Romazicon®) in an Animal Model

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Romazicon®) in an Animal Model Scientific Article Comparative pharmacokinetics of submucosal vs. intravenous flumazenil (Romazicon®) in an animal model Faith M. Oliver, DDS Trevor W. Sweatman, PhD John H. Unkel, DDS, MPA Michael A. Kahn, DDS Mildred M. Randolph, DVM Kristopher L. Arheart, EdD Timothy D. Mandrell, DVM Dr. Oliver is a resident, Pediatric Dentistry; Dr. Sweatman is an associate professor, Pharmacology; Dr. Unkel is an associate professor and postgraduate program director, Pediatric Dentistry; Dr. Kahn is a professor, Biologic & Diagnostic Sciences; Dr. Randolph is a veterinarian, Comparative Medicine; Dr. Arheart is an assistant professor, Preventive Medicine; and Dr. Mandrell is an associate professor, Comparative Medicine, they are all at the University of Tennessee. Correspond with Dr. Unkel at [email protected] Abstract Purpose: This study was performed to determine the in post-synaptic membrane hyperpolarization and reduced bioavailability and local tissue toxicological safety of flumazenil cortical stimulation via the lower brain centers. Traditional (Romazicon®) when administered by oral submucosal (SM) as endpoints for benzodiazepine-induced conscious sedation (pto- opposed to intravenous (IV) injection. sis, dysarthria, and drowsiness) are very close to an hypnotic Methods: Six dogs each received SM flumazenil (0.2 mg), and state in which the patient is unresponsive to verbal command.1,2 their serum was collected at predetermined time intervals (0-2 h) More recently, anxiolysis, amnesia, and patient cooperation and frozen (-70°C). Seven days later, the dogs received an iden- have been used as measures of drug effectiveness.3 With re- tical dose of IV flumazenil, and serum samples were again collected, gard to dentistry, the intranasal (IN: 0.2-0.4 mg/kg) or oral as above. Comparative quantitation of flumazenil levels (IV vs. (PO: up to 0.6-0.7 mg/kg) administration of the short-acting SM) was made using a sensitive HPLC assay (UV detection). water-soluble benzodiazepine midazolam is increasingly com- Direct/local drug toxicity was visually scored by unbiased raters of mon in the practice of pediatric sedation. Not only does color photographs (test and control mucosa) taken at 1, 2, and 7 midazolam produce a more rapid sedative effect than diazepam, days following SM flumazenil injection. An oral pathologist ex- but also the lack of pharmacologically-active midazolam me- amined slides processed from control and treatment tissues tabolites provides for a more rapid recovery with this agent, (hematoxylin and eosin staining) taken (punch biopsy) 1 week typically in 45-60 min.4 In general, midazolam is well toler- following SM injection to compare with direct clinical scores. ated with few significant hemodynamic effects. However, Results: Serum flumazenil levels reached a plateau (8.5 ± 1.5 either through inappropriate IV dosing (dose- and speed-sen- ng/mL, mean ± SD) within 4 min of SM drug injection and de- sitive) or by virtue of an iatrogenic response, midazolam, like clined thereafter to ~2 ng/mL by 2 h. Bioavailability of SM the other benzodiazepines, is capable of producing life-threat- flumazenil was 101 ± 14%, based upon measuring the area un- ening respiratory depression and apnea which may require der the serum concentration-time curves over 1.5 h (AUC 0- pharmacologic intervention. 1.5 h, SM vs. IV drug). Thus, serum drug levels following SM In contrast to other sedative drugs, one significant advan- drug administration were broadly comparable to those obtained tage of benzodiazepine-induced sedation is the clinical during the elimination phase of corresponding IV drug delivery. availability of a specific and potent antagonist, flumazenil Regarding drug tissue toxicity, no evidence of direct drug toxicity (Romazicon®). This imidobenzodiazepine derivative whose was observed by unbiased raters of color photographs (test and con- pharmacology as a benzodiazepine antagonist was first reported trol mucosa) taken at 1, 2, and 7 days following SM flumazenil in a series of publications almost two decades ago,5-8 does not injection. Following pathologic review, no difference was seen in itself possess intrinsic sedative activity at normal therapeutic the degree of inflammation between treatment and control tissue. doses3 and does not change the benzodiazepine pharmacoki- Conclusion: At the quantity and concentration used, SM drug netics when the two agents are present in the circulation at flumazenil administration appears to be both a safe and a viable clinical concentrations.9,10 Flumazenil has a very high speci- alternative to bolus IV drug delivery and worthy of further inves- ficity for the CNS benzodiazepine receptors where tigation. (Pediatr Dent 22:489-493, 2000) displacement of the benzodiazepine results in closure of the chloride channels, membrane re-stabilization, and rapid recov- ntravenous (IV) benzodiazepines such as diazepam ery of respiratory and cognitive function. Indeed, such is the (Valium®) and midazolam (Versed®) have been used for receptor specificity which this drug exhibits that radiolabeled more than 10 years both as components of general anes- (C11)-flumazenil has been employed during in vivo benzodiaz- I 11 thesia and, where appropriate, for conscious sedation during epine receptor binding studies and more recently as a means endoscopy, urology, cardiology, and outpatient surgery. These to study the reduction in CNS benzodiazepine receptor den- drugs act by enhancing gamma-amino butyric acid (GABA) sity and function during epilepsy.12 binding to specific receptors located in the central nervous sys- Flumazenil is pharmacologically effective when adminis- tem (CNS), thereby opening chloride ion channels. This results tered PO; however, the antagonist undergoes extensive first-pass hepatic metabolism, with a bioavailability of approxi- Received December 1, 1999 Revision Accepted July 27, 2000 Pediatric Dentistry – 22:6, 2000 American Academy of Pediatric Dentistry 489 mately 15%.13 Flumazenil has also proven effective in revers- ternative. Therefore, the purpose of our study was to investi- ing benzodiazepine sedation when administered rectally14 and gate the practicality of this rapid dosing technique by by endotracheal instillation,15 thereby indicating that this li- determining the bioavailability and toxicological safety of pophilic agent has the capacity to readily traverse biological flumazenil when administered by SM injection. membranes. Nevertheless, flumazenil is presently approved only for IV administration. In humans, IV flumazenil doses Methods of 0.5 mg or less produce recovery of cognitive function in a matter of seconds, i.e., one circulation time from arm to brain. Model description With regard to metabolism, less than 0.2% of an IV dose The dog was chosen as an animal model based upon compa- of flumazenil is recovered unchanged in the urine,16, 17 the prin- rable body weight to children (20-25 kg) and the ease of oral cipal excretory product being a glucuronide conjugate of access in this species. All experiments with dogs were con- flumazenil “acid.” The circulating metabolic products of ducted under protocols approved by the institutional ACUC flumazenil consist principally of cleaved products arising from review process. At no time were the animals subjected to pain- esterase activity and/or N-demethylation; none of these prod- ful procedures. Overall supervision of the animal experiments ucts possesses biological activity. As a result both of its extensive was the responsibility of the Department of Comparative Medi- and rapid hepatic extraction and through the action of ubiq- cine. uitous esterase enzymes, flumazenil has a short half-life in serum, in the order of 45-80 min; 18-21 by contrast, the serum Animal studies half life of midazolam is 1.5-3 h.22 Therefore, the potential Six anesthetized (isoflurane) male dogs (20-25 kg, overnight- for the re-emergence of residual benzodiazepine sedation ex- fasted) each received a single injected SM dose of flumazenil ists. Although a single IV dose of flumazenil provides effective (0.2 mg) in the mucobuccal fold mesial to the third-fourth pre- benzodiazepine antagonism for about 15 min, repeated doses molar (an area comparable to the first-second premolar of flumazenil may be necessary to maintain an antagonistic mucobuccal fold used by others in clinical studies).29 Imme- effect, most especially in patients who have received long-act- diately before (0 time) and at various times (1, 2, 3, 4, 6, 10, ing benzodiazepines and with intentional drug overdose. 15, 20, 30, 60, 90 and 120 min) following drug injection, blood Nonetheless, with respect to normal clinical midazolam doses, samples (5.0 mL) were obtained from an indwelling cephalic reversal of respiratory depression is rapidly accomplished with vein catheter (20G 1.25 in). Catheter patency was maintained a single flumazenil administration of 0.5 mg or less. In terms by back flushing with heparinized saline. No additional medi- of safety, the earlier reports of convulsions or seizures arising cations were administered to the dogs, and no physiological from flumazenil administration23-25 are now recognized as re- effects of flumazenil administration were observed over the sulting from rebound CNS stimulation following course of the study. Blood samples were transferred into ster- benzodiazepine receptor down regulation. This is a result of ile vacutainers, which were immediately placed on ice. either chronic benzodiazepine-induced or natural pathologi- Following centrifugation, the
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