De-labeling of ß-lactam allergy reduces intraoperative time and optimizes choice in antibiotic prophylaxis.

BACKGROUND: Suspected penicillin allergic individuals receive suboptimal non-ß-lactams for intraoperative prophylaxis which may prolong operations and have negative clinical outcomes. We therefore studied if ß-lactam de-labeling optimized choice of prophylactic antibiotics and improved intraoperative time efficiency. METHODS: A multistep approach was used. It included a risk assessment tool by an allergist, ß-lactam skin testing and oral provocation. To determine the value of de-labeling, we appraised intraoperative antibiotic choices and correlated them with time to first incision. RESULTS: A total of 194 patients were evaluated preoperatively. Four patients were diagnosed ß-lactam allergic on skin testing. Of the remaining 190 skin test negative patients, 146 were ß-lactam challenged. Only 5% reacted and were considered ß-lactam allergic. Cefazolin became the perioperative antibiotic of choice for 77% of patients requiring antibiotic prophylaxis. Only 5 confirmed ß-lactam allergic patients received intraoperative vancomycin. Patients avoiding use of vancomycin saved an average of 22 minutes in operative time. Of the 44 patients not having a ß-lactam challenge, 36 received antibiotics and 18 (50%) of these were prescribed intraoperative cefazolin. CONCLUSION: Using this three step process, almost all of those claiming penicillin allergy were de-labeled. In most patients that were drug challenged, ß-lactam antibiotics became the perioperative drug of choice. In cases where oral challenge was not used in the assessment only 50% were given a ß-lactam. The reduced use of vancomycin minimized delays in initiation of incision time, thus improving operative efficiency. Ultimately, randomized controlled studies are required to objectively determine the effectiveness of this approach.

Double-Blind, Placebo-Controlled, Randomized Phase I/IIa Study (Safety and Efficacy) with Buspirone/Levodopa/Carbidopa (SpinalonTM) in Subjects with Complete AIS A or Motor-Complete AIS B Spinal Cord Injury.

BACKGROUND: No drug treatment capable of restoring locomotor capabilities in patients suffering a motor-complete spinal cord injury (SCI) has ever been developed. We assessed the safety and efficacy of an activator of spinal locomotor neurons in humans, which were shown in paraplegic animals to elicit temporary episodes of involuntary walking. METHODS: Single administration of buspirone/levodopa/carbidopa (SpinalonTM), levodopa/carbidopa (ratio 4: 1), and buspirone or placebo was performed using a dose-escalation design in 45 subjects placed in supine position who had had an SCI classified as complete (AIS A) or motor-complete/sensory incomplete (AIS B) for at least 3 months. Blood samples before and at regular intervals (15, 30, 60, 120, 240 min) after treatment were collected for hematological and pharmacokinetic (PK) analyses. Electromyographic (EMG) activity of eight muscles (four per leg) was monitored prior to and at several time points after drug administration. RESULTS: SpinalonTM (10-35 mg buspirone/100-350 mg levodopa/25-85 mg carbidopa) displayed no sign of safety concerns - only mild nausea was found in 3 cases. At higher doses, 50 mg/500 mg/125 mg SpinalonTM was considered to have reached maximum tolerated dose (MTD) since 3 out of 4 subjects experienced related adverse events including vomiting. PK analyses showed comparable data between groups suggesting no significant drugdrug interaction with SpinalonTM. Only the SpinalonTM-treated groups displayed significant EMG activity accompanied by locomotor-like characteristics - that is with rhythmic and bilaterally alternating bursts. CONCLUSION: Therefore, this study provides evidence of safety and preliminary efficacy following a single administration of SpinalonTM in subjects with SCI.

Synthesis and preliminary evaluation of piperidinyl and pyrrolidinyl iodobenzoates as imaging agents for butyrylcholinesterase.

PURPOSE: The purpose of this study is to synthesize and evaluate specific agents for molecular imaging of butyrylcholinesterase (BuChE), known to be associated with neuritic plaques and neurofibrillary tangles in Alzheimer's disease (AD). In this study, these agents were tested in a normal rat model. The distribution of radiolabel was compared with known BuChE histochemical distribution in the rat brain. PROCEDURES: Iodobenzoate esters were synthesized and tested, through spectrophotometric analysis, as specific substrates for BuChE. These compounds were converted to the corresponding (123)I esters from tributyltin intermediates and purified for studies in the rat model. Whole body dynamic scintigraphic images were obtained for biodistribution studies. Autoradiograms of brain sections were obtained and compared to histochemical distribution of the enzyme in this model system. RESULTS: The three iodobenzoate esters studied were specific substrates for BuChE. Whole body biodistribution studies with (123)I-labeled compounds showed rapid disappearance from the body while radioactivity was retained in the head region. Brain section autoradiography of animals injected with these labeled compounds indicated that most areas known to contain BuChE corresponded to areas of radioactivity accumulation. CONCLUSION: BuChE-specific radiolabeled iodobenzoates enter the brain and, in general, label areas known to exhibit BuChE activity in histochemical studies. Such molecules may represent a new direction for the development of agents for the molecular imaging of BuChE in the living brain, especially in regions where BuChE-containing neuropathological structures appear in AD.

Characterization of (123)I-iodo-alpha-methyltyrosine transport in rat lymphoma cells.

(123)I-Iodo-alpha-methyltyrosine (IMT) transport into lymphomas has not been fully characterized. In rat Nb2-11C and Nb2-Sp lymphoma cell lines, linear uptake of (123)I-IMT occurred rapidly within 5-10 min. Eadie-Hoftee plots of (123)I-IMT uptake gave apparent Km's of 8.34+/-1.17 and 9.64+/-1.05 microM for Nb2-11C and Nb2-Sp cells, respectively, and involved the L and B(0,+) systems. In lymphoma-bearing rats, injected (123)I-IMT accumulated rapidly in the primary tumors but gave a low tumor-to-background ratio of 2:1. (123)I-IMT was transported rapidly into lymphoma cells both in vitro and in vivo, but low target-to-nontarget ratio may not make (123)I-IMT practical for scanning in vivo.

Complex intracranial arterial anatomy in swine is unsuitable for cerebral infarction projects.

OBJECTIVE: To see whether swine provide a suitable animal model for cerebral ischemia research projects related to apoptosis. Swine angiograms had not been obtained previously in our institution. METHODS: We performed angiography on an anesthetized pig. A right femoral artery cannulation was carried out, and angiographic images of the right cerebral arteries were obtained. RESULTS: We found that the swine cerebral circulatory system demonstrated a plexus of very small vessels, rete mirabile, in the base of the brain that was perfused by the ascending pharyngeal artery and reconstituted into the internal carotid artery downstream. CONCLUSION: Because of the presence of the rete mirabile, the swine brain circulatory system is not amenable to selective, intracranial, angiographic catheter-mediated infarction of cerebral arteries. Surgical occlusion of the common carotid or ascending pharyngeal artery, although technically possible, was also excluded as a method of creating reliable, reproducible cerebral ischemia because of the prompt and robust circle of Willis cross-perfusion that was observed on the angiograms.

Effects of theophylline on tracheal mucociliary clearance rates in healthy cats.

OBJECTIVE: To determine tracheal mucociliary clearance rate (TMCCR) by use of a standard protocol in healthy anesthetized cats and to determine the effect of theophylline on TMCCR in healthy anesthetized cats. ANIMALS: 6 healthy cats. PROCEDURE: Cats were anesthetized with propofol, and a droplet of the radiopharmaceutical technetium Tc 99m macroaggregated albumin was placed endoscopically at the carina. Dynamic acquisition scintigraphic imaging was performed, using the larynx as the end point. The TMCCR was determined by measuring the distance the droplet traveled by frame rate. Each cat was imaged 6 times as follows: 3 times following placebo administration and 3 times following the administration of sustained release theophylline (25 mg/kg, PO). Serum theophylline concentrations were assessed during imaging to ensure therapeutic concentrations. RESULTS: The TMCCR in healthy adult cats anesthetized with propofol was 22.2 +/- 2.8 mm/min. Tracheal mucociliary clearance rate in cats receiving theophylline was 21.8 +/- 3.5 mm/min. Theophylline administration did not significantly alterTMCCR. CONCLUSIONS AND CLINICAL RELEVANCE: Theophylline has been shown to increase TMCCR in humans and dogs. In our study, we determined TMCCR in healthy anesthetized cats and found that it was not accelerated by the administration of theophylline.