The bioavailability of cytarabine in dogs with meningoencephalitis of unknown etiology through iontophoresis and rectal delivery.

Background: Cytarabine (CA) is used to treat dogs with meningoencephalitis of unknown etiology (MUE) by subcutaneous or intravenous administration. Aim: The objective was to investigate transdermal iontophoresis and rectal administration as alternative routes of CA delivery. Methods: Two client-owned dogs with MUE were studied. The ActivaPatch® IONTOGO™ 12.0 iontophoresis drug delivery system delivered 200 mg/m2 CA transdermally. Blood samples were collected by sparse sampling technique after initiation of the device. At another visit, 100 mg/m2 CA was administered rectally. Blood samples were collected by sparse sampling technique after administration. Plasma CA concentrations were measured by high-pressure liquid chromatography. Results: The concentration of plasma CA after transdermal and rectal administration was below the limits of quantification (0.1 µg/ml) in all samples suggesting inadequate bioavailability with transdermal and rectal administration. Conclusion: Transdermal and rectal CA administration are not reasonable alternative routes of delivery.

Optimizing corneal riboflavin administration in ex vivo horse, dog, rabbit, and pig samples for use in corneal collagen cross-linking.

PURPOSE: Determine optimal iontophoresis times for riboflavin delivery to the corneal stroma across different species and compare these to corneal injection. METHODS: Ex vivo horse, dog, rabbit, and pig globes were treated with riboflavin administered with either iontophoresis for 2.5-20 minutes with or without corneal epithelium; or with purpose-designed precise corneal injection (PCI) application with intact epithelium. Immediately following riboflavin administration, samples were harvested, frozen, and sectioned. Riboflavin penetration was imaged using fluorescence microscopy. RESULTS: Horse samples processed with iontophoresis without epithelium for 2.5, 5, and 7.5 minutes, and processed with intact epithelium for 20 minutes, had mean percent stromal penetration (%SPmean ) of 63.4%, 93.8%, 100.0%, and 0.0% (respectively). Dog samples processed with iontophoresis without epithelium for 2.5 and 5 minutes, had %SPmean of 60.7% and 82.1% (respectively). Pig samples processed with iontophoresis for 5 minutes without and with epithelium had %SPmean of 63.3% and 35.1% (respectively). Rabbit samples processed with iontophoresis without epithelium for 2.5 and 5 minutes, had %SPmean of 81.8% and 100.0% (respectively). For all injected volumes, riboflavin was observed spanning throughout the corneal stroma, and lamellar separation was noted surrounding all sites of injection. CONCLUSIONS: Both iontophoresis and injection via PCI needles provide efficient and effective means of riboflavin administration in ex vivo horse, dog, rabbit, and pig corneas. Epithelial debridement is required for stromal delivery of riboflavin using iontophoresis in horses. Following epithelial removal, riboflavin penetrated through the horse corneal stroma faster than all other species tested.

Afferent and efferent connections of the nucleus rotundus demonstrated by WGA-HRP in the chick.

Organization of the fibre connections in the chick nucleus rotundus (Rt) was investigated by an axonal tracing method using wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP). After an injection of WGA-HRP into the Rt, labelled neurones were observed in the striatum griseum centrale (SGC) in both sides of the tectum (TO) and in the ipsilateral nucleus subpretectalis/nucleus interstito-pretecto-subpretectalis (SP/IPS). Labelled fibres and terminals were also found in the ipsilateral ectostriatum (Ect). These fibre connections were topographically organized rostrocaudally. In the TO-Rt projection, the rostral and the dorsocaudal parts of the Rt received afferents from the superficial part of the SGC, the middle part of the Rt received afferents from the intermediate part of the SGC, and the ventrocaudal part of the Rt received mainly fibres from the deep part of the SGC. These topographic projections were accompanied by a considerable number of diffuse projections to the thalamic regions surrounding the Rt. In addition, the rostral and middle caudal parts of the Rt received afferents from the lateral and medial parts of the SP/IPS, respectively, and respective parts of the Rt sent efferents to the lateral and medial parts of the Ect.

Ocular delivery of acetylsalicylic acid by repetitive coulomb-controlled iontophoresis.

To investigate the potential of transscleral coulomb-controlled iontophoresis (CCI) for repetitive delivery of acetylsalicylic acid (ASA) into the eye, a total of 50 rabbits was included in this study. Fourteen animals received serial CCI treatment. Fourteen animals underwent CCI with either ASA or balanced salt solution (BSS) for at least 6 days at 24- and 48-hour intervals. Eighteen animals received a single CCI application, while 18 animals were injected with 15 mg ASA/kg body weight intravenously. HPLC analysis was performed to determine the levels of salicylic acid (SA) in ocular tissues. Apart from clinical follow-up, 2 rabbits in the ASA and BSS groups were examined by electroretinography, and 2 animals were examined histologically. Though high concentrations of SA were measured, no alterations were observed clinically, histologically and electrophysiologically. Repetitive CCI demonstrated its potential as a topical drug delivery system for ASA into the eye. This transscleral delivery of ASA resulted in significant and sustained intraocular concentrations of SA without side effects. Iontophoresis may be advantageous in clinical administration maintaining therapeutic levels of ASA while avoiding adverse effects associated with the systemic administration of nonsteroidal anti-inflammatory drugs.

Evaluation of a combined laser Doppler flowmetry and iontophoresis technique for the assessment of equine cutaneous microvascular function.

A combined laser Doppler flowmetry and iontophoresis (LDFI) technique, used routinely to assess human microvascular function, was evaluated as a noninvasive technique for assessment of equine microvascular function, to facilitate the study of diseases such as laminitis. Baseline and vasoactive agonist-induced (acetylcholine and nitroprusside) microvascular flux was quantified at 2 sites (on the dorsal pastern adjacent to the coronary band and over the gluteals) in 6 clinically normal horses on 5 or 6 separate occasions under standardised conditions. Both agonists significantly increased microvascular flux. Skin pigmentation significantly attenuated the baseline flux, but not the magnitude of the agonist-mediated vasodilatory response. While LDFI was simple to perform, its value as a clinical and research tool for assessing the equine cutaneous microcirculation is limited by its poor reliability, as indicated by the marked intra- and intersubject variability in baseline and agonist-mediated microvascular flux.

Lontophoretic administration of dexamethasone into the tarsocrural joint in horses.

OBJECTIVE: To determine whether iontophoretic administration of dexamethasone to horses results in detectable concentrations in synovial fluid, plasma, and urine. ANIMALS: 6 adult mares. PROCEDURE: Iontophoresis was used to administer dexamethasone. Treatments (4 mA for 20 minutes) were administered to a tarsocrural joint of each mare. The drug electrode contained 3 ml of dexamethasone sodium phosphate at a concentration of 4 or 10 mg/ml. Samples of synovial fluid, blood, and urine were obtained before and 0.5, 4, 8, and 24 hours after each treatment. All samples were tested for dexamethasone using an ELISA. Synovial fluid also was evaluated for dexamethasone, using high-performance liquid chromatography. RESULTS: The lower and upper limits of detection for dexamethasone in synovial fluid with the ELISA were 0.21 and 1.5 ng/ml, respectively. Dexamethasone administered at a concentration of 10 mg/ml was detected by the ELISA in synovial fluid of 5 mares from 0.5 to 24 hours and in urine of 4 mares from 0.5 to 8 hours after each treatment, but it was not detected in plasma. Mean synovial fluid concentration of dexamethasone was 1.01 ng/ml. Dexamethasone administered at a concentration of 4 mg/ml was detected by the ELISA in urine of 2 mares at 0.5 and 4 hours after treatment, but it was not detected in synovial fluid or plasma. CONCLUSIONS AND CLINICAL RELEVANCE: Iontophoresis cannot be considered an effective method for delivery of dexamethasone to synovial fluid of horses, because drug concentrations achieved in this study were less than therapeutic concentrations.

Iontophoresis of dexamethosone-phosphate into the equine tibiotarsal joint.

In human rehabilitation medicine, dexamethasone-phosphate is theoretically iontophoresed to localized subcutaneous tissue where conversion to dexamethasone occurs. This delivery system has recently been introduced into veterinary medicine for the same purpose. However, the pharmacokinetic justification for parenteral delivery of this prodrug remains undocumented. Utilizing iontophoretic methods that are relevant to both human and veterinary clinical practice, the present investigation compared injection and iontophoresis of dexamethasone-phosphate into the equine tibiotarsal joint, also known as the tarsocrual joint. The tibiotarsal joints of seven horses were injected with 4 mL of 6 mg/mL dexamethasone-phosphate. With a similar drug concentration and over the same application site, six different horses underwent simultaneous cathodic iontophoresis (4 mA, 40 min) or passive application (0 mA, 40 min) on contralateral limbs. Following all applications, tibiotarsal joint synovium was collected. Local venous blood samples were also collected from the iontophoretic and passive application sites for analysis of plasma drug concentrations. Because of the potential for conversion of dexamethasone-phosphate to dexamethasone, an extraction and analysis protocol was developed for both chemicals. The technique demonstrated a linear range of detection (0.39-12 microg/mL) and a capability for measuring both chemicals in plasma and synovium. Conversion of dexamethasone-phosphate to dexamethasone occurred during synovial incubation (37 degrees C) and following freeze-thaw cycles. In contrast to the measurable synovial concentrations of dexamethasone-phosphate (2.3 +/- 0.96 mg/mL) and dexamethasone (0.27 +/- 0.07 mg/mL) following injection, neither drug was detected in the synovium or the local venous blood following iontophoretic or passive applications. In conclusion, these results do not confirm iontophoretic or passive delivery of measurable dexamethasone-phosphate into the tibiotarsal joint using current clinical methods.

Modes of local drug delivery to the musculoskeletal system.

A number of methods for the local delivery of drugs to musculoskeletal tissues in the horse are now available. Further research is required to document the disposition of drugs delivered by such methods and to correlate this information with efficacy. Perhaps the greatest potential area for the methods discussed is the treatment of synovial and bone infections. To be able to provide high and sustained therapeutic concentrations of antimicrobials to the site of infection should increase the chances of success in such cases. These methods of drug delivery need to be used in conjunction with other management procedures, however, including bacterial culture and sensitivity procedures, systemic antimicrobials, surgical drainage, removal of dead bone or surgical implants, establishment of fracture stability, use of autogenous bone grafts, systemic NSAIDs, and rest.