Rejected

ACT-539313 is a potent and selective orexin-1 receptor antagonist. CYP3A is the major cytochrome P450 (CYP) enzyme involved in the metabolism and clearance of ACT-539313 in man. The main objective of this study was to investigate the effect of ACT-539313 on the pharmacokinetics of orally administered midazolam. Thereby, this single-center, open-label, fixed-sequence study investigated the CYP3A interaction potential of ACT-539313 following single- (on day 2) and repeated-dose (on day 11) twice-daily administration of 200 mg ACT-539313. Exposure to midazolam was higher during concomitant administration of single as well as after repeated doses of ACT-539313 over 10 days compared to midazolam alone (day 1). In the presence of ACT-539313, the geometric mean ratio of the maximum plasma concentration and the area under the plasma concentration-time curve from time 0 to 24 hours increased by 1.18- and 1.79-fold on day 2, and by 2.13- and 4.54-fold on day 11, respectively. A similar outcome was also shown in the additionally evaluated urinary 6β-hydroxycortisol/cortisol ratio (6β-CR), as the geometric mean ratio of the 6β-CR showed a decrease to 0.78 on day 2 and to 0.61 on day 11. The most commonly reported adverse events (AEs) included somnolence and headache. All AEs were transient and of mild intensity. No treatment-related effects on vital signs, clinical laboratory, and electrocardiogram were observed. In summary, the observed corresponding decrease of both the validated, exogenous (midazolam/1-hydroxymidazolam ratio) and a frequently used endogenous (6β-CR) marker of CYP3A activity is indicative of CYP3A inhibition occurring after ACT-539313 treatment.

Women with dysmenorrhea plus symptomatic urinary calculosis experience enhanced pain and referred muscle hyperalgesia from both conditions than women with one condition only (viscero-visceral hyperalgesia). The study aimed at verifying if enhanced dysmenorrhea persists after urinary stone elimination in comorbid women and if local anesthetic inactivation of myofascial trigger points (TrPs) in the lumbar area (of urinary pain referral) also relieves dysmenorrhea.

Suboptimal analgesia significantly increases postoperative stress and anxiety contributing to an overall adverse patients' experience. Effective pain control is particularly relevant to gynaecological surgery with more procedures performed in outpatient settings under local anaesthesia daily.

Among children with pharyngitis who test positive for group A Streptococcus (GAS), 10%-25% are GAS carriers. Current laboratory methods cannot distinguish acute infection from colonization.

The primary somatosensory cortex (S1) and the anterior cingulate cortex (ACC) are two most important brain regions encoding the sensory-discriminative and affective-emotional aspects of pain, respectively. However, the functional connectivity of these two areas during cortical pain processing remains unclear. Developing methods to dissect the functional connectivity and directed information flow between cortical pain circuits can reveal insight into neural mechanisms of pain perception.

Opioid use disorder (OUD) is associated with chronic pain. We investigated the association between medication treatments for OUD and pain in a post-hoc secondary analysis of a randomized trial of methadone versus buprenorphine/naloxone.

Aspirin, the acetylsalicylic acid (ASA), is the most widely used medication to relieve pain, fever, and inflammation. Recent studies have revealed new benefits of aspirin, including reduction of heart attack, stroke, anti-cancer, and life-extension. Despite the profound effects of aspirin, the mechanism of its action remains to be elucidated. Here, we used a deuterium-labeled aspirin (D-aspirin) together with mass spectrometry-based acetylomic analysis, termed "DAcMS", to investigate the landscape of protein acetylation induced by aspirin. The DAcMS revealed the acetylomes of LPS-induced inflammatory BV2 cells and colon cancer HCT116 cells. The acetylation level was substantially induced upon aspirin treatment in both cell lines. In total, we identified 17,003 acetylation sites on 4,623 proteins in BV2 cells and 16,366 acetylated sites corresponding to 4,702 acetylated proteins in HCT116 cells. Importantly, functional analyses of these aspirin-induced acetylated proteins suggested that they were highly enriched in many key biological categories, which function importantly in inflammatory response. We further demonstrated that aspirin acetylates proteins through both acetyl-CoA-dependent and -independent pathways, and the accessible lysine residues at the protein surface are major acetylation targets of aspirin. Hence, our study provides the comprehensive atlas of aspirin-induced acetylome under disease conditions. These knowledge proffers new insight into the aspirin-directed acetylome and perhaps new drug target sites relevant to human cancer and inflammatory diseases. The MS data of this study have been deposited under the accession number IPX0001923000 at iProX.

Urinary tract stones are common and usually painful. Lifetime prevalence is approximately 10%. Direct healthcare costs are estimated to be over $10 billion dollars annually. First-line treatment is typically analgesia with non-steroid anti-inflammatory drugs until the stone passes. If the stone does not pass spontaneously, urological intervention may be necessary.

Oral isotretinoin is commonly prescribed for acne vulgaris. Several case reports and observational studies have reported serious musculoskeletal side effects; however, the incidence, imaging findings, and longitudinal follow-up data are limited for patients who develop inflammatory back pain (IBP).

Kümmell's disease is a special type of osteoporotic vertebral fracture that causes chronic low back pain and deformity, which seriously affects the living quality of patients. PVP is commonly used to treat osteoporotic vertebral fractures and can quickly relieve low back pain. So, the objective of this study was to analyze the clinical efficacy and experience of bipedicular percutaneous vertebroplasty combined with postural reduction for the treatment of Kümmell's disease.