thin slice (2 mm) and a rectangular FOV (RFOV) covering an area of 53 ⫻ 70 mm2. The image reconstruction matrix was 192 ⫻ 256 pixels, respectively, to the RFOV dimensions, compromising for a pixel matrix dimensions of 0.27 ⫻ 0.27 mm. Two signal averages (excitations) and a small receiver bandwidth (89 Hz/pixel) were used to improve the signal-to-noise ratio. The second and third series of images comprised 2-mm axial and axial oblique T1-weighted images obtained using the previously described single-echo multislice SE sequence applied at planes vertical to rabbit’s external ear and along the inner auditory canal of the ear undergoing iontophoresis, respectively. RESULTS The high signal of the gadopentetate dimeglumine solution was recognized in the middle ear cavity of the 8 iontophoresed ears (Fig 1). The contralateral middle ear cavities showed signal void consistent with the presence of air (Fig 1).

410 CHRISTODOULOU et al

Otolaryngology– Head and Neck Surgery October 2003

Fig 1. T1-weighted (TR, 400.0; TE, 14.0/1) coronal MR image with 2-mm slice thickness. High signal intensity fluid in the middle ear cavity of the right iontophoresed ear. The contralateral middle ear cavity shows low signal due to the presence of air.

There was no appreciable difference in signal intensity within the middle ear cavity between the 2 groups of iontophoresed ears, namely those undergoing iontophoresis for 15 and 20 minutes, respectively. The vestibule and at least 1 semicircular canal of all iontophoresed ears were filled with the high signal solution of gadopentetate dimeglumine (Fig 2), whereas the control ears did not show high signal in the inner ear. The signal intensity did not present any appreciable difference in the inner ears of the 2 groups of iontophoresed ears or between the vestibules and the middle ear cavities of iontophoresed ears. The high signal intensity of the contrast agent was demonstrated within the middle ear cavity and inner ear structures of all iontophoresed ears and in none of the noniontophoresed ones. This high

signal intensity, apart from contrast media, can be rendered by fatty tissue or blood on T1-weighted images. However, inspection of tympanic membrane with a surgical microscope did not reveal the presence of blood. DISCUSSION Iontophoresis was introduced as early as the 1740s by Pivati to treat arthritis.8,9 Not until 1879, however, did Munch truly demonstrate the ability to deliver ions, by delivering strychnine into a rabbit with an electric current.8 LeDuc10 performed the first scientific experiments relating to the mechanism of iontophoresis in 1908. Using 2 rabbits placed in series, he introduced strychnine into one and cyanide into other, each depending to the polarity. He was able to determine which ions were introduced by observing the signs preceding death.

Otolaryngology– Head and Neck Surgery Volume 129 Number 4

CHRISTODOULOU et al 411

Fig 2. T1-weighted (TR, 400.0; TE, 14.0/1) coronal (a) and axial (b) MR images with 2-mm slice thickness of 2 different animals that have been iontophoresed at the right ear (a) and the left ear (b), respectively. (a) The vestibule appears with high signal on the right (iontophoresed ear) and with low signal on the left. (b) A semicircular canal on the left (iontophoresed ear) is of high signal, whereas the corresponding semicircular canal on the right is of low signal.

In summary, the increased penetration across a membrane of an ionic species under the applied electric field can, thus, be due to (1) the electrochemical potential gradient across the membrane, (2) the increased membrane permeability under applied electric field, and (3) the current-induced water transport effect (electro-osmosis or convective transport or iontohydrokinesis). Iontohydrokinesis is another primary means by which ions and other substances, such proteins and peptides, traverse a membrane.11 According to Chien et al,12 there are several advantages of an effective, controlled percutaneous drug delivery system such as iontophoresis: (1) it avoids the risks and inconveniences of parenteral (injection/intravenous) therapy; (2) it prevents the variation in the absorption and metabo-

lism seen with oral administration; (3) it increases therapeutic efficacy by bypassing hepatic “firstpass” elimination—the reduction in the amount of the drug entering the systemic circulation due to metabolism by the liver as the drug passes through the hepatic circulation after absorption from the gastrointestinal tract; (4) it reduces the chance of overdosing or underdosing by providing continuous delivery of the drug, programmed at the required therapeutic rate; (5) it permits the use of a drug with short biologic half-life because the drug is delivered directly to the target organ without the need to circulate and recirculate in the blood or the drug flows directly into the bloodstream without delays due to absorption through the gastrointestinal tract; (6) it provides a simplified therapeutic regiment, leading to better patient compliance; and

Otolaryngology– Head and Neck Surgery October 2003

412 CHRISTODOULOU et al

Fig 2. Continued.

(7) it permits a rapid termination of medication administration, if needed, by simply turning off the iontophoretic delivery system. In the present study, by means of transtympanic iontophoresis of the ferromagnetic contrast agent gadopentetate dimeglumine, we achieved introduction of the contrast agent in the middle ear cavity and the inner ear structures. For the first time using radiographic evidence, the results of previous studies suggesting that transtympanic passage of pharmaceutical agents in the middle ear cavity and inner ear is feasible were confirmed. The high signal intensity of the contrast agent was demonstrated within the middle ear cavity and inner ear structures of all iontophoresed ears and in none of the noniontophoresed ones. This high signal intensity, apart from contrast media, can be rendered by fatty tissue or blood on T1-weighted images. However, inspection of tympanic mem-

brane with a surgical microscope did not reveal the presence of blood. Delineation of middle ear cavity, vestibule, and semicircular canals by contrast agent after iontophoresis may be helpful in MRI of the temporal bone in humans. Regularly, these spaces are of low signal on T1-weighted images. By filling these spaces with contrast media, one could expect better delineation of the anatomy and demonstration of anatomic details, in a manner similar to MR arthrography. Additionally, the high contrast between the high signal fluid within the middle and inner ear structures and the low signal walls of cavities and surrounding elements of temporal bones can provide the ideal basis for the application of virtual endoscopy in the middle and inner ear on MRI. Possible clinical applications that we have started to work on, based on the results of the present study,

Otolaryngology– Head and Neck Surgery Volume 129 Number 4

are to use transtympanic iontophoresis of gentamicin for the treatment of Me´ nie`re’s disease and corticosteroids for the management of sudden hearing loss and autoimmune inner ear diseases. Schuknecht13 first introduced the intratympanic injection of gentamicin in 1957. The technique has evolved with a trend toward lower doses and greater time intervals between doses.14 A wide variety of techniques with intratympanic gentamicin is successfully used in treating Me´ nie`re’s disease.15-17 Proposed treatment procedures have included the placement of polyethylene tubes or catheters, hospitalization, and repeated injections until evidence of vestibular toxicity is manifested.18 No particular method can be recommended as the most effective based on the literature, and iontophoresis could be a good alternative technique for this application. Medical and nonmedical factors such as patient safety, patient convenience, less atraumatic technique, and cost may play a role in selection of the technique used.19 In a recent report, Parnes et al20 investigated the effects of intratympanic injection of corticosteroids for the treatment of hearing loss in inner ear disorders. They established cochlear fluid pharmacokinetic profiles of hydrocortisone, methylprednisolone, and dexamethasone in the guinea pig after oral, intravenous, and topical (intratympanic) administration. Their findings demonstrated a much higher penetration of all 3 drugs into the cochlear fluids after topical (intratympanic) application compared with systemic administration. They managed to treat sudden deafness, autoimmune inner ear disease, and Cogan’s syndrome through the injection of intratympanic corticosteroids. We assume that iontophoresis, being less traumatic and easy to be performed, might be used for these applications. Transtympanic iontophoresis could be an effective method for the passage of pharmaceutical agents into the middle and inner ear for the treatment of middle and inner ear diseases. It is a noninvasive method of low cost, which does not seem to compromise patient safety or convenience. REFERENCES

1. Passali D, Bellussi L, Masieri S. Transtympanic iontophoresis: personal experience. Laryngoscope 1984;94: 802-6.

CHRISTODOULOU et al 413

2. Sato H, Takahashi H, Honjo I. Transtympanic iontophoresis of dexamethasone and fosfomycin. Arch Otolaryngol Head Neck Surg 1988;114:531-3. 3. Gillespie CA, Swanson GC, Johnson CM, et al. Inner ear lidocaine concentration following iontophoresis. Laryngoscope 1980;90:1845-51. 4. Shulman A. Medical methods, drug therapy, and tinnitus control strategies. In: Shulman A, Aran JM, Tonndorf J, et al, editors. Tinnitus. Diagnosis/treatment. San Diego (CA): Singular Publishing; 1997. p. 453-89. 5. Brusis T, Loennecken I. Treatment of tinnitus with iontophoresis and local anesthesia. Laryngol Rhinol Otol (Stuttg) 1985;64:355-8. 6. Laffre´ e JB, Vermeij P, Hulshof JH. The effect of iontophoresis of lignocaine in the treatment of tinnitus. Clin Otolaryngol 1989;14:401-4. 7. Willat DJ. A sequential double-blind crossover trial of iontophoresis. In: Feldmann H, Third International Tinnitus Seminar 1987. Karlsruhe,. Proceedings, . Germany: Verlag; 1987. p. 316-9. 8. Licht S. History of electrotherapy. In: Stillwell GK, editor. Therapeutic electricity and ultraviolet radiation. Baltimore (MD): Williams & Williams; 1983. p. 8-21. 9. Chien YW, Banga AK. Iontophoretic (transdermal) delivery of drugs: overview of historical development. J Pharm Sci 1989;78:353-4. 10. LeDuc S. Electric ions and their uses in medicine. London: Rebman; 1908. p. 87. 11. Gangarosa LP, Park NH, Wiggins CA, et al. Increased penetration of nonelectrolytes into mouse skin during iontophoretic water transport (iontohydrokinesis). J Pharmacol Exp Ther 1980;212:377-81. 12. Chien YW, Siddiqui O, Shi WM, et al. Direct current iontophoretic transdermal delivery of peptide and protein drugs. J Pharm Sci 1989;78:376-83. 13. Schuknecht HF. Ablation therapy in the management of Me´ nie`re’s disease. Acta Otolaryngol (Stockh) 1957;132: 3-42. 14. Magnusson M, Padoan S. Delayed onset of ototoxic effects of gentamicin in treatment of Me´ nie`re’s disease. Rationale for extremely low dose therapy. Acta Otolaryngol (Stockh) 1991;111:671-6. 15. Driscoll CL, Kasperbauer JL, Facer GW, et al. Low-dose intratympanic gentamicin and the treatment of Me´ nie`re’s disease: preliminary results. Laryngoscope 1997;107: 83-9. 16. Kaasinen S, Pyykko I, Ishizaki H, et al. Intratympanic gentamicin in Me´ nie`re’s disease. Acta Otolaryngol (Stockh) 1998;118:294-8. 17. McFeely WJ, Singleton GT, Rodriguez FJ, et al. Intratympanic gentamicin treatment for Me´ nie`re’s disease. Otolaryngol Head Neck Surg 1998;118:589-96. 18. Blakley BW. Update on intratympanic gentamicin for Me´ nie`re’s disease. Laryngoscope 2000;110:236-40. 19. Silverstein H, Isaacson JE, Olds MJ, et al. Dexamethasone inner ear perfusion for the treatment of Me´ nie`re’s disease: a prospective, randomized, double-blind, crossover trial. Am J Otol 1998;19:196-201. 20. Parnes LS, Sun AH, Freeman DJ. Corticosteroid pharmacokinetics in the inner ear fluids: an animal study followed by clinical application. Laryngoscope 1999; 109(Suppl 91):1-17.

Lihat lebih banyak...

Comentários

Copyright © 2017 DADOSPDF Inc.