Pharmacology/Drug Development

Implantable devices for localized and controlled drug release are important, e.g., for therapies of cancer and chronic pain. However, most of the existing active implants are limited by the usage of nonbiodegradable materials; thus, surgery is needed to extract them after the treatment, which leads to secondary damage. Here, we show a fully biodegradable composite membrane made from silk fibroin and magnetic nanoparticles (MNPs). The membrane porosity can be remotely modified by an alternating magnetic field, which opens nanopores by local heating of MNPs in the composite allowing a liquid to diffuse through them. The stability of the silk membrane in water can be prolonged up to several months by increasing its β-sheet content through ethanol annealing. We present the following original findings. (a) Nanopores can be generated inside the silk/MNP composite membrane by exposing it to an external alternating magnetic field. (b) A longer exposure time results in more nanopore sites. (c) The controllable release of rhodamine B dye is achieved by tuning the period of exposure to the magnetic field. The obtained results demonstrate the suitability of the investigated silk/MNP composite membrane as a potential functional material for implantable drug delivery.

Chemotherapy-induced peripheral neuropathy is a debilitating pain syndrome produced as a side effect of antineoplastic drugs like paclitaxel. Despite efforts, the currently available therapeutics suffer from serious drawbacks like unwanted side effects, poor efficacy and provide only symptomatic relief. Hence, there is a need to find new therapeutic alternatives for the treatment of Chemotherapy-induced peripheral neuropathy.

The combination of cross-linked hyaluronate (cHA) and corticosteroid showed more rapid pain or functional improvement in knee osteoarthritis and adhesive capsulitis. However, rare evidence of this combination in treating tendinopathy has been reported. We hypothesized that the specific formulations of cHA and dexamethasone (DEX) conferred amelioration of tendinopathy via anti-apoptosis and anti-senescence. In this controlled laboratory study, primary tenocytes from the human tendinopathic long head of biceps were treated with three cHA formulations (cHA:linealized HA = 80:20, 50:50, and 20:80) + DEX with or without IL-1β stimulation. Cell viability, inflammatory cytokines, tendon-related proliferation markers, matrix metalloproteinases (MMPs), senescent markers, and apoptosis were examined. The in vivo therapeutic effects of the selected cHA + DEX combinations were evaluated in a collagenase-induced rat patellar tendinopathy model. The expression levels of inflammatory mediators, including IL-1β, IL-6, COX-2, MMP-1, and MMP-3 were significantly reduced in all cHA + DEX-treated tenocytes ( < 0.05, all). The cHA (50:50) + DEX and cHA (20:80) + DEX combinations protected tenocytes from cytotoxicity, senescence, and apoptosis induced by DEX in either IL-1β stimulation or none. Furthermore, the two combinations significantly improved the rat experimental tendinopathy by reducing ultrasound feature scores and histological scores as well as the levels of apoptosis, senescence, and senescence-associated secretory phenotypes ( < 0.05, all). We identified two specific cHA formulations (cHA (50:50) and cHA (20:80)) + DEX that could ameliorate tendinopathy through anti-senescence and -apoptosis without cytotoxicity. This study provides a possible approach to treating tendinopathy using the combination of two well-known agents.

The widespread use of opioid drugs has contributed to escalating rates of addiction, overdoses, and drug-related deaths. Targeted urine drug screening plays an important role in supporting the care of patients with chronic pain or addiction. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) can provide excellent sensitivity and specificity, and, as a result, remains the definitive choice for confirmatory urine drug testing. However, the complexities of LC-MS/MS operation present major challenges to the clinical laboratory. In this study, we leveraged upgraded instrumentation to develop and validate a simplified "dilute-and-shoot" LC-MS/MS opioid assay. By modifying the chromatographic gradient, isobaric interferences were well-resolved and eliminated. Analytical ranges were expanded by utilizing alternative mass transitions, and updated quality assurance parameters were established. Results from 204 clinical samples correlated well between the new method and a previous version. The upgraded systems provided better sensitivity, greater dynamic ranges, and the new method reduced carryover, which enabled us to eliminate extra injections and chromatogram reviews. The new method also reduced turnaround time and doubled testing capacity. These improvements could serve as a model for other laboratories approaching a similar transition in mass spectrometric instrumentation.

Osteoarthritis is one of the foremost disabling disorders in the world. There is no definitive treatment to prevent the progression of osteoarthritis. Hence, palliative treatment aims at minimizing pain, disability and improving function, performance and quality of life. Oral administration of nonsteroidal anti-inflammatory drug is associated with number of adverse effects and reduced therapeutic efficacy. Intra-articular injection has been the preferred route of drug administration. However, the clearance of drug from the arthritic site, risk of infections, cost and the pain associated with frequent injections make this route highly non-compliant to patients. Since osteoarthritis is a chronic condition which requires treatment for prolonged duration, there is an urgent need for another administration route which circumvents the hindrances linked with intra-articular route. Transdermal route across the skin locally at the osteoarthritis site could help in surpassing the disadvantages associated with intra-articular route. However, traversing skin barrier and reaching the chondrocytes with sufficient amount of the drug is extremely difficult. Nanocarrier-based approaches could hold an answer to the said shortcomings owing to their reduced size, targeting tunability and site specificity. In this article, we discuss the pathophysiology of osteoarthritis, molecular targets, and utilization of nanocarrier-based approaches to strategize the treatment of osteoarthritis in a new direction, i.e. topical delivery of nanocarriers in osteoarthritis.

This study examines changes in utilization and costs trends associated with migraine medications.

Patients with injury may be at high risk of long-term opioid use due to the specific features of injury (e.g., injury severity), as well as patient, treatment, and provider characteristics that may influence their injury-related pain management.

Messenger RNA (mRNA) is an emerging drug modality for protein replacement therapy. As mRNA efficiently provides protein expression in post-mitotic cells without the risk of insertional mutagenesis, direct delivery of mRNA can be applied, not only as an alternative to gene therapy, but also for various common diseases such as osteoarthritis (OA). In this study, using an mRNA-encoding interleukin-1 receptor antagonist (IL-1Ra), we attempted anti-inflammatory therapy in a rat model of the temporomandibular joint (TMJ) OA, which causes long-lasting joint pain with chronic inflammation. For the intra-articular injection of mRNA, a polyplex nanomicelle, our original polymer-based carrier, was used to offer the advantage of excellent tissue penetration with few immunogenic responses. While the protein expression was transient, a single administration of IL-1Ra mRNA provided sustained pain relief and an inhibitory effect on OA progression for 4 weeks. The mRNA-loaded nanomicelles provided the encoded protein diffusely in the disc and articular cartilage without upregulation of the expression levels of the pro-inflammatory cytokines IL-6 and tumor necrosis factor-α (TNF-α). This proof-of-concept study demonstrates how anti-inflammatory proteins delivered by mRNA delivery using a polyplex nanomicelle could act to alleviate OA, stimulating the development of mRNA therapeutics.

The strongly encourages the use of pharmaceutical-grade chemicals and analgesics. Sustained-release buprenorphine (SRB) is administered extralabel to rodents to mitigate moderate to severe pain. An FDA indexed buprenorphine formulation-extended-release buprenorphine (XRB)-has recently become available and is currently the only pharmaceutical-grade slow-release buprenorphine formulation approved for use in mice and rats. However, no studies have directly compared the pharmacokinetic parameters of SRB and XRB in surgically catheterized mice. To this end, we compared the plasma buprenorphine concentrations and pharmacokinetic parameters of SRB and XRB in mice after surgical catheterization. We hypothesized that mice treated before surgery with SRB or XRB would have circulating buprenorphine concentrations that exceeded the therapeutic threshold for as long as 72 h after surgery. Male and female C57Bl/6J mice were anesthetized, treated with a single dose of either SRB (1 mg/kg SC) or XRB (3.25 mg/kg SC), and underwent surgical catheterization. Arterial blood samples were collected at 6, 24, 48, and 72 h after administration. Weight loss after surgery (mean ± SEM) was similar between groups (SRB: males, 12% ± 2%; females, 8% ± 2%; XRB: males, 12% ± 1%; females, 8% ± 1%). Both SRB and XRB maintained circulating buprenorphine concentrations above the therapeutic level of 1.0 ng/mL for 72 h after administration. Plasma buprenorphine concentrations at 6, 24, and 48 h were significantly greater (3- to 4-fold) with XRB than SRB, commensurate with XRB's higher dose. These results support the use of either SRB or XRB for the alleviation of postoperative pain in mice. The availability of FDA-indexed XRB increases options for safe and effective pharmaceutical-grade analgesia in rodents.