betadex and Dysmenorrhea

Although NSAIDs are very effective drugs, their use is associated with a broad spectrum of adverse reactions in the liver, kidney, cardiovascular (CV) system, skin and gut. Gastrointestinal (GI) side effects are the most common and constitute a wide clinical spectrum ranging from dyspepsia, heartburn and abdominal discomfort to more serious events such as peptic ulcer with life-threatening complications of bleeding and perforation. The appreciation that CV risk is also increased further complicates the choices of physicians prescribing anti-inflammatory therapy. Despite prevention strategies should be implemented in patients at risk, gastroprotection is often underused and adherence to treatment is generally poor. A more appealing approach would be therefore to develop drugs that are devoid of or have reduced GI toxicity. Gastro- duodenal mucosa possesses many defensive mechanisms and NSAIDs have a deleterious effect on most of them. This results in a mucosa less able to cope with even a reduced acid load. NSAIDs cause gastro-duodenal damage, by two main mechanisms: a physiochemical disruption of the gastric mucosal barrier and systemic inhibition of gastric mucosal protection, through inhibition of cyclooxygenase (COX, PG endoperoxide G/H synthase) activity of the GI mucosa. However, against a background of COX inhibition by anti-inflammatory doses of NSAIDs, their physicochemical properties, in particular their acidity, underlie the topical effect leading to short-term damage. It has been shown that esterification of acidic NSAIDs suppresses their gastrotoxicity without adversely affecting anti-inflammatory activity. Another way to develop NSAIDs with better GI tolerability is to complex these molecules with cyclodextrins (CDs), giving rise to so-called "inclusion complexes" that can have physical, chemical and biological properties very different from either those of the drug or the cyclodextrin. Complexation of NSAIDs with β-cyclodextrin potentially leads to a more rapid onset of action after oral administration and improved GI tolerability because of minimization of the drug gastric effects. One such drug, piroxicam-β-cyclodextrin (PBC), has been used in Europe for 25 years. Preclinical and clinical pharmacology of PBC do show that the β-cyclodextrin inclusion complex of piroxicam is better tolerated from the upper GI tract than free piroxicam, while retaining all the analgesic and anti-inflammatory properties of the parent compound. In addition, the

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; beta-Cyclodextrins; Dysmenorrhea; Female; Gastrointestinal Tract; Humans; Models, Molecular; Musculoskeletal Diseases; Pain; Piroxicam

What is the expression pattern and functionality of caveolin 1 (CAV1) in the endometrium of patients with adenomyosis?. The stromal CAV1 expression is down-regulated that leads to the release of a variety of molecules that either enhance the metastatic capacity of endometrial cells or contribute to adenomyosis-associated dysmenorrhea.. Adenomyosis is characterized by invasion of endometrium into the uterine myometrium. CAV1 has been linked to tumor progression and clinical outcome in a variety of human malignancies; however, its role in adenomyosis development and adenomyosis-associated dysmenorrhea is still poorly recognized.. We retrospectively analyzed the expression levels of CAV1 and RANTES protein using immunohistochemistry in 65 patients who were pathologically diagnosed with adenomyosis and 12 control women without related pathology, who were subjected to surgery between 2009 and 2010. Endometrial tissues from six additional normal females without related pathology were collected from 2011 to 2012; these tissues were subjected to subsequent primary cell culture experiments.. The expression of CAV1 and RANTES was examined by immunohistochemistry in ectopic endometrium and paired eutopic endometrium of 65 adenomyosis patients and 12 control patients. Primary endometrial stromal cells (ESCs) and endometrial epithelial cells (EECs) were isolated from 6 additional control females without related pathology. The expression of CAV1 in ESCs was either (i) inhibited by siRNA transfection and methyl-β-cyclodextrin (MβCD) treatment or (ii) increased by pcDNA3.1/CAV1 transfection. The impact of each treatment on the proliferation, migration and invasion of both ESCs and EECs was evaluated by methylthiazolydiphenyl-tetrazolium assay, colony formation assay, Transwell migration and invasion assay. Furthermore, ESC treatment with MβCD and siCAV1 was assessed for the effect on the expression of a panel of inflammatory cytokines. The levels of two pain mediators, nitric oxide (NO) and prostaglandin E2 (PGE2), were assessed in CAV-1-depleted and control ESCs, whereas immunoblotting was performed to characterize signaling pathways downstream to loss of stromal CAV1 in endometrium. The correlation between dysmenorrhea severity and stromal CAV1 and RANTES expression was further examined using 'Pearson's' correlation analysis.. Stromal CAV1 expression in ectopic endometrium of adenomyosis patients was significantly lower than that of paired eutopic endometrium or normal controls as analyzed by immunohistochemistry (P < 0.001). Although no significant difference was observed in the proliferation of CAV1-depleted ESCs when compared with control group, EECs cultured with conditioned media from CAV1-depleted ESCs demonstrated a significantly elevated proliferation rate when compared with those treated with control ESC-conditioned media. Moreover, both CAV1-depleted ESCs and EECs cultured with conditioned media from CAV1-depleted ESCs showed enhanced migration and invasion capacity when compared with control group (P < 0.05). In contrast, incubation with conditioned media of ESCs with enforced CAV1 expression led to decreased proliferation capacity of EECs. Furthermore, the expression of RANTES in ESCs treated with MβCD and siCAV1 was significantly increased. Stromal RANTES expression in the ectopic endometrium of adenomyosis patients was significantly higher than that of paired eutopic endometrium or normal controls as analyzed by immunohistochemistry (P = 0.0026). Stromal CAV1 expression in eutopic endometrium was significantly lower in women with more severe dysmenorrhea (P < 0.05) and was negatively correlated with dysmenorrhea severity in adenomyosis patients (r(2) = 0.1549; P = 0.012, 'Pearson's' χ(2) test), whereas stromal RANTES expression in eutopic endometrium was significantly higher in women with more severe dysmenorrhea (P < 0.05) and was positively correlated with dysmenorrhea severity in adenomyosis patients (r(2) = 0.1646; P = 0.0094, 'Pearson's' χ(2) test). Silencing of CAV1 in ESCs led to increased release of NO and PGE2 when compared with control and was associated with enhanced activity of ERK-FAK signaling pathway.. This study assessed the functional role of stromal CAV1 and RANTES in a small number of human adenomyosis samples by immunohistochemistry and in primary human ESCs by functional studies. In future investigations, a larger sample size should be adopted and the functional role of stromal CAV1 should be further characterized in animal models.. Loss of stromal CAV1 expression may play a critical role in the pathogenesis of adenomyosis and is correlated with adenomyosis-related dysmenorrhea.. National Basic Research Program of China and Ph.D. Programs Foundation of Ministry of Education of China.. None.

Topics: Adenomyosis; Adult; beta-Cyclodextrins; Caveolin 1; Cell Movement; Cell Proliferation; Chemokine CCL5; Cytokines; Dinoprostone; Dysmenorrhea; Endometrium; Female; Gene Expression Regulation; Humans; Immunohistochemistry; Middle Aged; Myometrium; RNA, Small Interfering; Stromal Cells