Lacosamide extended-release capsules are bioequivalent to lacosamide immediate-release tablets: Pharmacokinetic observations and simulations.

OBJECTIVES: Assess the bioequivalence of lacosamide extended-release (XR) capsules and immediate-release (IR) tablets and answer real-world clinical questions regarding the use of lacosamide XR. METHODS: An open-label, randomized, two-treatment, two-sequence, oral comparative bioavailability study was conducted to assess the bioequivalence of two lacosamide formulations. Participants were randomized 1:1 to receive lacosamide XR capsules (400 mg once-daily) or IR tablets (200 mg twice-daily) in 1 of 2 sequences over 7-day periods. Primary outcome was the area under the lacosamide concentration-time curve over 24 h at steady-state (AUC0-τ,ss). Secondary outcomes were maximum (Cmax,ss) and minimum concentrations at steady-state (Cmin,ss). Bioequivalence was established when 90% confidence intervals (CIs) for geometric least square means ratios (GLSMs) were between 80% and 125%. Adverse events (AEs) and other safety outcomes were also assessed. Pharmacokinetic simulations, including adherent and partially adherent dosing scenarios with XR and IR formulations, modeled the clinical use of lacosamide XR. RESULTS: Thirty-five healthy adult males were enrolled in the bioequivalence study. After 7 days of study drug, mean AUC0-τ,ss, Cmax,ss, and Cmin,ss values were similar between XR and IR formulations; all 90% CIs for GLSMs were between 80% and 125%. AEs were mild and no serious AEs or other clinically significant safety findings were observed. Pharmacokinetic simulations suggested that partial adherence affected formulations similarly; and the best strategy for switching formulations was to take the morning lacosamide IR dose followed by the evening lacosamide XR dose, as this resulted in the most consistent lacosamide plasma concentrations. CONCLUSIONS: Once-daily lacosamide XR capsules were bioequivalent to twice-daily lacosamide IR tablets. Pharmacokinetic simulations indicated lacosamide XR and IR formulations were similarly affected by partial adherence, though once-daily dosing with lacosamide XR may offer clinical advantages, and formulations can be easily switched. These results support the use of lacosamide XR capsules as a once-daily alternative to lacosamide IR tablets.

Muscle Relaxants for Acute and Chronic Pain.

Utilization of muscle relaxants varies for treatment of acute and chronic pain. This article provides an overview of the different types muscles relaxants and their adverse effects. Appropriate medication selection based on clinical indications is also examined.

Toll-like receptor signaling in liver ischemia and reperfusion.

Liver ischemia-reperfusion (I/R) injuries are significant clinical challenges implicated in various hepatic surgical procedures and transplantations. Associated with varying degrees of insult, the hallmark of I/R is the excessive inflammatory response potentiated by the host immune system. Toll-like receptors (TLRs), known to play an important role in pathogen-derived inflammation, are now thought to participate in I/R injury-derived inflammation signaling pathways. Endogenous particles (proteins, cytokines, nucleic acids) that are released from damaged host cells bind to TLR2, TLR4, and TLR9, resulting in even further injury by subsequent inflammatory reactions and activation of the innate immune system. This review aims to systematically examine the current literature about TLR signaling mechanisms, allowing for a greater understanding of the precise role of TLRs in hepatic I/R injuries.

Intracellular calcium signaling pathways during liver ischemia and reperfusion.

Calcium plays a major role in intracellular signaling mechanisms during ischemia reperfusion (I/R) injury of a liver cell. Under ischemic conditions, the absence of oxygen arrests oxidative phosphorylation, thereby eliminating the energy source by which hepatocellular mechanisms maintain homeostasis of calcium. This, in turn, leaves nonselective plasma membrane influx pores unopposed and results in a net increase in intracellular calcium concentrations. Subsequent reperfusion marks the onset and progression of apoptosis and necrosis, as it involves inflammatory responses as well as free-radical formation due to re-oxygenation of cells. These processes destroy the structural integrity of organelles, leading to disruptive redistribution of calcium between cellular and subcellular compartments. This initial elevation and later imbalance of intracellular calcium concentrations associated with I/R induce various molecular responses within each organelle. In the cytoplasm, a series of pro-apoptotic pathways involving various calcium sensitive enzymes are activated. The injury is further exacerbated in the endoplasmic reticulum (ER) due to the malfunction of mechanisms responsible for intracellular calcium sequestration. Both the mitochondria and the nucleus are also adversely affected, as their structural integrity and physiologic functions are disrupted. To date, however, the precise pathophysiology of these calcium-mediated signaling pathways is not fully understood due to its complex nature. This review aims to systematically examine the current literature about individual molecular signaling pathways in the cytoplasm, ER, mitochondria, and the nucleus prior to causing time-sensitive progression of permanent tissue injury.

Peripherally inserted central catheter placement using the Sonic Flashlight.

The Sonic Flashlight is an ultrasound (US) device that projects real-time US images into patients with use of a semireflective/transparent mirror. The present study evaluated the feasibility of use of the Sonic Flashlight for clinical peripherally inserted central catheter placements, originally with the mirror located inside a sterile cover (n = 15), then with the mirror outside (n = 11). Successful access was obtained in all cases. Results show that this new design improved visibility, as judged subjectively firsthand and in photographs. The study demonstrated the feasibility of the Sonic Flashlight and the new design to help assure sterility without degrading visibility, allowing further clinical trials involving physicians and nurses.

Vascular access: comparison of US guidance with the sonic flashlight and conventional US in phantoms.

PURPOSE: To prospectively evaluate whether ultrasonography (US)-guided vascular access can be learned and performed faster with the sonic flashlight than with conventional US and to demonstrate sonic flashlight-guided vascular access in a cadaver. MATERIALS AND METHODS: Institutional review board approval and oral and written informed consent were obtained. The sonic flashlight replaces the standard US monitor with a real-time US image that appears to float beneath the skin and is displayed where it is scanned. In studies 1 and 2, participants performed sonic flashlight-guided needle insertion tasks in vascular phantoms. In study 1, 16 participants (nine women, seven men) with no US experience performed 60 simulated vascular access trials with sonic flashlight or conventional US guidance. With analysis of variance (ANOVA) and power-curve fitting, improvement with practice rate and mean differences between techniques and tasks were examined. In study 2, 14 female nurses (mean age, 50.1 years) proficient with conventional US performed simulated vascular access trials on three tasks with the sonic flashlight and conventional US. With random assignment, half the participants used the sonic flashlight first and half used conventional US first. Mean performance with each technique and that with each task were compared by using ANOVA. In study 3, feasibility of sonic flashlight guidance for access to internal jugular and basilic veins was demonstrated in a cadaver. RESULTS: For study 1, learning rates (ie, decrease in access time over trials) did not differ for vascular access with sonic flashlight and conventional US. Overall, participants achieved faster vascular access times with sonic flashlight guidance (P < .007). In study 2, participants performed procedures faster overall with the sonic flashlight (P < .02) and found the sonic flashlight easier to use. In study 3, sonic flashlight-guided vascular access was gained in the cadaver. CONCLUSION: Learning and performance of vascular access were significantly faster with the sonic flashlight than with conventional US, and vascular access could be gained in a cadaver; the sonic flashlight is ready for clinical trials.

C-mode real-time tomographic reflection for a matrix array ultrasound sonic flashlight.

RATIONALE AND OBJECTIVES: Real-time tomographic reflection (RTTR) permits in situ visualization of tomographic images so that natural hand-eye coordination can be used directly during invasive procedures. The method uses a half-silvered mirror to merge the visual outer surface of the patient with a simultaneous scan of the patient's interior without requiring a head-mounted display or tracking. A viewpoint-independent virtual image is reflected precisely into its actual location. When applied to ultrasound, we call the resulting RTTR device the sonic flashlight. We previously implemented the sonic flashlight using conventional two-dimensional ultrasound scanners that produce B-mode slices. Real-time three-dimensional (RT3D) ultrasound scanners recently have been developed that permit RTTR to be applied to slices with other orientations, including C-mode (parallel to the face of the transducer). Such slice orientation may offer advantages for image-guided intervention. MATERIALS AND METHODS: Using a prototype scanner developed at Duke University (Durham, NC) with a matrix array that electronically steers an ultrasound beam at high speed in 3D, we implemented a sonic flashlight capable of displaying C-mode images in situ in real time. RESULTS: We present the first images from the C-mode sonic flashlight, showing bones in the hand and the cardiac ventricles. CONCLUSION: The extension of RTTR to matrix array RT3D ultrasound offers the ability to visualize in situ slices other than the conventional B-mode slice, including C-mode slices parallel to the face of the transducer. This orientation may provide a broader target, facilitating certain interventional procedures. Future work is discussed, including display of slices with arbitrary orientation and use of a holographic optical element instead of a mirror.

Intuitive intraoperative ultrasound guidance using the Sonic Flashlight: a novel ultrasound display system.

OBJECTIVE: The Sonic Flashlight (SF) is a new handheld ultrasound (US) display device being developed at our institution. It replaces the standard monitor on a conventional ultrasound (CUS) system with a miniature monitor and half-silvered mirror to reflect real-time US images into the body. With the SF, the imaged body part appears translucent, with the US image appearing to float below the surface of the anatomy, exactly where it is being scanned. The SF merges the patient, US image, instrument, and operator's hands into the same field of view, allowing the user to operate directly on the US image using normal hand-eye coordination. In contrast, CUS procedures result in displaced hand-eye coordination when the operator looks away from the patient to view the CUS monitor. Intraoperatively, the SF may make localizing and accessing tumors, foreign bodies, hematomas, vascular malformations, and ventricles easier and more accurate, especially for those without extensive CUS training. METHODS: In this cadaver study, the SF was used to visualize the brain and guide a needle into an implanted simulated tumor. The needle was inserted both in the US plane and outside of the US plane. INSTRUMENTATION: Sonic Flashlight fifth generation research prototype. CONCLUSION: The needle was easily and intuitively visualized and guided into the lesion, both within and outside of the US plane. By having the US image appear directly beneath the brain surface, the surgeon can easily and quickly guide the needle or surgical instrument to the lesion. The operator's eyes never have to leave the surgical field, as they do with CUS technology. The impact of this device on neurosurgical procedures could be significant. The ease of use, intuitive function, and small instrument size allow the surgeon to quickly localize lesions, confirm surgical positioning, and assess postoperative results.

Guidance of retrobulbar injection with real-time tomographic reflection.

OBJECTIVE: Retrobulbar and peribulbar injections are common ophthalmologic procedures used to deliver anesthetics and other medications for ophthalmic therapy and surgery. These injections, typically performed without any type of guidance, can lead to complications that are rare but visually devastating. The needle may penetrate the optic nerve, perforate the globe, or disperse toxic quantities of drugs intraocularly, causing major visual loss. Sonographic guidance may increase the accuracy of the needle placement, thereby decreasing the incidence of complications. However, difficulties arise in coordinating the relative location of the image, the needle, and the patient. Real-time tomographic reflection is a new method for in situ visualization of sonographic images, permitting direct hand-eye coordination to guide invasive instruments beneath the surface of the skin. METHOD: In this preliminary study, real-time tomographic reflection was used to visualize the eye and surrounding anatomic structures in a cadaver during a simulated retrobulbar injection. RESULT: The needle tip was easily followed as it was advanced into the retrobulbar space. CONCLUSIONS: The images presented in this preliminary study show the use of real-time tomographic reflection to visualize insertion of an invasive instrument into the human body.