Rejected

Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models can serve as a powerful framework for predicting the influence as well as the interaction of formulation, genetic polymorphism and co-medication on the pharmacokinetics and pharmacodynamics of drug substances. In this study, flurbiprofen, a potent non-steroid anti-inflammatory drug, was chosen as a model drug. Flurbiprofen has absolute bioavailability of ~95% and linear pharmacokinetics in the dose range of 50-300 mg. Its absorption is considered variable and complex, often associated with double peak phenomena, and its pharmacokinetics are characterized by high inter-subject variability, mainly due to its metabolism by the polymorphic CYP2C9 (fmCYP2C9 ≥ 0.71). In this study, by leveraging and data, an integrated PBPK/PD model with mechanistic absorption was developed and evaluated against clinical data from PK, PD, drug-drug and gene-drug interaction studies. The PBPK model successfully predicted (within 2-fold) 36 out of 38 observed concentration-time profiles of flurbiprofen as well as the CYP2C9 genetic effects after administration of different intravenous and oral dosage forms over a dose range of 40-300 mg in both Caucasian and Chinese healthy volunteers. All model predictions for C, AUC and CL/F were within two-fold of their respective mean or geometric mean values, while 90% of the predictions of C, 81% of the predictions of AUC and 74% of the predictions of Cl/F were within 1.25 fold. In addition, the drug-drug and drug-gene interactions were predicted within 1.5-fold of the observed interaction ratios (AUC, C ratios). The validated PBPK model was further expanded by linking it to an inhibitory model describing the analgesic efficacy of flurbiprofen and applying it to explore the effect of formulation and genetic polymorphisms on the onset and duration of pain relief. This comprehensive PBPK/PD analysis, along with a detailed translational biopharmaceutic framework including appropriately designed biorelevant experiments and extrapolation, provided mechanistic insight on the impact of formulation and genetic variations, two major determinants of the population variability, on the PK/PD of flurbiprofen. Clinically relevant specifications and potential dose adjustments were also proposed. Overall, the present work highlights the value of a translational PBPK/PD approach, tailored to target populations and genotypes, as an approach towards achieving personalized medicine.

There is a growing interest in the impact of body posture influences on outcome measures of cervicogenic headache (CGH).

Endometriosis is a gynocological disease characterized by the presence of the endometrial glands and stroma outside the uterine cavity. This disease affects %6-10 of women with reproductive age and it causes serious problems such as pelvic pain, dysmenorrhea and infertility. Although endometriosis is one of the most investigated disease of gynecology, its pathogenesis is not clear completely. In recent years, many studies revealed the inflammatory nature of endometriosis. Many of the immune cells and their secretory products cytokines and chemokines has been detected in body fluids of women with endometriosis. Cytokines are protein or glycoprotein in structures and hormon-like molecules that act generally in a paracrine fashion to regulate immun responses. They involved in chemotaxis, cell proliferation, cell activation, motility, adhesion and morphogenesis. Tumor necrosis factor alpha (TNF-α) is a proenflammatory cytokine secreted by the macrophages, monocytes, neutrophiles, T cells and natural killer cells. It stimulates increase in the level of the chemokines in body fluids. Monocyte chemotactic protein 2 (MCP-2) is a chemokine act to recruit and activate monocytes into sites of inflammation area. The aim of this study to investigate the ultrastructural properties and whether the expression and localization of TNF-α and MCP-2 in the eutopic endometrium (normal endometrium of women with endometriosis) and endometritic tissues of women with endometriosis. Eutopic endometrial and endometriotic tissue samples were obtained from the women with endometriosis range 20-41 years and normal endometrial tissues were collected from 5 women without endometriosis as a control group. Tissues were processed for light and electron microscopy and examined. The epithelial cells of endometriotic tissues were revealed strongly cytoplasmic TNFα and MCP-2 immunreactivities. Eutopic endometrial tissues were also stained prominently for both TNF-α and MCP-2. Furthermore, a significant increase in stromal macrophages cells were observed in endometriotic tissues. Moreover, the ultrastructural observations on the normal and endometriotic tissues were exhibited microvilli-rich cells and ciliated cells. These findings suggest that TNF-α and MCP-2 may be involved in normal endometrial biology and in the pathogenesis of endometriosis.

Few studies have examined associations between vascular compression and post-operative pain relief in patients undergoing microvascular decompression (MVD) for treatment of medically refractory Type 1 trigeminal neuralgia (T1TN). The authors sought to examine for associations between vascular compression and post-operative pain relief in order to determine the utility of pre-operative MRI in surgical decision making for TN.

Mexico is considered an ancestral center of diversity of Salvia species, however many of them lack scientific information. Salvia circinnata Cav. (syn. Salvia amarissima Ortega) is an endemic species used in traditional medicine to treat disorders attributed to a cold state like anxiety in the central nervous system, as well as gastrointestinal ailments and pain relief.

The Chinese traditional medicine of Siegesbeckia pubescens Makino (SM), which has the effect of healing rheumatism and promoting joint health, is often used to treat rheumatoid arthritis and ischemic stroke.

Mirogabalin is a novel, preferentially selective α2δ-1 ligand to treat neuropathic pain. However, this agent is not always effective for patients with neuropathic pain. We therefore attempted to identify factors that could predict the efficacy of mirogabalin. The study comprised 133 patients given mirogabalin for alleviation of neuropathic pain between April and November 2019 at our hospital. Variables were extracted from medical records for regression analysis of factors associated to alleviation of neuropathic pain. We evaluated the effect of mirogabalin at two weeks after administration. Groups were categorized according to degree of improvement: poor, effective, or very effective. Multivariate ordered logistic regression analysis was conducted to identify predictors for the usefulness of mirogabalin. Threshold measures were analysed using receiver operating characteristic (ROC) curves. Maintenance dose [odds ratio (OR) = 0.90; 95% confidence interval (CI) = 0.84-0.98; P = 0.01], concomitant use of opioids (OR = 0.26, 95% CI = 0.08-0.83; P = 0.023) and Neurotropin (NTP) (OR = 4.78, 95% CI =1.04-21.93; P = 0.044) were factors significantly correlated to the effect of mirogabalin. ROC curve analysis of the effective group indicated a threshold maintenance dose of≤ 20 mg/day (area under the curve [AUC] = 0.53). In conclusion, maintenance dose (≤ 20 mg), concomitant use of opioids and NTP were identified as predictors for the utility of mirogabalin.

Cutaneous lupus is an autoimmune disease that can be represented individually or as part of the systemic disease, systemic lupus erythematosus (SLE). Initial presentation of skin manifestations, such as chronic urticatia, should raise the possibility that it might be the first manifestation of an active disease, for example SLE. Despite the broad differential diagnosis of chronic urticaria, other plausible diagnosis should be ruled out with complete anamnesis that includes family background, substance exposure, new and chronic drug therapy, serological and immunological blood tests, diagnostic biopsy of the skin and imaging as needed to rule out malignancy. We present a case of a patient with a family history of various autoimmune diseases, who presented with chronic urticatia and joint pain with partial response to steroid therapy over a period of several months.

Gout is caused by monosodium urate crystal deposition in joints and tissues. Risk factors include male sex; obesity; hypertension; alcohol intake; diuretic use; a diet rich in meat and seafood; chronic kidney disease; a diet heavy in fructose-rich food and beverages; being a member of certain ethnic groups, including Taiwanese, Pacific Islander, and New Zealand Maori; and living in high-income countries. Gout is characterized by swelling, pain, or tenderness in a peripheral joint or bursa, including the development of a tophus. Diagnosis of gout can be made using several validated clinical prediction rules. Arthrocentesis should be performed when suspicion for an underlying septic joint is present; synovial fluid or tophus analysis should be performed if the diagnosis is uncertain. Colchicine, nonsteroidal anti-inflammatory drugs, and corticosteroids relieve pain in adults with acute gout episodes. Indications for long-term urate-lowering therapy include chronic kidney disease, two or more flare-ups per year, urolithiasis, the presence of tophus, chronic gouty arthritis, and joint damage. Allopurinol and febuxostat are used to prevent flare-ups, although febuxostat is associated with an increase in all-cause and cardiovascular mortality and is therefore not routinely recommended.

Pain is a frequent problem faced by emergency medical services (EMS) in pre-hospital settings. This large observational study aims to assess the prevalence of sufficiently provided analgesia and to analyze the efficacy of different analgesics. Moreover, we evaluated if quality of analgesia changed with an emergency physician on scene or depended on paramedics' gender.