Enolate-Forming Phloretin Pharmacophores: Hepatoprotection in an Experimental Model of Drug-Induced Toxicity.

Drug-induced toxicity is often mediated by electrophilic metabolites, such as bioactivation of acetaminophen (APAP) to N-acetyl-p-benzoquinone imine (NAPQI). We have shown that APAP hepatotoxicity can be prevented by 2-acetylcyclopentanone (2-ACP). This 1,3-dicarbonyl compound ionizes to form an enolate nucleophile that scavenges NAPQI and other electrophilic intermediates. In this study, we expanded our investigation of enolate-forming compounds to include analyses of the phloretin pharmacophores, 2',4',6'-trihydroxyacetophenone (THA) and phloroglucinol (PG). Studies in a mouse model of APAP overdose showed that THA provided hepatoprotection when given either by intraperitoneal injection or oral administration, whereas PG was hepatoprotective only when given intraperitoneally. Corroborative research characterized the molecular pharmacology (efficacy, potency) of 2-ACP, THA, and PG in APAP-exposed isolated mouse hepatocytes. For comparative purposes, N-acetylcysteine (NAC) cytoprotection was also evaluated. Measurements of multiple cell parameters (e.g., cell viability, mitochondrial membrane depolarization) indicated that THA and, to a lesser extent, PG provided concentration-dependent protection against APAP toxicity, which exceeded that of 2-ACP or NAC. The enolate-forming compounds and NAC truncated ongoing APAP exposure and thereby returned intoxicated hepatocytes toward normal viability. The superior ability of THA to protect is related to multifaceted modes of action that include metal ion chelation, free radical trapping, and scavenging of NAPQI and other soft electrophiles involved in oxidative stress. The rank order of potency for the tested cytoprotectants was consistent with that determined in a parallel mouse model. These data suggest that THA or a derivative might be useful in treating drug-induced toxicities and other conditions that involve electrophile-mediated pathogenesis.

The Use of Electrical Impedance to Identify Intraneural Needle Placement in Human Peripheral Nerves: A Study on Amputated Human Limbs.

BACKGROUND: Even as the use of peripheral nerve blockade in the perioperative setting is increasing, neural injury secondary to accidental intraneural injection remains a significant patient safety concern. Current modalities, including electrical stimulation and ultrasound imaging, still lack consistency and absolute reliability in both the detection and prevention of this complication. The measurement of electrical impedance (EI) could be an easy and valuable additional tool to detect intraneural needle placement. Our objectives in this study were to measure the change in EI with intraneural needle advancement in recently amputated human limbs. METHODS: The study was conducted within 45 minutes of amputation. The nerves that were studied were the sciatic nerve in the popliteal fossa in above-knee amputations or the tibial nerve below the calf in below-knee amputations. The amputated limb was placed on a tray and under ultrasound imaging guidance, an insulated peripheral block needle connected to a nerve stimulator was placed extraneurally and subsequently advanced intraneurally. The experiment was repeated on the same nerve after exposure by surgical dissection. The differences in impedance measurements between intraneural and extraneural needle placement were compared. RESULTS: In the below-knee amputated extremity (tibial nerve, n = 6) specimens based on the ultrasound methods, mean ± SD for ultrasound-guided intraneural impedance was 10 ± 2 kΩ compared with an extraneural impedance of 6 ± 1.6 kΩ (P = 0.005). The difference between intraneural and extraneural impedance after open dissection was also significant when we repeated the analysis based on the same specimens (P = 0.005). Similarly, in the above-the-knee amputated extremity (sciatic nerve, n = 5) specimens, mean intraneural impedance was 35.2 ± 7.9 kΩ compared with an extraneural impedance of 25.2 ± 5.3 kΩ (P = 0.037). The difference between intraneural and extraneural impedance obtained after open dissection was also significant when we repeated the analysis based on the same specimens (P = 0.0002). The impedance values were consistent and similar to those obtained after open dissection. CONCLUSIONS: There is no reliable "gold standard" to predict or prevent intraneural needle placement during peripheral nerve blockade. This small sample-sized study demonstrated that there is a change in EI with intraneural needle advancement. In clinical practice, measurement of the EI in conjunction with nerve stimulation may serve as another tool to use for identifying intraneural needle placement during peripheral nerve blockade.

2-Acetylcyclopentanone, an enolate-forming 1,3-dicarbonyl compound, is cytoprotective in warm ischemia-reperfusion injury of rat liver.

We have previously shown that 2-acetylcyclopentanone (2-ACP), an enolate-forming 1,3-dicarbonyl compound, provides protection in cell culture and animal models of oxidative stress. The pathophysiology of ischemia-reperfusion injury (IRI) involves oxidative stress, and, therefore, we determined the ability of 2-ACP to prevent this injury in a rat liver model. IRI was induced by clamping the portal vasculature for 45 minutes (ischemia phase), followed by recirculation for 180 minutes (reperfusion phase). This sequence was associated with substantial derangement of plasma liver enzyme activities, histopathological indices, and markers of oxidative stress. The 2-ACP (0.80-2.40 mmol/kg), administered by intraperitoneal injection 10 minutes prior to reperfusion, provided dose-dependent cytoprotection, as indicated by normalization of the IRI-altered liver histologic and biochemical parameters. The 2-ACP (2.40 mmol/kg) was also hepatoprotective when injected before clamping the circulation (ischemia phase). In contrast, an equimolar dose of N-acetylcysteine (2.40 mmol/kg) was not hepatoprotective when administered prior to reperfusion. Our studies to date suggest that during reperfusion the enolate nucleophile of 2-ACP limits the consequences of mitochondrial-based oxidative stress through scavenging unsaturated aldehyde electrophiles (e.g., acrolein) and chelation of metal ions that catalyze the free radical-generating Fenton reaction. The ability of 2-ACP to reduce IRI when injected prior to ischemia most likely reflects the short duration of this experimental phase (45 minutes) and favorable pharmacokinetics that maintain effective 2-ACP liver concentrations during subsequent reperfusion. These results provide evidence that 2-ACP or an analog might be useful in treating IRI and other conditions that have oxidative stress as a common molecular etiology.

Interventional pain management in the palliative care patient.

For the majority of patients, cancer pain can be treated using the World Health Organization cancer pain guidelines; however, for 10-20% of patients with advanced cancer, adequate pain control cannot be achieved using these methods owing to disease pathophysiology preventing administration/absorption of pain medications or intolerance due to opioid toxicities. The need to expand analgesic treatment when oral, transdermal, and intravenous therapies fail requires exploration of interventional pain management techniques such as neuraxial (e.g. epidural and intrathecal) infusion therapies and neurolytic interventions. Nurses caring for patients with cancer pain should develop their knowledge of these multimodal approaches to cancer pain management.

A mechanism-based combination therapy reduces local tumor growth and metastasis in an orthotopic model of prostate cancer.

Therapy-induced stimulation of angiogenic molecules can promote tumor angiogenesis leading to enhanced tumor growth and cancer metastasis. Several standard and emerging therapies, such as radiation and photodynamic therapy (PDT), can induce angiogenic molecules, thus limiting their effectiveness. PDT is approved for the treatment of several cancers; however, its induction of vascular endothelial growth factor (VEGF) creates conditions favorable to enhanced tumor growth and metastasis, therefore mitigating its cytotoxic and antivascular effects. This is the first report showing that subcurative PDT in an orthotopic model of prostate cancer (LNCaP) increases not only VEGF secretion (2.1-fold) but also the fraction of animals with lymph node metastases. PDT followed by administration of an antiangiogenic agent, TNP-470, abolished this increase and reduced local tumor growth. On the other hand, administration of TNP-470 before PDT was less effective at local tumor control. In addition, animals in all groups, except in the PDT + TNP-470 group, had a weight loss of >3 g at the time of sacrifice; the weight of the animals in the PDT + TNP-470 group did not change. The significant reduction (P < 0.05) in tumor weight and volume observed between the PDT + TNP-470 group and the control group suggests that the combination of PDT and antiangiogenic treatment administered in the appropriate sequence was not only more effective at controlling local tumor growth and metastases but also reduced disease-related toxicities. Such molecular response-based combinations merit further investigations as they enhance both monotherapies and lead to improved treatment outcomes.

A Randomized Comparison of Pain Control and Functional Mobility between Proximal and Distal Adductor Canal Blocks for Total Knee Replacement.

BACKGROUND: Adductor canal blocks (ACBs) have become a popular technique for postoperative pain control in total knee arthroplasty patients. Proximal and distal ACB have been compared previously, but important postoperative outcomes have yet to be assessed. AIMS: The primary objective of this study is to compare postoperative analgesia between proximal and distal ACB. Secondary outcomes include functional mobility, length of stay (LOS), and adverse events. SETTINGS AND DESIGN: This study was a single-center, assessor-blinded, randomized trial. SUBJECTS AND METHODS: Fifty-seven patients were randomly assigned to receive a proximal (n = 28) or distal (n = 29) ACB. A 20 mL bolus of 5 mg/mL ropivacaine was injected at the respective location followed by 2.0 mg/mL ropivacaine infusion for 24 h. STATISTICAL ANALYSIS: The primary outcome was intra- and postoperative 24-h opioid consumption in intravenous (IV) morphine equivalents. Secondary outcomes include percentage change in timed "Up and Go" (TUG) times, LOS, and average postoperative pain scores. Continuous variables were compared using Student's t-test. RESULTS: The mean (±standard deviation) 24-h intra-and postoperative opioid consumption showed no difference between the proximal and distal groups (39.72 ± 23.6 and 41.28 ± 19.6 mg IV morphine equivalents, respectively, P = 0.793). There was also no significant difference in the median [minimum, maximum] percentage change in TUG times relative to preoperative performance comparing proximal and distal ACB (334.0 [131, 1084] %-change and 458.5 [169, 1696] %-change, respectively, P = 0.130). In addition, there were no differences in postoperative pain scores or LOS. CONCLUSIONS: ACB performed at either proximal or distal locations shows no difference in postoperative pain measured by opioid consumption or pain scores. Better TUG performance seen in the proximal group was not statistically significant but might represent a clinically important difference in functional mobility.

[Lumbar discogenic pain. Disk degeneration and minimally invasive interventional therapies]. / Lumbaler diskogener Schmerz. Bandscheibendegeneration und minimalinvasive Therapie.

Discogenic pain has been responsible for a countless number of missed workdays and millions if not billions of dollars of lost revenue. Minimally invasive interventional therapies of the discogenic back pain gained significant acceptance among the proceduralists. The centuries old dilemma of discogenic low back pain has by no means been answered. We know today that discogenic low back pain has a multitude of causes. The leaking "chemical soup" within the nucleus pulposus is certainly responsible for causing inflammation and thus pain. However, neuropeptides released from peripheral endings of nociceptive afferents are also inflammatory mediators and pain generators. The nerves innervating the discs have been identified and in many cases denervated with good results. These nerves from posterior to anterior include the sinuvertebral nerve, the rami communicantes, and the sympathetic trunk. Diagnosing discogenic low back pain is the key to successful treatment. Classically this should be a low back pain in a "band-like" distribution without radiculopathy that is worse in the morning, worse with Valsalva, and aggravated by standing in flexion. Provocative discography with manometric monitoring is essential in aiding the diagnosis. Once the diagnosis is confirmed, a multitude of invasive therapy may be offered including: L2 root sleeve blocks, intradiscal RFTC, RFTC of the rami communicantes, or Comparative data on the effectiveness of the above-mentioned procedures is lacking and may in fact be an excellent topic for future discussion.

The Anatomic Relationship of the Tibial Nerve to the Common Peroneal Nerve in the Popliteal Fossa: Implications for Selective Tibial Nerve Block in Total Knee Arthroplasty.

Background. A recently described selective tibial nerve block at the popliteal crease presents a viable alternative to sciatic nerve block for patients undergoing total knee arthroplasty. In this two-part investigation, we describe the effects of a tibial nerve block at the popliteal crease. Methods. In embalmed cadavers, after the ultrasound-guided dye injection the dissection revealed proximal spread of dye within the paraneural sheath. Consequentially, in the clinical study twenty patients scheduled for total knee arthroplasty received the ultrasound-guided selective tibial nerve block at the popliteal crease, which also resulted in proximal spread of local anesthetic. A sensorimotor exam was performed to monitor the effect on the peroneal nerve. Results. In the cadaver study, dye was observed to spread proximal in the paraneural sheath to reach the sciatic nerve. In the clinical observational study, local anesthetic was observed to spread a mean of 4.7 + 1.9 (SD) cm proximal to popliteal crease. A negative correlation was found between the excess spread of local anesthetic and bifurcation distance. Conclusions. There is significant proximal spread of local anesthetic following tibial nerve block at the popliteal crease with possibility of the undesirable motor blocks of the peroneal nerve.

Feasibility of spinal cord stimulation in a patient with a cardiac pacemaker.

OBJECTIVE: To report about the safe use of a spinal cord stimulator (SCS) and a permanent cardiac pacemaker (PPM). DESIGN: Open-label case report. CASE DESCRIPTION: A 75-year-old male with a history of diabetic polyneuropathy and a permanent pacemaker was followed for 6 months after implantation of a SCS. CONCLUSION: The simultaneous use of bipolar SCS in a patient with a PPM is not contraindicated. However, because false inhibition of a cardiac pacemaker may potentially lead to serious events, individual testing is mandatory to ascertain safety in each patient.

Is Genicular Nerve Radiofrequency Ablation Safe? A Literature Review and Anatomical Study.

Genicular nerve radiofrequency ablation (RFA) has recently gained popularity as an intervention for chronic knee pain in patients who have failed other conservative or surgical treatments. Long-term efficacy and adverse events are still largely unknown. Under fluoroscopic guidance, thermal RFA targets the lateral superior, medial superior, and medial inferior genicular nerves, which run in close proximity to the genicular arteries that play a crucial role in supplying the distal femur, knee joint, meniscus, and patella. RFA targets nerves by relying on bony landmarks, but fails to provide visualization of vascular structures. Although vascular injuries after genicular nerve RFA have not been reported, genicular vascular complications are well documented in the surgical literature. This article describes the anatomy, including detailed cadaveric dissections and schematic drawings, of the genicular neurovascular bundle. The present investigation also included a comprehensive literature review of genicular vascular injuries involving those arteries which lie near the targets of genicular nerve RFA. These adverse vascular events are documented in the literature as case reports. Of the 27 cases analyzed, 25.9% (7/27) involved the lateral superior genicular artery, 40.7% (11/27) involved the medial superior genicular artery, and 33.3% (9/27) involved the medial inferior genicular artery. Most often, these vascular injuries result in the formation of pseudoaneurysm, arteriovenous fistula (AVF), hemarthrosis, and/or osteonecrosis of the patella. Although rare, these complications carry significant morbidities. Based on the detailed dissections and review of the literature, our investigation suggests that vascular injury is a possible risk of genicular RFA. Lastly, recommendations are offered to minimize potential iatrogenic complications.

Intrathecal analgesia: time to consider it for your patient?

When systemic analgesics or antispasmodics fail to control chronic pain or cause intolerable adverse effects, an intrathecal drug delivery system may be the best bet.

Resolution of long standing tinnitus following radiofrequency ablation of C2-C3 medial branches--a case report.

Tinnitus is described as an auditory phantom perception analogous to central neuropathic pain. Despite the high prevalence of this debilitating symptom, no intervention is recognized that reliably eliminates tinnitus symptoms; a cause has yet to be determined. A 65-year-old healthy man presented with a 3 year history of left-sided tinnitus. Full workup performed by the primary care physician including blood tests for electrolyte imbalance, consultations by 2 independent otholaryngologists, and imaging did not reveal abnormalities to provide etiology of the tinnitus. No other complaints were noted except for occasional minimal left sided neck pain. Cervical spine x-ray showed degenerative changes with facet hypertrophy more pronounced on the left side. Subsequently, the patient underwent diagnostic left-sided C2-C3 medial branch block, resulting in complete resolution of tinnitus for more than 6 hours. After successful radiofrequency ablation of left C2-C3 medial branches, the patient became asymptomatic. At one year follow-up, he continued to be symptom free. Sparce studies have shown interaction between the somatosensory and auditory system at dorsal cochlear nucleus (DCN), inferior colliculus, and parietal association areas. Upper cervical nerve (C2) electrical stimulation evokes potentials in the DCN, eliciting strong patterns of inhibition and weak excitation of the DCN principal cells. New evidence demonstrated successful transcutaneous electrical nerve stimulation (TENS) of upper cervical nerve (C2) for treatment of somatic tinnitus in 240 patients. This case indicates that C2-C3 facet arthropathy may cause tinnitus and radiofrequency ablation of C2-C3 medial branches can provide an effective approach not previously considered.

Timing of neuraxial pain interventions following blood patch for post dural puncture headache.

Post dural puncture headache (PDPH) is a common complication of interventional neuraxial procedures. Larger needle gauge, younger patients, low body mass index, women (especially pregnant women), and "traumatic" needle types are all associated with a higher incidence of PDPH. Currently, an epidural blood patch is the gold-standard treatment for this complication. However, despite the high PDPH cure rate through the use of this therapy, little is known about the physiology behind the success of the epidural blood patch, specifically, the time course of patch formation within the epidural space or how long it takes for the blood patch volume to be resorbed by the body. Of the many unanswered and debated topics related to PDPH and epidural blood patches, one additional specific question that may alter clinical management is when it is safe for patients who have experienced a disruption of the thecal space and have undergone this procedure to have a subsequent epidural or spinal procedure, such as a neuraxial anesthetic (i.e. a spinal anesthetic for an elective outpatient procedure) or an interventional pain procedure for chronic pain management. This question becomes more unclear if the new procedure includes a steroid medication. As an example, an older patient presents with a history of lumbar disc disease and during lumbar epidural steroid injection, an inadvertent wet tap occurs leading to PDPH. Following management with fluids, caffeine, medications, and a successful epidural blood patch, it remains unclear as to when would be the best time frame to consider a second lumbar epidural steroid injection. We identified the 3 main risk factors of subsequent interventional neuraxial procedures as (1) disruption of the epidural blood patch and ongoing reparative processes, (2) epidural procedure failure, and (3) infection. We looked at the literature, and summarized the existing literature in order to enable health care professionals to understand the time course of dural repair as well as the risks of subsequent neuraxial procedures after epidural blood patches. This review poses the question using an evidence based review to discuss the appropriate time course to proceed.

Intravenous infusions in chronic pain management.

In the United States, millions of Americans are affected by chronic pain, which adds heavily to national rates of morbidity, mortality, and disability, with an ever-increasing prevalence. According to a 2011 report titled Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research by the Institute of Medicine of the National Academies, pain not only exacts its toll on people's lives but also on the economy with an estimated annual economic cost of at least $560 - 635 billion in health care costs and the cost of lost productivity attributed to chronic pain. Intravenous infusions of certain pharmacologic agents have been known to provide substantial pain relief in patients with various chronic painful conditions. Some of these infusions are better, and although not necessarily the first therapeutic choice, have been widely used and extensively studied. The others show promise, however are in need of further investigations. This article will focus on non-opiate intravenous infusions that have been utilized for chronic painful disorders such as fibromyalgia, neuropathic pain, phantom limb pain, post-herpetic neuralgia, complex regional pain syndromes (CRPS), diabetic neuropathy, and central pain related to stroke or spinal cord injuries. The management of patients with chronic pain conditions is challenging and continues to evolve as new treatment modalities are explored and tested. The following intravenous infusions used to treat the aforementioned chronic pain conditions will be reviewed: lidocaine, ketamine, phentolamine, dexmedetomidine, and bisphosphonates. This overview is intended to familiarize the practitioner with the variety of infusions for patients with chronic pain. It will not, however, be able to provide guidelines for their use due to the lack of sufficient evidence.