Identification of tetracycline combinations as EphB1 tyrosine kinase inhibitors for treatment of neuropathic pain.

Previous studies have demonstrated that the synaptic EphB1 receptor tyrosine kinase is a major mediator of neuropathic pain, suggesting that targeting the activity of this receptor might be a viable therapeutic option. Therefore, we set out to determine if any FDA-approved drugs can act as inhibitors of the EphB1 intracellular catalytic domain. An in silico screen was first used to identify a number of tetracycline antibiotics which demonstrated potential docking to the ATP-binding catalytic domain of EphB1. Kinase assays showed that demeclocycline, chlortetracycline, and minocycline inhibit EphB1 kinase activity at low micromolar concentrations. In addition, we cocrystallized chlortetracycline and EphB1 receptor, which confirmed its binding to the ATP-binding domain. Finally, in vivo administration of the three-tetracycline combination inhibited the phosphorylation of EphB1 in the brain, spinal cord, and dorsal root ganglion (DRG) and effectively blocked neuropathic pain in mice. These results indicate that demeclocycline, chlortetracycline, and minocycline can be repurposed for treatment of neuropathic pain and potentially for other indications that would benefit from inhibition of EphB1 receptor kinase activity.

Minimally-invasive pain management techniques in palliative care.

Pain is a common source of suffering for seriously ill patients. Typical first-line treatments consist of lifestyle modifications and medication therapy, including opioids. However, medical treatments often fail or are associated with limiting systemic toxicities, and more targeted interventional approaches are necessary. Herein, we present options for minimally invasive techniques for the alleviation of pain in palliative patients from a head-to-toe approach, with a focus on emerging therapies and advanced techniques. Head and neck: image-guided interventions targeted to sympathetic ganglia of the head and neck, such as sphenopalatine ganglion (SPG) and stellate ganglion, have been shown to be effective for some forms of sympathetically-maintained and visceral pain. Interventions targeting branches of cranial nerves and upper cervical nerves, such as the glossopharyngeal nerve (GPN), are options in treating somatic head and face pain. Abdominal and pelvic: sympathetic blocks, including celiac plexus, inferior hypogastric, and ganglion impar can relieve visceral abdominal and pelvic pain. Spine and somatic pain: fascial plane blocks of the chest and abdominal wall and myofascial trigger point injections can be used for somatic pain indications. Cementoplasties, such as kyphoplasty and vertebroplasty, are used for pain related to bony metastases and compression fractures. Tumor ablative techniques can also be used for lytic lesions of the bone. Spinal cord stimulation (SCS), intrathecal drug delivery systems (IDDS), and cordotomy have also been used successfully in patients requiring advanced options, such as those with significant spinal, ischemic, or visceral pain.

Complex regional pain syndrome type 1 predictors - Epidemiological perspective from a national database analysis.

OBJECTIVE: Complex regional pain syndrome type 1 is a disabling pain disorder with unclear etiology. It is usually triggered by an injury to a limb with or without specific nerve injury. The objective of this study is to explore the risk factors and predictors for this disease utilizing a large national database. DESIGN: Retrospective analysis of the Nationwide Inpatient Sample database from 2007 to 2011 in the United States. SETTING AND PATIENTS: Adult inpatients diagnosed with complex regional pain syndrome type 1. STATISTICAL ANALYSIS: Chi-square, simple and multivariate logistic regression analyses were conducted. The regression model was adjusted to the patient's demographics and comorbidities. MAIN RESULTS: There were 22,533 patients with the discharge diagnosis of complex regional pain syndrome type 1 of an inpatient sample of 33,406,123. It peaks between age 45 and 55. Female gender, Caucasian race, higher median household income, headache, depression, drug abuse and private insurance patients (vs Medicaid patients) were associated with higher rate of complex regional pain syndrome type 1. On the other hand, diabetes, obesity, hypothyroidism, and anemia were associated with a lower rate. CONCLUSIONS: Utilizing a large database, our study added more information to the risk profile of the complex regional pain syndrome type 1 in an inpatient population. Such information should be useful for physician for early recognition, diagnosis of patients at risk.

Anesthetic management for laser excision of recurrent respiratory papillomatosis in a third trimester parturient.

Recurrent respiratory papillomatosis (RRP) is characterized by the development of laryngeal papillomas, which can produce partial to complete upper airway obstruction. Patients with RRP often require intermittent surgical excision to treat symptoms such as hoarseness and stridor, and to control progression of the lesions. The anesthetic management of such patients is challenging, and it requires carefully coordinated care between an anesthesiologist and otolaryngologist. We present 2 cases of general anesthesia administration during surgical excision of laryngeal papillomas, both occurring during the third trimester of separate pregnancies in the same parturient. The complexity of management was amplified in these cases because of the physiological and anatomical changes associated with pregnancy, along with the need to monitor fetal well-being. Possible complications included complete airway obstruction, pulmonary aspiration of gastric contents, hypoxemia, fetal distress, and preterm labor. Because pregnancy may lead to activation of human papillomavirus, the causative organism of RRP, management guidelines are provided for anesthesiologists who may care for patients with RRP during pregnancy.

Outcomes of a preoperative "bridging" strategy with glycoprotein IIb/IIIa inhibitors to prevent perioperative stent thrombosis in patients with drug-eluting stents who undergo surgery necessitating interruption of thienopyridine administration.

AIMS: Surgery after drug-eluting stent (DES) implantation may be associated with increased risk for perioperative stent thrombosis (ST). METHODS AND RESULTS: We evaluated the outcomes of 67 patients who underwent non-cardiac (n=51) or cardiac (n=16) surgery after DES implantation at our institution between 2008 and 2010 and who underwent preoperative "bridging" with a glycoprotein IIb/IIIa inhibitor. Surgery occurred after a mean time of 13.9 ± 1.7 and 8.7 ± 2 months post stenting for non-cardiac (NCS) and cardiac surgery, respectively. Glycoprotein IIb/IIIa inhibitors were administered preoperatively for a mean of 7.1 ± 0.4 and 7.8 ± 0.7 days, respectively, then discontinued four to six hours before surgery. Most patients received aspirin through the perioperative period (33 NCS patients and 15 cardiac surgery patients). Clopidogrel was restarted as early as possible in the postoperative period. In the non-cardiac surgery group, two patients (3.9%, 95% confidence intervals 0.5% to 13.5%) suffered acute ST in the immediate postoperative period and four patients suffered major bleeding by the Global Utilisation of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) criteria. One cardiac surgery patient had probable ST one hour postoperatively. CONCLUSIONS: In spite of preoperative "bridging" with a glycoprotein IIb/IIIa inhibitor, postoperative stent thrombosis can still occur in patients with prior DES undergoing surgery requiring antiplatelet medication interruption.