Effect of oral administration of a continuous 18 day regimen of meloxicam on ovulation: experience of a randomized controlled trial

Background

Cyclooxygenase-2 (COX-2) is expressed in all female reproductive organs. Therefore, inhibitors of COX-2 may affect reproductive function. We evaluated the effect of extended administration of meloxicam on ovulation and the menstrual cycle. Our hypothesis was that meloxicam administered from menstrual cycle day 5- 22 could interfere with follicular rupture, without disrupting the menstrual cycle, and could be a potential non-hormonal contraceptive method.

Methods

The study was conducted in 56 healthy sterilized women. Before the onset of treatment and after the end of treatment, participants were observed during a control cycle to ensure that they had progesterone (P₄) serum levels (> 12 nmol/l) consistent with ovulation. Participants were treated for 18 days, during three consecutive cycles. They were randomized to 15 or 30 mg/day. The menstrual cycle was monitored with serial ultrasound and hormone assays in blood.

Results

Fifty-six volunteers completed the study. In 55% of cycles treated with 15 mg/day and in 78% of cycles treated with 30mg/day (p<0.001) we observed dysfunctional ovulation defined as follicular rupture not preceded 24–48 h earlier by an LH peak or preceded by a blunted LH peak (< 21 IU/l) or not followed by an elevated serum P₄ level > 12 nmol/l. Ovulation was observed in 44.6% and in 21.7% of women in the lower dose group and the higher dose group, respectively. There were no differences between the two doses in other parameters measured. There were no serious adverse events and adverse events were not different between doses or between control and treated cycles.

Conclusions

Although administration of meloxicam on menstrual cycle days 5- 22 resulted in a dose-dependent inhibition of ovulation, more than 20% of subjects had normal ovulation with the highest dose.

Implications

Previous studies have shown that oral meloxicam can delay follicle rupture. This study investigated daily oral meloxicam as a non-hormonal contraceptive. Since ovulation occurs in over 20% of cycles even with a high dose of 30 mg daily, it is not likely that the approach would be a highly effective contraceptive strategy.     

Genetic polymorphisms in the Toll-like receptor signalling pathway in Helicobacter pylori infection and related gastric cancer

Background

Gastric cancer (GC) is a progressive process initiated by Helicobacter pylori-induced inflammation. Initial recognition of H. pylori involves Toll-like receptors (TLRs), central molecules in the host inflammatory response. Here, we investigated the association between novel polymorphisms in genes involved in the TLR signalling pathway, including TLR2, TLR4, LBP, MD-2, CD14 and TIRAP, and risk of H. pylori infection and related GC.

Methods

A case-control study comprising 310 ethnic Chinese individuals (87 non-cardia GC cases and 223 controls with functional dyspepsia) was conducted. Twenty-five polymorphisms were detected by MALDI-TOF mass spectrometry, PCR, PCR–RFLP and real-time PCR.

Results

Seven polymorphisms showed significant associations with GC (TLR4 rs11536889, TLR4 rs10759931, TLR4 rs1927911, TLR4 rs10116253, TLR4 rs10759932, TLR4 rs2149356 and CD14 −260 C/T). In multivariate analyses, TLR4 rs11536889 remained a risk factor for GC (OR: 3.58, 95% CI: 1.20–10.65). TLR4 rs10759932 decreased the risk of H. pylori infection (OR: 0.59, 95% CI: 0.41–0.86). Statistical analyses assessing the joint effect of H. pylori infection and the selected polymorphisms revealed strong associations with GC (TLR2, TLR4, MD-2, LBP and TIRAP polymorphisms).

Conclusions

Novel polymorphisms in TLR2, TLR4, MD-2, LBP, CD14 and TIRAP, genes encoding important molecules of the TLR signalling pathway, showed clear associations with H. pylori-related GC in Chinese.     

Cyclooxygenase-2 expression in rat microglia is induced by adenosine A2a-receptors

We investigated the regulation of COX-2 expression and activity by adenosine receptors in rat microglial cells. The selective adenosine A_2a-receptor agonist CGS21680 and the non-selective adenosine A₁- and A₂-receptor agonist 5′-N-ethylcarboxi-amidoadenosine (NECA) induced an increase in COX-2 mRNA levels and the synthesis of prostaglandin E₂ (PGE₂). The adenosine A₁-receptor agonist cyclopentyladenosine (CPA) was less potent, and the adenosine A₃-receptor-specific agonist N⁶-2-(-aminophenylo)ethyladenosine (APNEA) showed only marginal effects. Microglia expressed adenosine A₁-, A_2a-, and A₃-, but not A_2b-receptor mRNAs, whereas astroglial cells expressed adenosine A_2b- but not A_2a-receptor mRNA. The adenosine A_2a-receptor selective antagonist (E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine (KF17837) inhibited both CGS21680-induced COX-2 expression and PGE₂ release. CGS21680-increased PGE₂ levels were inhibited by dexamethasone, by the nonsteroidal antiinflammatory drug meloxicam, and by the adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine (SQ22536). CGS21680 and NECA both increased intracellular cAMP levels in microglial cells. Dibutyryl cAMP as well as forskolin induced the release of PGE₂. The results strongly suggest that adenosine A_2a-receptor-induced intracellular signaling events cause an up-regulation of the COX-2 gene and the release of PGE₂. Apparently, the cAMP second messenger system plays a crucial role in COX-2 gene regulation in rat microglial cells. The results are discussed with respect to neurodegenerative disorders of the CNS such as Alzheimer's disease, in which activated microglia are critically involved and COX inhibitors may be of therapeutic benefit. © 1996 Wiley-Liss, Inc.     

2005年我院非甾体类抗炎药使用情况分析

目的:分析我院2005年非甾体类抗炎药(NSAIDs)的使用情况,为临床安全、有效、经济地选用NSAIDs提供科学依据。方法:收集我院2005年门诊非甾体类抗炎药的处方,计算DDDs、DUI,并进行排序。结果:2005年非甾体类抗炎药的使用有14个品种,年销售额374.7万元,占当年医院药品总销售金额比为2.47%。用药处于前10位的分别为双氯芬酸钠、芬必得、美洛昔康、尼美舒利、复方氯唑沙宗、快克、萘丁美酮、阿司匹林、去痛片、速效感冒颗粒和感冒通;所有药品的DUI<1.00,表明我院非甾体类抗炎镇痛药用药合理。结论:我院NSAIDs的临床应用较为合理,品种数正向着高效、长效、低毒和使用方便的方向发展。     

Compatibility of Drotaverine Hydrochloride with Ibuprofen and Ketoprofen Nonsteroidal Anti-Inflammatory Drugs Mixtures

Formulations with two or more active pharmaceutical ingredients (APIs) are a researched trend due to their convenient use compared with multiple medications. Moreover, drug-drug combinations may have a synergistic effect. Drotaverine hydrochloride (D-HCl) is commonly used for its antispasmodic action. The combination of a spasmolytic and an analgesic drug such as ibuprofen (Ibu) or ketoprofen (Ket) could become the answer for the treatment of localized pain. D-HCl:Ibu and D-HCl:Ket drug-drug interactions leading to the formation of eutectic compositions with increased bioavailability, obtained by mechanosynthesis, a green, solvent-free method was explored for the first time. The compatibility of Ibuprofen, Ketoprofen, and Drotaverine Hydrochloride was investigated using differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier-Transform Infrared spectroscopy (FTIR). Solid-liquid equilibrium (SLE) phase diagrams for the binary systems of active pharmaceutical ingredients were developed and the Tammann diagrams were designed to determine the eutectic compositions. The excess thermodynamic functions G^E for the pre-, post-, and eutectic compositions were obtained using the computed activity coefficients data. Results show that drotaverine-based pharmaceutical forms for pain treatment may be obtained at 0.9 respectively 0.8 molar fractions of ibuprofen and ketoprofen which is advantageous because the maximum allowed daily dose of Ibu is about 6 times higher than those of D-HCl and Ket. The obtained eutectics may be a viable option for the treatment of pain associated with cancer therapy.     

Guidelines of the French Society of Otorhinolaryngology (SFORL): Nonsteroidal anti-inflammatory drugs (NSAIDs) and pediatric ENT infections. Short version

ObjectivesTo present the guidelines of the French Society of Otolaryngology-Head and Neck Surgery concerning the use of non-steroidal anti-inflammatory drugs (NSAIDs) in pediatric ENT infections.MethodsBased on a critical analysis of the medical literature up to November 2016, a multidisciplinary workgroup of 11 practitioners wrote clinical practice guidelines. Levels of evidence were classified according to the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) system: GRADE A, B, C or “expert opinion”. The first version of the text was reworked by the workgroup following comments by the 22 members of the reading group.ResultsThe main recommendations are: NSAIDs are indicated at analgesic doses (e.g. 20–30 mg/kg/day for ibuprofen) in combination with paracetamol (acetaminophen) in uncomplicated pediatric ENT infections (acute otitis media, tonsillitis, upper respiratory infections, and maxillary sinusitis) if: o pain is of medium intensity (visual analogue scale (VAS) score 3–5 or “Evaluation Enfant Douleur” (EVENDOL) child pain score 4–7) and insufficiently relieved by first-line paracetamol (residual VAS ≥ 3 or EVENDOL ≥ 4); o pain is moderate to intense (VAS 5–7 or EVENDOL 7–10). When combined, paracetamol and ibuprofen are ideally taken simultaneously every 6 h. It is recommended: (1) o not to prescribe NSAIDs in severe or complicated pediatric ENT infections; (2) o to suspend NSAIDs treatment in case of unusual clinical presentation of the infection (duration or symptoms); (3) o not to prescribe NSAIDs for more than 72 h.     

非甾体抗炎药相关性上消化道出血的临床分析

目的 探讨非甾体抗炎药(NSAIDs)相关性上消化道出血的临床及内镜特点.方法 对177例上消化道出血病人的临床资料进行回顾性分析,根据出血前1周内是否服用NSAIDs分为NSAIDs组(36例)和非NSAIDs组(141例).对比分析两组患者的临床资料.结果 177例上消化道出血患者中有36例(20.34%)服用过NSAIDs.两组比较,NSAIDs组在年龄、溃疡类型、临床症状等方面均有显著差异,但在性别、Hp阳性率、既往溃疡病史上无显著性差异.结论 加强对非甾体抗炎药相关性上消化道出血的认识,合理用药,并采取相应措施,以降低使用NSAIDs引起上消化道出血的风险.     

Inhibition of the phosphatidylinositol 3’-kinase signaling pathway increases the responsiveness of pancreatic carcinoma cells to sulindac

Nonsteroidal anti-inflammatory drugs (NSAIDs) may be effective treatment for pancreatic cancer. We have previously demonstrated that NSAIDs suppress pancreatic cell growth in vitro by inhibiting cell cycle progression but have little effect on apoptosis. In fact, we have shown that NSAIDs, in some instances, increase Akt phosphorylation in human pancreatic carcinoma cells suggesting activation of the phosphatidy linositol 3’-kinase (PI3K)-Akt survival (antiapoptotic) pathway. We subsequently examined the effects of treating the human pancreatic cancer cell lines BxPC-3 and PaCa-2 with a specific inhibitor of the PI3K/Akt pathway, LY294002, in the presence or absence of the NSAID sulindac. The growth effects of sulindac (250 to 500 ώmol/L) and/or LY2 94002 (1 to 100 ώmol/L) were determined by a colorimetric proliferation assay and cell counts. The combination of low-dose LY294002 (10 ώmol/L) and sulindac enhanced the growth inhibitory effects of sulindac in BxPC-3 and PaCa-2 cells. Treatment of both cell lines with the LY294002/sulindac combination altered the cell cycle distribution as determined by flow cytometry and also lowered the apoptotic threshold as measured with an enzyme-linked immunosorbent asssay to detect DNA fragmentation. These effects were associated with changes in the expression and/or phosphorylation level of proteins and kinases that regulate cell cycle progression and apoptosis. Taken together, our results suggest that inhibition of the PI3K/Akt signaling pathway may sensitize pancreatic tumor cells to therapy with NSAIDs such as sulindac. Presented at the Forty-Third Annual Meeting of The Society for Surgery of the Alimentary Tract, San Francisco, California, May 19–22, 2002 (poster presentation). Supported by institutional research grant IRG-84-002-18 from the American Cancer Society.