Robotic mitral valve repair: a review of anesthetic management of the first 200 patients.

OBJECTIVE: The aim of this study was to describe the evolution in anesthetic technique used for the first 200 patients undergoing robotic mitral valve surgery. DESIGN: A retrospective review. SETTING: A single tertiary referral academic hospital. PARTICIPANTS: Two hundred consecutive patients undergoing robotic mitral valve surgery using the da Vinci Surgical System (Intuitive Surgical, Inc., Sunnyvale, CA) at Mayo Clinic Rochester. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: After obtaining institutional review board approval, surgical and anesthetic data were recorded. For analysis, patients were placed in 4 groups, each containing 50 consecutive patients, labeled Quartiles 1 to 4. Over time, there were statistically significant decreases in cardiopulmonary bypass and aortic cross-clamp times. Significant differences in the anesthetic management were shown, with a reduction of intraoperative fentanyl and midazolam doses, and the introduction of paravertebral blockade in Quartile 2. There was a reduction of time between incision closure and extubation, and nearly 90% of patients were extubated in the operating room in Quartiles 3 and 4. Despite changes to the intraoperative analgesic management, and focus on earlier extubation, there were no differences seen in visual analog scale (VAS) pain scores over the 4 quartiles. Reductions were seen in total intensive care unit and hospital length of stay during the study period. CONCLUSIONS: Changes to the practice, including efforts to limit intraoperative opioid administration and the addition of preoperative paravertebral blockade, helped facilitate earlier extubation. In the second half of the study period, close to 90% of patients were extubated in the operating room safely and without delaying patient transition to the intensive care unit.

Comparison of electroencephalography and cerebral oximetry to determine the need for in-line arterial shunting in patients undergoing carotid endarterectomy.

OBJECTIVE: To compare cerebral near-infrared regional spectroscopy (NIRS) with the 12-lead electroencephalogram for the detection of ischemia during carotid artery clamping for carotid endarterectomy (CEA). DESIGN: Prospective, observational. SETTING: Single, tertiary care center. PARTICIPANTS: Ninety patients older than 18 undergoing elective, unilateral CEA. INTERVENTIONS: In addition to EEG monitoring, all patients underwent continuous blinded NIRS monitoring with sensors placed bilaterally above the supraorbital ridge. MEASUREMENTS AND MAIN RESULTS: Seventeen patients were excluded, leaving 73 patients available for evaluation. Four patients (5.5%) required shunting based on EEG findings. Changes in cerebral oxygen saturation (rSO2) were assessed on the operative side using the average value for the 1 minute prior to cross-clamp and the lowest rSO2 value the first 5 minutes postclamp. Each 1% absolute decrease and each 1% relative decrease from baseline conferred a 50% increase in the need for shunt placement (OR 1.5; 95% CI (1.03-2.26); p = 0.03 and OR 1.4; 95% CI (1.02-1.81); p = 0.04 respectively). Sensitivity, specificity, and positive and negative predictive values were determined using significant cutoffs of≥5% absolute change or≥10% relative change. Positive predictive value was low (<25%) for both absolute and relative changes. CONCLUSIONS: A decrease in rSO2 during carotid cross-clamping for CEA is associated with EEG-determined need for shunting, but the positive predictive value is low. Using the above cutoffs in the current series would have resulted in an increase in the shunt rate by approximately 20% when it was not indicated by EEG.

Pyrrolopyrimidine Bumped Kinase Inhibitors for the Treatment of Cryptosporidiosis.

Bumped kinase inhibitors (BKIs) that target Cryptosporidium parvum calcium-dependent protein kinase 1 have been well established as potential drug candidates against cryptosporidiosis. Recently, BKI-1649, with a 7H-pyrrolo[2,3-d]pyrimidin-4-amine, or "pyrrolopyrimidine", central scaffold, has shown improved efficacy in mouse models of Cryptosporidium at substantially reduced doses compared to previously explored analogs of the pyrazolopyrimidine scaffold. Here, two pyrrolopyrimidines with varied substituent groups, BKI-1812 and BKI-1814, were explored in several in vitro and in vivo models and show improvements in potency over the previously utilized pyrazolopyrimidine bumped kinase inhibitors while maintaining equivalent results in other key properties, such as toxicity and efficacy, with their pyrazolopyrimidine isosteric counterparts.

Refinement of the rodent pentylenetetrazole proconvulsion assay, which is a good predictor of convulsions in repeat-dose toxicology studies.

INTRODUCTION: The pentylenetetrazole (PTZ)-induced seizure assay in rodents is an established method for investigating drug-induced alterations in seizure threshold such as proconvulsant effects. The standard procedure in our laboratory was to administer the test item prior to 75-120 mg/kg subcutaneous PTZ. However, this dose range is associated with a high incidence of mortality, including approximately 40% or greater deaths of control animals. METHODS: The predictivity of the PTZ-induced seizure assay was retrospectively evaluated by relating drug plasma levels associated with proconvulsant effects to exposures observed during convulsions in repeat-dose toxicology studies. Margins to estimated efficacious doses were also considered. To investigate potential refinements, a high PTZ dose (80 mg/kg, subcutaneously) was compared to two lower doses (40 and 60 mg/kg), and a range of doses of theophylline was orally administered as positive control. RESULTS: The PTZ-induced proconvulsion assay proved to be a good predictor of convulsions in toxicology studies. In the refinement study, theophylline potentiated PTZ-induced seizures over all doses tested. At 60 mg/kg PTZ, the proconvulsant dose-dependency of theophylline was best observed. At both 40 and 60 mg/kg PTZ, mortality in control animals was significantly reduced. DISCUSSION: Risk assessment at an early stage of drug development supports candidate selection and, along that approach, the PTZ proconvulsion assay was proven to be a good predictor of convulsions in subsequent toxicology studies. It was also demonstrated that a relatively lower PTZ dose (60 mg/kg) improved the dose-response-curve of the positive control tested, decreased mortality overall and, therefore, contributes to refining this standard procedure for CNS safety evaluation.

Mechanical and structural characterisation of the dural venous sinuses.

The dural venous sinuses play an integral role in draining venous blood from the cranial cavity. As a result of the sinuses anatomical location, they are of significant importance when evaluating the mechanopathology of traumatic brain injury (TBI). Despite the importance of the dural venous sinuses in normal neurophysiology, no mechanical analyses have been conducted on the tissues. In this study, we conduct mechanical and structural analysis on porcine dural venous sinus tissue to help elucidate the tissues' function in healthy and diseased conditions. With longitudinal elastic moduli values ranging from 33 to 58 MPa, we demonstrate that the sinuses exhibit higher mechanical stiffness than that of native dural tissue, which may be of interest to the field of TBI modelling. Furthermore, by employing histological staining and a colour deconvolution protocol, we show that the sinuses have a collagen-dominant extracellular matrix, with collagen area fractions ranging from 84 to 94%, which likely explains the tissue's large mechanical stiffness. In summary, we provide the first investigation of the dural venous sinus mechanical behaviour with accompanying structural analysis, which may aid in understanding TBI mechanopathology.

Bumped Kinase Inhibitors as therapy for apicomplexan parasitic diseases: lessons learned.

Bumped Kinase Inhibitors, targeting Calcium-dependent Protein Kinase 1 in apicomplexan parasites with a glycine gatekeeper, are promising new therapeutics for apicomplexan diseases. Here we will review advances, as well as challenges and lessons learned regarding efficacy, safety, and pharmacology that have shaped our selection of pre-clinical candidates.

Screening Strategies and Methods for Better Off-Target Liability Prediction and Identification of Small-Molecule Pharmaceuticals.

Pharmaceutical discovery and development is a long and expensive process that, unfortunately, still results in a low success rate, with drug safety continuing to be a major impedance. Improved safety screening strategies and methods are needed to more effectively fill this critical gap. Recent advances in informatics are now making it possible to manage bigger data sets and integrate multiple sources of screening data in a manner that can potentially improve the selection of higher-quality drug candidates. Integrated screening paradigms have become the norm in Pharma, both in discovery screening and in the identification of off-target toxicity mechanisms during later-stage development. Furthermore, advances in computational methods are making in silico screens more relevant and suggest that they may represent a feasible option for augmenting the current screening paradigm. This paper outlines several fundamental methods of the current drug screening processes across Pharma and emerging techniques/technologies that promise to improve molecule selection. In addition, the authors discuss integrated screening strategies and provide examples of advanced screening paradigms.

Increased stress associated with head-out plethysmography testing can exacerbate respiratory effects and lead to mortality in rats.

INTRODUCTION: DSM421, a dihydroorotate dehydrogenase inhibitor, was in preclinical development as a potential treatment option for malaria. When tested in a core battery of safety pharmacology assays, DSM421 did not produce any effects at oral doses up to 750 mg/kg in an Irwin test in rats, but a respiratory study in rats using head-out plethysmography resulted in substantial changes in respiratory function as well as moribundity and mortality at that and lower doses. An investigation was performed to determine the source of this discrepancy. METHODS: Potential testing errors, differences in types of plethysmography testing chambers, effects on stress indicators, and off-target activity were investigated. RESULTS: Respiratory changes and toxicity (resulting in euthanasia in extremis) were confirmed in a repeat, head-out plethysmography test, but the effects of DSM421 were much less severe overall when the rats were tested in whole-body chambers. Additionally, at the end of the 5-h post-dosing respiratory monitoring periods, levels of stress-related hormones (particularly corticosterone) were higher overall in the head-out, than in the whole-body, tested rats. Furthermore, DSM421 was found to produce changes in cardiovascular function in unrestrained rats, and it was shown to have off-target binding affinity at the adenosine A3 receptor (which is associated with bronchoconstriction). DISCUSSION: The generalized stress inherent to head-out plethysmography testing exacerbated the respiratory effects of DSM421 and was possibly compounded by DSM421's cardiovascular effects, thus artifactually resulting in moribundity and mortality in rats. Care should be taken when choosing whether to use head-out versus whole-body plethysmography chambers during respiratory function testing in animals.

Digital and Mechanical Characterization of Ureteral Stent Luminal Reduction in Response to Extrinsic Compression Forces.

PURPOSE: To investigate the principles that govern ureteral stent failure by digitally and mechanically characterizing their luminal reduction in response to various extrinsic compression forces. To explore the relationship between ureteral stent "material area," "luminal area," and "cross-sectional area (CSA)" for resisting extrinsic compression forces. MATERIALS AND METHODS: We mechanically investigated 4.8F (n = 9), 6F (n = 9), and 7F (n = 9) ureteral stents to determine parameters that contribute to resisting radial compression forces. Digitalized images of luminal reduction values under incrementally increased reductions of stent outer diameters were obtained (0%, 25%, 50%, and 60% of original outer diameter). Forces (Newton [N]) and percentage luminal reduction that resulted in complete ureteral stent obstruction were determined. RESULTS: Uniaxial incremental compression in the radial direction demonstrated complete luminal reduction (95%-100%) when 58% to 62% of the outer stent diameter was compressed. The 6F ureteral stents demonstrated the greatest resistance to extrinsic compression and the greatest "material area" relative to "CSA" (mm2). The force (N) required for 50% compression of outer stent diameter was 10.44, 28.13, and 25.39 N for 4.8F, 6F, and 7F ureteral stents, respectively. The "material area"/"CSA" at 50% compression of the outer stent diameter was 76%, 86%, and 78% for 4.8F, 6F, and 7F ureteral stents, respectively. CONCLUSIONS: Maintenance of intraluminal stent diameter in the presence of extrinsic compressive forces is primarily dependent on the stent's ratio of "material area" to "CSA." Urologists should be aware of these findings to decrease the risk of ureteral stent failure when treating extrinsic ureteral obstruction.

Surgical management of traumatic thoracic spondyloptosis: review of 2 cases.

Spondyloptosis due to trauma is a very rare injury typically associated with motor vehicle accidents and typically at the lumbosacral junction. This report describes two patients with T6-7 and T12-L1 spondyloptosis secondary to trauma. The former was a 36-year-old man who was pinned under a 200 kg hay bale, suffering immediate paraplegia and undergoing successful posterior reduction and stabilization via a single stage posterior approach. Two years after his injury he has not developed any new deformity or neurological deterioration. The latter was a 22-year-old miner who was thrown against the ceiling of a coalmine and suffered a hyperflexion injury resulting in an immediate T12 paraplegia. Again successful reduction and stabilization was able to be achieved through pedicle screw instrumentation via a single-stage posterior approach. These two patients are the first reported cases of traumatic thoracic spondyloptosis. This report describes the rationale, likely mechanisms and surgical technique required for operative reduction and stabilization via a single-stage posterior approach.

Potential functional and pathological side effects related to off-target pharmacological activity.

Most pharmaceutical companies test their discovery-stage proprietary molecules in a battery of in vitro pharmacology assays to try to determine off-target interactions. During all phases of drug discovery and development, various questions arise regarding potential side effects associated with such off-target pharmacological activity. Here we present a scientific literature curation effort undertaken to determine and summarize the most likely functional and pathological outcomes associated with interactions at 70 receptors, enzymes, ion channels and transporters with established links to adverse effects. To that end, the scientific literature was reviewed using an on-line database, and the most commonly reported effects were summarized in tabular format. The resultant table should serve as a practical guide for research scientists and clinical investigators for the prediction and interpretation of adverse side effects associated with molecules interacting with components of this screening battery.

Preclinical abuse liability assessment of ABT-126, an agonist at the α7 nicotinic acetylcholine receptor (nAChR).

ABT-126 is a nicotinic acetylcholine receptor (nAChR) agonist that is selective for the α7 subtype of the receptor. nAChRs are thought to play a role in a variety of neurocognitive processes and have been a pharmacologic target for disorders with cognitive impairment, including schizophrenia and Alzheimer's disease. As part of the preclinical safety package for ABT-126, its potential for abuse was assessed. While the involvement of the α4ß2 subtype of the nicotinic receptor in the addictive properties of nicotine has been demonstrated, the role of the α7 receptor has been studied much less extensively. A number of preclinical assays of abuse potential including open-field, drug discrimination and self-administration were employed in male rats. ABT-126 had modest effects on locomotor activity in the open-field assay. In nicotine and d-amphetamine drug discrimination assays, ABT-126 administration failed to produce appreciable d-amphetamine-like or nicotine-like responding, suggesting that its interoceptive effects are distinct from those of these drugs of abuse. In rats trained to self-administer cocaine, substitution with ABT-126 was similar to substitution with saline, indicating that it lacks reinforcing effects. No evidence of physical dependence was noted following subchronic administration. Overall, these data suggest that ABT-126 has a low potential for abuse. Together with other literature on this drug class, it appears that drugs that selectively activate α7 nAChRs are not likely to result in abuse or dependence.

Advances in bumped kinase inhibitors for human and animal therapy for cryptosporidiosis.

Improvements have been made to the safety and efficacy of bumped kinase inhibitors, and they are advancing toward human and animal use for treatment of cryptosporidiosis. As the understanding of bumped kinase inhibitor pharmacodynamics for cryptosporidiosis therapy has increased, it has become clear that better compounds for efficacy do not necessarily require substantial systemic exposure. We now have a bumped kinase inhibitor with reduced systemic exposure, acceptable safety parameters, and efficacy in both the mouse and newborn calf models of cryptosporidiosis. Potential cardiotoxicity is the limiting safety parameter to monitor for this bumped kinase inhibitor. This compound is a promising pre-clinical lead for cryptosporidiosis therapy in animals and humans.

Diastolic Mitral Regurgitation in a Patient With Complex Native Mitral and Aortic Valve Endocarditis: A Rare Phenomenon With Potential Catastrophic Consequences.

Diastolic mitral valve regurgitation is a rare phenomenon described in patients with atrioventricular conduction abnormalities, severe left ventricular systolic or diastolic dysfunction with regional wall motion dyssynchrony, or severe acute aortic valve regurgitation. The presence of diastolic mitral valve regurgitation in acute aortic regurgitation due to endocarditis suggests critical severity requiring urgent surgical valve replacement. We describe a case of diastolic mitral regurgitation in the setting of complex native mitral-aortic valve endocarditis in a patient in normal sinus rhythm and review the etiologic mechanisms of this phenomenon, echocardiographic assessment, and therapeutic implications for hemodynamic management.

ABT-594 (a nicotinic acetylcholine agonist): anti-allodynia in a rat chemotherapy-induced pain model.

ABT-594 ((R)-5-(2-azetidinylmethoxy)-2-chloropyridine) represents a novel class of broad-spectrum analgesics whose primary mechanism of action is activation of the neuronal nicotinic acetylcholine receptors. The present study characterized the effects of ABT-594 in a rat chemotherapy-induced neuropathic pain model, where it attenuated mechanical allodynia with an ED50 = 40 nmol/kg (i.p.). This anti-allodynic effect was not blocked by systemic (i.p.) pretreatment with naloxone but was blocked completely with mecamylamine. Pretreatment with chlorisondamine (0.2-5 micromol/kg, i.p.) only partially blocked the effects of ABT-594 at the higher doses tested. In contrast, central (i.c.v.) pretreatment with chlorisondamine completely blocked ABT-594's anti-allodynic effect. Taken together, the data demonstrate that ABT-594 has a potent anti-allodynic effect in the rat vincristine model and that, in addition to its strong central site of action, ABT-594's effects are partially mediated by peripheral nicotinic acetylcholine receptors in this animal model of chemotherapy-induced neuropathic pain.

Biomechanical comparison of C1-2 posterior fixation techniques.

OBJECT: In a nondestructive, repeated-measures in vitro flexibility experiment, the authors compared the acute stability of C1-2 after placement of C-1 lateral mass and C-2 pars interarticularis (LC1-PC2) instrumentation with that of C1-2 transarticular screw fixation. METHODS: The effect of C-1 laminectomy and C1-2 interspinous cable/graft fixation on LC1-PC2 stability was studied. Screw pullout strengths were also compared. Seven human cadaveric occiput-C3 specimens were loaded nondestructively with pure moments while measuring nonconstrained atlantoaxial motion. Specimens were tested with graft alone, LC1-PC2 alone, LC1-PC2 combined with C-1 laminectomy, and graft-augmented LC1-PC2. Interspinous cable/graft fixation significantly enhanced LC1-PC2 stability during extension. After C-1 laminectomy, the LC1-PC2 construct allowed increased motion during flexion and extension. There was no significant difference in lax zone or range of motion between LC1-PC2 fixation and transarticular screw fixation, but graft-assisted transarticular screws yielded a significantly smaller stiff zone during extension. The difference in pullout resistance between C-1 lateral mass screws and C-2 pars interarticularis screws was insignificant. The LC1-PC2 region restricted motion to within the normal range during all loading modes. Atlantal laminectomy reduced LC1-PC2 stability during flexion and extension. CONCLUSIONS: The instrumentation-augmented LC1-PC2 construct performed biomechanically similarly to the C1-2 transarticular screw fixation. The LC1-PC2 construct resisted flexion, lateral bending, and axial rotation well. The weakness of the LC1-PC2 fixation in resisting extension can be overcome by adding an interspinous graft to the construct.

Translational Biomarkers of Neurotoxicity: A Health and Environmental Sciences Institute Perspective on the Way Forward.

Neurotoxicity has been linked to a number of common drugs and chemicals, yet efficient and accurate methods to detect it are lacking. There is a need for more sensitive and specific biomarkers of neurotoxicity that can help diagnose and predict neurotoxicity that are relevant across animal models and translational from nonclinical to clinical data. Fluid-based biomarkers such as those found in serum, plasma, urine, and cerebrospinal fluid (CSF) have great potential due to the relative ease of sampling compared with tissues. Increasing evidence supports the potential utility of fluid-based biomarkers of neurotoxicity such as microRNAs, F2-isoprostanes, translocator protein, glial fibrillary acidic protein, ubiquitin C-terminal hydrolase L1, myelin basic protein, microtubule-associated protein-2, and total tau. However, some of these biomarkers such as those in CSF require invasive sampling or are specific to one disease such as Alzheimer's, while others require further validation. Additionally, neuroimaging methodologies, including magnetic resonance imaging, magnetic resonance spectroscopy, and positron emission tomography, may also serve as potential biomarkers and have several advantages including being minimally invasive. The development of biomarkers of neurotoxicity is a goal shared by scientists across academia, government, and industry and is an ideal topic to be addressed via the Health and Environmental Sciences Institute (HESI) framework which provides a forum to collaborate on key challenging scientific topics. Here we utilize the HESI framework to propose a consensus on the relative potential of currently described biomarkers of neurotoxicity to assess utility of the selected biomarkers using a nonclinical model.

Attenuation of mechanical allodynia by clinically utilized drugs in a rat chemotherapy-induced neuropathic pain model.

Chemotherapy-induced peripheral neuropathy is a common, dose-limiting side effect of cancer chemotherapeutic agents, including the vinca alkaloids such as vincristine. The resulting symptoms, which frequently include moderate to severe pain, can often be disabling. The current study utilized a vincristine-induced neuropathic pain animal model [Pain 93 (2001) 69], in which rats were surgically implanted with mini-osmotic pumps set to deliver vincristine sulfate (30 microg kg(-1)day(-1), i.v.), to examine the time course of progression of various pain modalities and to compare the dose-response effects of clinically utilized drugs on mechanical allodynia to further validate the relevance of this model to clinical pathology. Vincristine infusion resulted in significant cold allodynia after 1 week post-infusion, however mechanical and thermal nociception showed little to no effect. In contrast, marked mechanical allodynia occurred by 1 week of vincristine infusion and returned nearly to pre-infusion levels by the 4th week after infusion pump implantation. ED(50) values (micromol/kg, p.o.) were determined in the mechanical allodynia assay for lamotrigine (82), dextromethorphan (94), gabapentin (400), acetaminophen (1100) and carbamazepine (3600); however, aspirin and ibuprofen had no effects up to 300 and 1000 micromol/kg, respectively. Additionally, ED(50) values (micromol/kg, i.p.) were determined in the mechanical allodynia assay for clonidine (0.35) and morphine (0.62), but desipramine and celecoxib had no effects up to 66 and 260 micromol/kg, respectively. Findings from the current, preclinical study further validate this model as clinically relevant for chemotherapy-induced pain. The surprisingly good effects observed with acetaminophen warrant further investigation of its mechanism(s) of action in neuropathic pain.