Pharmacology/Drug Development

To establish the prevalence of long-term and serious harms of medical cannabis for chronic pain.

Immunoglobulins (IG) are widely used for the treatment of a variety of immune-mediated diseases. The exact mechanism of action remains unknown, but IG modulate the expression and function of Fc receptors, interfere with complement activation and production of cytokines, neutralize pathogenic autoantibodies, and affect the activation and effector functions of B and T lymphocytes. Immunoglobulins are usually delivered intravenously, and are effective in ameliorating motor symptoms, and/or preventing disease progression in immune-mediated neuropathies, including Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy.

Persistent pain despite satisfactory disease treatment is frequent in rheumatoid arthritis (RA) and spondyloarthritis (Spa) and may result from specific changes in central pain processing. We assessed these mechanisms further, by systematically comparing thermal pain thresholds and conditioned pain modulation (CPM) between patients with active RA or Spa and healthy controls.We included 50 RA and 50 Spa patients and 100 age- and sex-matched controls. Heat and cold pain thresholds (HPT-CPT) were measured on the dominant forearm, and CPM was assessed by applying conditioning stimuli (immersion in a cold water bath) to one foot and the non-dominant hand in two successive randomized sequences. Descending pain modulation was assessed as the difference in HPT (in °C) before and after conditioning. Larger HPT differences (i.e. a larger CPM effect) reflected more efficient descending inhibition. Potential associations between changes in CPM and clinical data, including disease activity, pain intensity, psychological and functional variables, were systematically assessed.HPT and CPT were similar in patients and controls. Mean CPM effect was significantly weaker in patients than controls for conditioning applied to either the foot (0.25°C ±2.57 vs. 2.79°C ±2.31; p<0.001) or the non-dominant hand (0.57°C ±2.74 vs. 2.68°C ±2.12; p<0.001).The smaller CPM effect in patients was correlated with average pain intensity, but not with disease activity or other clinical characteristics, suggesting a significant pathophysiological role for changes in endogenous pain modulation in the mechanisms of chronic pain associated with inflammatory rheumatism.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans. Current AF antiarrhythmic drugs have limited efficacy and carry the risk of ventricular pro-arrhythmia. GsMTx4, a mechanosensitive channel (MSC)-selective inhibitor, has been shown to suppress arrhythmias through the inhibition of stretch-activated channels (SACs) in the heart. The cost of synthesizing this peptide is a major obstacle to clinical use. Here, we studied two types of short peptides derived from GsMTx4 for their effects on a stretch-activated big potassium (BK) channel (SAKcaC) from the heart. Type I, a 17-residue peptide (referred to as Pept 01), showed comparable efficacy, whereas type II (i.e. Pept 02), a 10-residue peptide, exerted even more potent inhibitory efficacy on SAKcaC compared to GsMTx4. We identified through mutagenesis important sequences required for peptide functions. Additionally, molecular dynamics (MD) simulations revealed common structural features with a hydrophobic head followed by a positively charged protrusion that may be involved in peptide-channel/lipid interactions. Furthermore, we suggest that these short peptides may inhibit SAKcaC through a specific modification to the mechano-gate, as the inhibitory effects for both types of peptides were mostly abolished when tested with a mechano-insensitive channel variant (STREX-del) and a non-mechanosensitive BK (mSlo1) channel. These findings may offer an opportunity for the development of a new class of drugs in the treatment of cardiac arrhythmia generated by excitatory SACs in the heart..

Rheumatoid arthritis (RA) severely threatens human health by causing inflammation, swelling, and pain in the joints and resulting in persistent synovitis and irreversible joint disability. In the development of RA, pro-inflammatory M1 macrophages, which express high levels of reactive oxygen species (ROS) and nitric oxide (NO), induce synovial inflammation and bone erosion. Eliminating ROS and NO in the inflamed joints is a potential RA therapeutic approach, which can drive the transition of pro-inflammatory M1 macrophages to the anti-inflammatory M2 phenotype. Taking advantage of the intrinsic ROS- and NO-scavenging capability of DNA molecules, herein, we report the development of folic acid-modified triangular DNA origami nanostructures (FA-tDONs) for targeted RA treatment. FA-tDONs could efficiently scavenge ROS and NO and actively target M1 macrophages, facilitating the M1-to-M2 transition and the recovery of associated cytokines and biomarkers to the normal level. The therapeutic efficacy of FA-tDONs was examined in the RA mouse model. As validated by appearance, histological, and serum examinations, FA-tDONs treatment effectively alleviated synovial infiltration and cartilage damage, attenuating disease progression. This study demonstrated the usage of DNA origami for RA treatment and suggested its potential in other antioxidant therapies.

Osteoarthritis (OA) is a chronic, painful, degenerative inflammatory disease of the synovial joints. Regular use of nonsteroidal anti-inflammatory drugs to decrease OA pain can have severe side effects, such as gastric irritation, ulcers, and heart problems. Natural products are extensively used to minimize OA-associated pain and inflammatory reactions. is commonly used to alleviate several diseases through its anti-inflammatory effects. This study examined the impact of extract on alleviating pain and inflammation associated with articular cartilage damage.

Peyronie's disease (PD) can be subdivided into acute and chronic phases. Intralesional collagenase has been shown to improve curvature in the chronic phase. Initial clinical trials excluded patients in the acute phase from treatment. Recent studies show comparable results among men in the acute phase. The definition of acute phase varies among existing studies, but it is generally understood to last 12-18 months and is accompanied by penile pain and progression of deformity. We sought to evaluate the safety and efficacy of intralesional collagenase injection therapy during the acute phase of PD using multiple definitions of the acute phase.

Surgery is a major risk factor for chronic opioid use among patients who had not recently been prescribed opioids. This study identifies the rate of, and risk factors for, persistent opioid use following laparoscopic cholecystectomy and open inguinal hernia repair in patients not recently prescribed opioids.

The most common presentation of cluneal neuropathy is ipsilateral low back and gluteal pain. Cluneal neuralgia has been described historically in surgical contexts, with much of the description and treatment related to entrapment and decompression, respectively. Treatment options for addressing axial low back pain have evolved with advancements in the field of interventional pain medicine, though clinical results remain inconsistent. Recent attention has turned toward peripheral nerve stimulation. Nonsurgical interventions targeting the superior and medial cluneal nerve branches have been performed in cases of low back and buttock pain, but there is no known review of the resulting evidence to support these practices.