Exploiting multivalency and cooperativity of gold nanoparticles for binding phosphatidylinositol (3,4,5)-trisphosphate at sub-nanomolar concentrations.

Cationic, monolayer-protected gold nanoparticles provide a multivalent charged surface and a hydrophobic monolayer that synergistically contribute to the binding of phosphatidylinositol (3,4,5)-trisphosphate, a relevant biomarker. The observed dissociation constant is in the picomolar region, providing the possibility of using these gold nanoparticles for the selective extraction of this molecule from biological fluids.

Evaluation of Lumbar Adhesiolysis Using a Radiofrequency Catheter During Epiduroscopy in the Treatment of Failed Back Surgery Syndrome (FBSS).

Failed back surgery syndrome (FBSS) is a complication of spinal surgery that results in severe and disabling back/leg pain. Epiduroscopy is a percutaneous minimally invasive surgical technique used in the treatment of lumbar radicular pain that enables both direct visualization of epidural adhesions in patients with FBSS and the mechanical release of fibrotic scars in the epidural space. Although the use of a balloon catheter during epiduroscopy can usually remove adhesions between the dura and the vertebrae, in the thickest areas of fibrosis, the use of a catheter with a molecular quantum resonance radiofrequency generator may resect hard epidural fibrotic obstructions. The aim of this study was to evaluate the efficacy and safety of this radiofrequency catheter in the treatment of severe epidural fibrotic scars. Ninety-three patients with FBSS were enrolled in this study. In 49 cases, a thick area of fibrosis was visualized during epiduroscopy and the use of a balloon catheter could not remove the fibrotic scars. In all of these cases, we used a molecular quantum resonance radiofrequency catheter to remove dense fibrotic areas. Intraoperatively during epiduroscopy, we could directly visualize lysis of the fibrotic scars. Immediately after the procedure and at 1-month and 6-month follow-up, the patients reported significant pain reduction. Pain reduction and patient satisfaction were also reported at 12 months in all but 5 cases. This study found a clinically relevant reduction of pain at 1 and 6 months after epiduroscopy in patients with FBSS. The use of a radiofrequency catheter is safe and effective in resection of hard and thick epidural scars.

Cadaveric Model Simulations for Training in Ultrasound-Guided Percutaneous Placement of a Novel Peripheral Nerve Stimulation Electrode.

Peripheral nerve stimulation (PNS) electrodes are used to treat intractable painful conditions involving peripheral nerves. Methods for performing PNS continue to evolve, from open surgical to minimally invasive placement of electrodes. A PNS system consisting of subcutaneously implanted leads with an integrated anchor and electrodes, and an external pulse generator to produce peripheral neuromodulation, is now available for use in the clinical setting. This novel system allows either surgical or percutaneous lead positioning, and avoids the use of long leads or extensions crossing the joints, which are exposed to mechanical stress and damage. To identify methods for successfully inserting these electrodes, we investigated if a cadaver model could be an effective educational tool for teaching PNS electrode placement using ultrasound guidance. Six cadavers were studied in an attempt to find an ideal approach for ultrasound-guided electrode placement into the upper and lower extremities and cervical spine, and to describe the unique anatomy of the peripheral nerves relative to percutaneous stimulation-electrode placement. The use of cadaveric model simulations offers opportunities to practice percutaneous placement of PNS electrodes under stress-free conditions without patient discomfort, to acquire skill and confidence in performing these surgical approaches. Ultrasound-guided percutaneous placement of PNS electrodes should be learned in a simulation laboratory before such placement is performed in actual patients.

Factors Predicting Successful Outcome for Ozone Chemonucleolysis in Lumbar Disk Herniation.

OBJECTIVES: The aim of this study was to retrospectively investigate factors predicting a successful outcome after ozone chemonucleolysis (OCN) in patients with radicular pain and poor response to conservative treatments. METHODS: Univariable and multivariable logistic regression analysis was used to identify the predictors of good outcome after OCN. Good outcome was defined as 33% Oswestry Disability Index (ODI) reduction (model 1) or 13-point ODI improvement (model 2) at 1 month after OCN. RESULTS: Two hundred seventy-three patients were analyzed. A significant pain reduction (pre-operative Numerical Rating Scale [NRS] 6.7 ± 1.5, postoperative NRS 2.6 ± 2.2, P < 0.0001) and ODI improvement (pre-operative ODI 39 ± 13.7, postoperative ODI 21.4 ± 13.8, P < 0.0001) was obtained 1 month after OCN. Pain duration (< 1 year), type of disk herniation based on Michigan State University classification (MSU), stages of disk degeneration revealed by discogram and absence of foraminal stenosis (bony or ligament flavum hypertrophy) appeared as predictors of successful outcome. Age, gender, previous spine surgery, level site of disk herniation, presence of uncontained lumbar disk herniation, and vertebral Modic changes were not statistically associated with the outcome. Both the models showed a good accuracy (model 1, area under the curve [AUC] = 0.84 ± 0.027, 95% confidence interval [CI] = 0.79 to 0.89; model 2, AUC = 0.86 ± 0.024, 95% CI = 0.81 to 0.91). CONCLUSIONS: OCN is an effective treatment for radicular pain due to disk herniation. Pain duration (< 1 year), MSU disk herniation type (1A, 1B, 1C, 2A, and 2B), disk degeneration grade 2, and absence of foraminal stenosis are all associated with the successful outcome and should be carefully evaluated before OCN.

Novel morpholine scaffolds as selective dopamine (DA) D3 receptor antagonists.

A new series of morpholine derivatives has been identified as selective DA D3 receptor antagonists; their in vitro profile and pharmacokinetic data are provided.

1,2,4-Triazolyl octahydropyrrolo[2,3-b]pyrroles: A new series of potent and selective dopamine D3 receptor antagonists.

A novel series of 1,2,4-triazolyl octahydropyrrolo[2,3-b]pyrroles showing high affinity and selectivity at the DA D3 receptor is reported here. Compounds endowed with high selectivity over the hERG channel were identified and their pharmacokinetic properties thoroughly analyzed. A few derivatives with appropriate developability characteristics were selected for further studies and progression along the screening cascade. In particular, derivative 60a, (DA D3 pKi=8.4, DA D2 pKi=6.0 and hERG fpKi=5.2) showed a balanced profile and further refinements are in progress around this molecule.

Radiation Exposure during Fluoroscopy-Guided Ozone Chemonucleolysis for Lumbar Disc Herniation.

Introduction: Radiation exposure is a frequent drawback of spinal surgery, even if X-ray guidance plays a pivotal role in improving the accuracy and safety of spinal procedures. Consequently, radiation protection is essential to reduce potential negative biological effects. The aim of this study was to evaluate patients' radiation exposure, the radiation dose emission during fluoroscopy-guided ozone chemonucleolysis (OCN), and the potential role of patient characteristics. Methods: The radiation dose emission reports were retrospectively evaluated in patients who underwent single-level OCN for lumbar disc herniation. A generalized linear model (GLM) with a gamma distribution and log link function was used to assess the association between radiation emission and patients' characteristics such as age, sex, BMI, level of disc herniation, disc height, and site of disc herniation. Results: Two hundred and forty OCN cases were analyzed. A safe and low level of radiation exposure was registered during OCN. The median fluoroscopy time for OCN was 26.3 (19.4−35.9) seconds, the median radiation emission dose was 19.3 (13.2−27.3) mGy, and he median kerma area product (KAP) was 0.46 (0.33−0.68) mGy ⋅ m2. The resulting KAP values were highly dependent on patient variables. In particular, sex, obesity, and residual disc height < 50% significantly increased the measured KAP, while levels of disc herniations other than L5-S1 reduced the KAP values. Conclusions: The radiation exposure during OCN is low and quite similar to a simple discography. However, patient characteristics are significantly related to radiation exposure and should be carefully evaluated before planning OCN.

1-Heteroaryl-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane: further insights into a class of triple re-uptake inhibitors.

Further exploration around the recently disclosed potent triple re-uptake inhibitor 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane led to the identification of a new series of potent triple re-uptake inhibitors endowed with good developability characteristics. The insertion of a further aryl moiety into the template allowed the 'titration' of the SERT/NET/DAT ratio leading to the identification of further tools in this important area.

Food for Special Medical Purposes and Nutraceuticals for Pain: A Narrative Review.

INTRODUCTION: The present paper focuses on the possible contribution of food compounds to alleviate symptomatic pains. Chronic pain can more easily be linked to anticipatory signals such as thirst and hunger than it is to sensory perceptions as its chronicity makes it fall under the behavioural category rather than it does senses. In fact, pain often negatively affects one's normal feeding behavioural patterns, both directly and indirectly, as it is associated with pain or because of its prostrating effects. NUTRITIONAL COMPOUNDS FOR PAIN: Several nutraceuticals and Foods for Special Medical Purposes (FSMPs) are reported to have significant pain relief efficacy with multiple antioxidant and anti-inflammatory properties. Apart from the aforementioned properties, amino acids, fatty acids, trace elements and vitamins may have a role in the modulation of pain signals to and within the nervous system. CONCLUSION: In our opinion, this review could be of great interest to clinicians, as it offers a complementary perspective in the management of pain. Trials with well-defined patient and symptoms selection and a robust pharmacological design are pivotal points to let these promising compounds become better accepted by the medical community.

Prediction of 28-day mortality in critically ill patients with COVID-19: Development and internal validation of a clinical prediction model.

BACKGROUND: COVID-19 pandemic has rapidly required a high demand of hospitalization and an increased number of intensive care units (ICUs) admission. Therefore, it became mandatory to develop prognostic models to evaluate critical COVID-19 patients. MATERIALS AND METHODS: We retrospectively evaluate a cohort of consecutive COVID-19 critically ill patients admitted to ICU with a confirmed diagnosis of SARS-CoV-2 pneumonia. A multivariable Cox regression model including demographic, clinical and laboratory findings was developed to assess the predictive value of these variables. Internal validation was performed using the bootstrap resampling technique. The model's discriminatory ability was assessed with Harrell's C-statistic and the goodness-of-fit was evaluated with calibration plot. RESULTS: 242 patients were included [median age, 64 years (56-71 IQR), 196 (81%) males]. Hypertension was the most common comorbidity (46.7%), followed by diabetes (15.3%) and heart disease (14.5%). Eighty-five patients (35.1%) died within 28 days after ICU admission and the median time from ICU admission to death was 11 days (IQR 6-18). In multivariable model after internal validation, age, obesity, procaltitonin, SOFA score and PaO2/FiO2 resulted as independent predictors of 28-day mortality. The C-statistic of the model showed a very good discriminatory capacity (0.82). CONCLUSIONS: We present the results of a multivariable prediction model for mortality of critically ill COVID-19 patients admitted to ICU. After adjustment for other factors, age, obesity, procalcitonin, SOFA and PaO2/FiO2 were independently associated with 28-day mortality in critically ill COVID-19 patients. The calibration plot revealed good agreements between the observed and expected probability of death.

A specific and direct comparison of the trifluoromethyl and pentafluoro sulfanyl groups on the selective dopamine D(3) antagonist 3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazol-3-yl]thio}propyl)-1-phenyl-3-azabicyclo[3.1.0]hexane template.

A direct and specific comparison of a trifluoromethyl group with the corresponding pentafluorosulfanyl group is made in terms of primary affinity and pharmacokinetic properties.

2-Methyl-3-furanyl-4H-1,2,4-triazol-3-ylthioamides: a new class of selective orexin 2 antagonists.

A new class of selective orexin 2 antagonist was identified among commercial products. Initial SAR was obtained using commercial derivatives only prior to starting ad hoc medicinal chemistry activities.

[3-azabicyclo[3.1.0]hex-1-yl]phenyl-benzenesulfonamides as selective dopamine D3 antagonists.

A new class of azabicyclo[3.1.0]benzenesulfonamides is presented as selective dopamine D3 antagonists together with SAR and selectivity data.

Pyrrolo[1,2-a]pyrazine and pyrazolo[1,5-a]pyrazine: novel, potent, and selective series of Vasopressin 1b receptor antagonists.

Novel series of pyrrole-pyrazinone and pyrazole-pyrazinone have been identified as potent and selective Vasopressin(1b) receptor antagonists. Exploration of the substitution pattern around the core of these templates allowed generation of compounds with high inhibitory potency at the Vasopressin(1b) receptor, including examples that showed good selectivity with respect to Vasopressin(1a), Vasopressin(2), and Oxytocin receptor subtypes.

Synthesis and pharmacological characterization of 5-phenyl-2-[2-(1-piperidinylcarbonyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-1-ones: a new class of Neuropeptide S antagonists.

A new class of selective NPS antagonist was developed starting from a commercially available product identified by screening activities. Experimental NMR observations and computational experiments allowed the discovery of a new class of derivatives. 5-Phenyl-2-[2-(1-piperidinylcarbonyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-1-one represents a new lead compound in the NPS antagonist field.

The identification of a selective dopamine D2 partial agonist, D3 antagonist displaying high levels of brain exposure.

The identification of a highly selective D(2) partial agonist, D(3) antagonist tool molecule which demonstrates high levels of brain exposure and selectivity against an extensive range of dopamine, serotonin, adrenergic, histamine, and muscarinic receptors is described.

Dopamine D3 receptor antagonists: the quest for a potentially selective PET ligand. Part one: lead identification.

The synthesis and SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported.

Dopamine D(3) receptor antagonists: The quest for a potentially selective PET ligand. Part two: Lead optimization.

The lead optimization process to identify new selective dopamine D(3) receptor antagonists is reported. DMPK parameters and binding data suggest that selective D(3) receptor antagonists as potential PET ligands might have been identified.

Dopamine D3 receptor antagonists: the quest for a potentially selective PET ligand. Part 3: Radiosynthesis and in vivo studies.

Compound 1 is a potent and selective antagonist of the dopamine D(3) receptor. With the aim of developing a carbon-11 labeled ligand for the dopamine D(3) receptor, 1 was selected as a potential PET probe. [(11)C]1 was obtained by palladium catalyzed cross coupling using [(11)C]cyanide and 4 with a specific activity of 55.5+/-25.9GBq/micromol (1.5+/-0.7Ci/micromol). [(11)C]1 was tested in porcine and non-human primate models to assess its potential as a radioligand for PET imaging of the dopamine D(3) receptor. We conclude that in both species and despite appropriate in vitro properties, [(11)C]1 does not show any specific signal for the dopamine D(3) receptor.

Development of novel multipotent compounds modulating endocannabinoid and dopaminergic systems.

Polypharmacology approaches may help the discovery of pharmacological tools for the study or the potential treatment of complex and multifactorial diseases as well as for addictions and also smoke cessation. In this frame, following our interest in the development of molecules able to modulate either the endocannabinoid or the dopaminergic system, and given the multiple and reciprocal interconnections between them, we decided to merge the pharmacophoric elements of some of our early leads for identifying new molecules as tools able to modulate both systems. We herein describe the synthesis and biological characterization of compounds 5a-j inspired by the structure of our potent and selective fatty acid amide hydrolase (FAAH) inhibitors (3a-c) and ligands of dopamine D2 or D3 receptor subtypes (4a,b). Notably, the majority of the new molecules showed a nanomolar potency of interaction with the targets of interest. The drug-likeliness of the developed compounds (5a-j) was investigated in silico while hERG affinity, selectivity profile (for some proteins of the endocannabinoid system), cytotoxicity profiles (on fibroblast and astrocytes), and mutagenicity (Ames test) were experimentally determined. Metabolic studies also served to complement the preliminary drug-likeliness profiling for compounds 3a and 5c. Interestingly, after assessing the lack of toxicity for the neuroblastoma cell line (IMR 32), we demonstrated a potential anti-inflammatory profile for 3a and 5c in the same cell line.