Adenosine A2A antagonists and Parkinson's disease.

Although there is no cure for Parkinson's disease (PD), there are several classes of medications with various mechanisms of action that can help improve the functionality of someone with PD. Dopamine derivatives are first line therapies for PD, hence dopamine receptor agonists (DAs) have been shown to improve functionality of symptoms in PD patients. The two main formulations of dopamine agonist medications in PD therapy are ergoline and non-ergoline derivatives. Additionally, it has been shown that PD can involve irregularities in other neurotransmitters, such as acetylcholine, norepinephrine, and serotonin, hence why non-dopaminergic medications are also vital in PD management. Examples include NMDA receptor antagonists, dopamine antagonists (i.e. neuroleptics), acetylcholine receptor antagonists, serotonin receptor 2A agonists, and adenosine A2 antagonists. In general, dopaminergic medications are the most effective in improving motor involvement with PD, whereas non-dopaminergic medications tend to focus on the non-motor involvement of PD. In this chapter, we will focus on the chemistry and medication background on dopaminergic vs non-dopaminergic therapy, with a focus of adenosine A2 antagonists at the end.

Cardioprotection for Anti-HER2 Therapy: Considerations for Primary Prevention and Use in Mildly Reduced Left Ventricular Ejection Fraction.

PURPOSE OF REVIEW: This review summarizes current HER2-targeted therapies and clinical studies that have investigated primary and secondary prevention of cardiac dysfunction for HER2 + breast cancer patients undergoing targeted therapy. RECENT FINDINGS: Primary and secondary prevention clinical trials highlight the importance of cardioprotective measures during HER2 + cancer treatment. Together, these studies suggest the safety of neurohormonal drugs, the importance for an individualized approach in starting cardiopreventive therapies, and the potential to expand HER2 + treatment options to patients with cardiac dysfunction. Cardiac dysfunction is a concerning adverse effect for HER2-targeted treatment. The goal of primary and secondary prevention is to prevent (further) cardiac function decline and heart failure symptoms, while delivering appropriate cancer therapy. Clinical trials investigating preventative therapies in the context of primary and secondary prevention are paving the path for reducing adverse cardiac effects and expanding treatment options for patients previously unable to undergo HER + therapy.

Cirq robotic arm-assisted transpedicular instrumentation with intraoperative navigation: technical note and case series with 714 thoracolumbar screws.

The Cirq is a surgeon-controlled robotic arm that provides a new technique for accurately placing transpedicular screws. This report aims to present a technical report and our experience with this new robotic arm combined with intraoperative navigation. Technique and workflow using the Cirq robotic arm with intraoperative navigation is described. A retrospective review was conducted of all patients undergoing elective open thoracic/lumbar fusion surgery by a single surgeon in the first year of using the novel Cirq robotic arm. Descriptive analysis of patient and operative variables was performed. A total of 84 patients underwent placement of a total 714 transpedicular screws using the Cirq robotic arm. Most (69.1%) underwent 3-6 level fusion procedures. Mean operative time was 198 min total and 28 min when adjusted per screw. There was a learning curve with operative time per screw decreasing from 32 to 25 min from the first to second half of cases (p = 0.057). There were no intraoperative screw revisions and 2.4% (2/84) required instrumentation revision and return to the operating room. The Cirq robotic arm is seamlessly incorporated into the workflow of a transpedicular fusion. Our experience with over 700 pedicle screw placements using the Cirq robot demonstrates efficacy and safety although further comparative studies are needed.

Drug Repurposing for Glioblastoma and Current Advances in Drug Delivery-A Comprehensive Review of the Literature.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with an extremely poor prognosis. There is a dire need to develop effective therapeutics to overcome the intrinsic and acquired resistance of GBM to current therapies. The process of developing novel anti-neoplastic drugs from bench to bedside can incur significant time and cost implications. Drug repurposing may help overcome that obstacle. A wide range of drugs that are already approved for clinical use for the treatment of other diseases have been found to target GBM-associated signaling pathways and are being repurposed for the treatment of GBM. While many of these drugs are undergoing pre-clinical testing, others are in the clinical trial phase. Since GBM stem cells (GSCs) have been found to be a main source of tumor recurrence after surgery, recent studies have also investigated whether repurposed drugs that target these pathways can be used to counteract tumor recurrence. While several repurposed drugs have shown significant efficacy against GBM cell lines, the blood-brain barrier (BBB) can limit the ability of many of these drugs to reach intratumoral therapeutic concentrations. Localized intracranial delivery may help to achieve therapeutic drug concentration at the site of tumor resection while simultaneously minimizing toxicity and side effects. These strategies can be considered while repurposing drugs for GBM.

Local delivery of cancer-cell glycolytic inhibitors in high-grade glioma.

BACKGROUND: 3-bromopyruvate (3-BrPA) and dichloroacetate (DCA) are inhibitors of cancer-cell specific aerobic glycolysis. Their application in glioma is limited by 3-BrPA's inability to cross the blood-brain-barrier and DCA's dose-limiting toxicity. The safety and efficacy of intracranial delivery of these compounds were assessed. METHODS: Cytotoxicity of 3-BrPA and DCA were analyzed in U87, 9L, and F98 glioma cell lines. 3-BrPA and DCA were incorporated into biodegradable pCPP:SA wafers, and the maximally tolerated dose was determined in F344 rats. Efficacies of the intracranial 3-BrPA wafer and DCA wafer were assessed in a rodent allograft model of high-grade glioma, both as a monotherapy and in combination with temozolomide (TMZ) and radiation therapy (XRT). RESULTS: 3-BrPA and DCA were found to have similar IC50 values across the 3 glioma cell lines. 5% 3-BrPA wafer-treated animals had significantly increased survival compared with controls (P = .0027). The median survival of rats with the 50% DCA wafer increased significantly compared with both the oral DCA group (P = .050) and the controls (P = .02). Rats implanted on day 0 with a 5% 3-BrPA wafer in combination with TMZ had significantly increased survival over either therapy alone. No statistical difference in survival was noted when the wafers were added to the combination therapy of TMZ and XRT, but the 5% 3-BrPA wafer given on day 0 in combination with TMZ and XRT resulted in long-term survivorship of 30%. CONCLUSION: Intracranial delivery of 3-BrPA and DCA polymer was safe and significantly increased survival in an animal model of glioma, a potential novel therapeutic approach. The combination of intracranial 3-BrPA and TMZ provided a synergistic effect.

Radiosensitization of malignant gliomas following intracranial delivery of paclitaxel biodegradable polymer microspheres.

OBJECT: The aim of this study was to demonstrate that paclitaxel could function as a radiosensitizer for malignant glioma in vitro and in vivo. METHODS: The radiosensitizing effect of paclitaxel was tested in vitro using the human U373MG and rat 9L glioma cell lines. Cell cycle arrest in response to paclitaxel exposure was quantified by flow cytometry. Cells were subsequently irradiated, and toxicity was measured using the clonogenic assay. In vivo studies were performed in Fischer 344 rats implanted with intracranial 9L gliosarcoma. Rats were treated with control polymer implants, paclitaxel controlled-release polymers, radiotherapy, or a combination of the 2 treatments. The study end point was survival. RESULTS: Flow cytometry demonstrated G2-M arrest in both U373MG and 9L cells following 6-12 hours of paclitaxel exposure. The order in which the combination treatment was administered was significant. Exposure to radiation treatment (XRT) during the 6-12 hours after paclitaxel treatment resulted in a synergistic reduction in colony formation. This effect was greater than the effect from either treatment alone and was also greater than the effect of radiation exposure followed by paclitaxel. Rats bearing 9L gliosarcoma tumors treated with paclitaxel polymer administration followed by single-fraction radiotherapy demonstrated a synergistic improvement in survival compared with any other treatment, including radiotherapy followed by paclitaxel treatment. Median survival for control animals was 13 days; for those treated with paclitaxel alone, 21 days; for those treated with XRT alone, 21 days; for those treated with XRT followed by paclitaxel, 45 days; and for those treated with paclitaxel followed by XRT, more than 150 days (p < 0.0001). CONCLUSIONS: These results indicate that paclitaxel is an effective radiosensitizer for malignant gliomas because it renders glioma cells more sensitive to ionizing radiation by causing G2-M arrest, and induces a synergistic response to chemoradiotherapy.