Mefenamic acid exhibits antitumor activity against osteosarcoma by impeding cell growth and prompting apoptosis in human osteosarcoma cells and xenograft mice model.

The study investigates the anticancer activity of mefenamic acid against osteosarcoma, shedding light on its underlying mechanisms and therapeutic potential. Mefenamic acid exhibited robust inhibitory effects on the proliferation of MG-63, HOS, and H2OS osteosarcoma cells in a dose-dependent manner. Moreover, mefenamic acid induced cellular toxicity in MG63 cells, as evidenced by LDH leakage, reflecting its cytotoxic impact. Furthermore, mefenamic acid effectively suppressed the migration and invasion of MG-63 cells. Mechanistically, mefenamic acid induced apoptosis in MG-63 cells through mitochondrial depolarization, activation of caspase-dependent pathways, and modulation of the Bcl-2/Bax axis. Additionally, mefenamic acid promoted autophagy and inhibited the PI3K/Akt/mTOR pathway, further contributing to its antitumor effects. The molecular docking studies provide compelling evidence that mefenamic acid interacts specifically and strongly with key proteins in the PI3K/AKT/mTOR pathway, suggesting a novel mechanism by which mefenamic acid could exert anti-osteosarcoma effects. In vivo studies using a xenograft mouse model demonstrated significant inhibition of MG-63 tumor growth without adverse effects, supporting the translational potential of mefenamic acid as a safe and effective therapeutic agent against osteosarcoma. Immunohistochemistry staining corroborated the in vivo findings, highlighting mefenamic acid's ability to suppress tumor proliferation and inhibit the PI3K/AKT/mTOR pathway within the tumor microenvironment. Collectively, these results underscore the promising therapeutic implications of mefenamic acid in combating osteosarcoma, warranting further investigation for clinical translation and development.

The effect of vitamin D on the severity of dysmenorrhea and menstrual blood loss: a randomized clinical trial.

BACKGROUND: Primary dysmenorrhea is considered as one of the women's main problems during reproductive age. The present study aimed to investigate the effect of vitamin D on the severity of dysmenorrhea and menstrual blood loss. METHODS: This double-blind, randomized, placebo-controlled trial, was performed on 84 single female college students between 18 and 25 years old who living in dormitories. Students with primary dysmenorrhea and vitamin D deficiency were divided into experimental (n = 42) and control (n = 42) groups. Five days before the putative beginning of their next menstrual cycle, the experimental group received 300,000 IU vitamin D (50,000 IU, two tablets every 8 h), and the control group received a placebo (oral paraffin). The effects of the supplement on the severity of dysmenorrhea and menstrual blood loss were evaluated one cycle before and during two successive cycles. Using the visual analog scale (VAS), verbal multidimensional scoring system (VMS), and pictorial blood assessment chart (PBLAC) questionnaires. Fisher's exact, Chi-square, independent sample t-test and repeated measurements were used. RESULTS: In total, 78 of the 84 students completed the study (39 students per group). The intervention resulted in a significant reduction in the mean scores of both the VAS and VMS in the experimental group, in the first and second menstrual cycles (p < 0.001, p < 0.001, respectively), but not in the means score of PBLAC. Mefenamic acid consumption at the first and second menstruation period, in the experimental group was lower than the control group (p = 0.009, p < 0.001, respectively). CONCLUSIONS: The results indicate that vitamin D supplementation could decrease the severity of primary dysmenorrhea and the need to consume pain-relief medications. Contrariwise vitamin D supplementation had no significant effect on menstrual blood loss. TRIAL REGISTRATION: This trial was registered in the Iranian Registry of Clinical Trials with code IRCT201305212324N on 18/1/2014. URL of registry: https://en.irct.ir/trial/1964 .

Interventions to prevent or treat heavy menstrual bleeding or pain associated with intrauterine-device use.

BACKGROUND: Heavy menstrual bleeding and pain are common reasons women discontinue intrauterine device (IUD) use. Copper IUD (Cu IUD) users tend to experience increased menstrual bleeding, whereas levonorgestrel IUD (LNG IUD) users tend to have irregular menstruation. Medical therapies used to reduce heavy menstrual bleeding or pain associated with Cu and LNG IUD use include non-steroidal anti-inflammatory drugs (NSAIDs), anti-fibrinolytics and paracetamol. We analysed treatment and prevention interventions separately because the expected outcomes for treatment and prevention interventions differ. We did not combine different drug classes in the analysis as they have different mechanisms of action. This is an update of a review originally on NSAIDs. The review scope has been widened to include all interventions for treatment or prevention of heavy menstrual bleeding or pain associated with IUD use. OBJECTIVES: To evaluate all randomized controlled trials (RCTs) that have assessed strategies for treatment and prevention of heavy menstrual bleeding or pain associated with IUD use, for example, pharmacotherapy and alternative therapies. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase and CINAHL to January 2021. SELECTION CRITERIA: We included RCTs in any language that tested strategies for treatment or prevention of heavy menstrual bleeding or pain associated with IUD (Cu IUD, LNG IUD or other IUD) use. The comparison could be no intervention, placebo or another active intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, and extracted data. Primary outcomes were volume of menstrual blood loss, duration of menstruation and painful menstruation. We used a random-effects model in all meta-analyses. Review authors assessed the certainty of evidence using GRADE. MAIN RESULTS: This review includes 21 trials involving 3689 participants from middle- and high-income countries. Women were 18 to 45 years old and either already using an IUD or had just had one placed for contraception. The included trials examined NSAIDs and other interventions. Eleven were treatment trials, of these seven were on users of the Cu IUD, one on LNG IUD and three on an unknown type. Ten were prevention trials, six focused on Cu IUD users, and four on LNG IUD users. Sixteen trials had high risk of detection bias due to subjective assessment of pain and bleeding. Treatment of heavy menstrual bleeding Cu IUD Vitamin B1 resulted in fewer pads used per day (mean difference (MD) -7.00, 95% confidence interval (CI) -8.50 to -5.50) and fewer bleeding days (MD -2.00, 95% CI -2.38 to -1.62; 1 trial; 110 women; low-certainty evidence) compared to placebo. The evidence is very uncertain about the effect of naproxen on the volume of menstruation compared to placebo (odds ratio (OR) 0.09, 95% CI 0.00 to 1.78; 1 trial, 40 women; very low-certainty evidence). Treatment with mefenamic acid resulted in less volume of blood loss compared to tranexamic acid (MD -64.26, 95% CI -105.65 to -22.87; 1 trial, 94 women; low-certainty evidence). However, there was no difference in duration of bleeding with treatment of mefenamic acid or tranexamic acid (MD 0.08 days, 95% CI -0.27 to 0.42, 2 trials, 152 women; low-certainty evidence). LNG IUD The use of ulipristal acetate in LNG IUD may not reduce the number of bleeding days in 90 days in comparison to placebo (MD -9.30 days, 95% CI -26.76 to 8.16; 1 trial, 24 women; low-certainty evidence). Unknown IUD type Mefenamic acid may not reduce volume of bleeding compared to Vitex agnus measured by pictorial blood assessment chart (MD -2.40, 95% CI -13.77 to 8.97; 1 trial; 84 women; low-certainty evidence). Treatment of pain Cu IUD Treatment with tranexamic acid and sodium diclofenac may result in little or no difference in the occurrence of pain (OR 1.00, 95% CI 0.06 to 17.25; 1 trial, 38 women; very low-certainty evidence). Unknown IUD type Naproxen may reduce pain (MD 4.10, 95% CI 0.91 to 7.29; 1 trial, 33 women; low-certainty evidence). Prevention of heavy menstrual bleeding Cu IUD We found very low-certainty evidence that tolfenamic acid may prevent heavy bleeding compared to placebo (OR 0.54, 95% CI 0.34 to 0.85; 1 trial, 310 women). There was no difference between ibuprofen and placebo in blood volume reduction (MD -14.11, 95% CI -36.04 to 7.82) and duration of bleeding (MD -0.2 days, 95% CI -1.40 to 1.0; 1 trial, 28 women, low-certainty evidence). Aspirin may not prevent heavy bleeding in comparison to paracetamol (MD -0.30, 95% CI -26.16 to 25.56; 1 trial, 20 women; very low-certainty evidence). LNG IUD Ulipristal acetate may increase the percentage of bleeding days compared to placebo (MD 9.50, 95% CI 1.48 to 17.52; 1 trial, 118 women; low-certainty evidence). There were insufficient data for analysis in a single trial comparing mifepristone and vitamin B. There were insufficient data for analysis in the single trial comparing tranexamic acid and mefenamic acid and in another trial comparing naproxen with estradiol. Prevention of pain Cu IUD There was low-certainty evidence that tolfenamic acid may not be effective to prevent painful menstruation compared to placebo (OR 0.71, 95% CI 0.44 to 1.14; 1 trial, 310 women). Ibuprofen may not reduce menstrual cramps compared to placebo (OR 1.00, 95% CI 0.11 to 8.95; 1 trial, 20 women, low-certainty evidence). AUTHORS' CONCLUSIONS: Findings from this review should be interpreted with caution due to low- and very low-certainty evidence. Included trials were limited; the majority of the evidence was derived from single trials with few participants. Further research requires larger trials and improved trial reporting. The use of vitamin B1 and mefenamic acid to treat heavy menstruation and tolfenamic acid to prevent heavy menstruation associated with Cu IUD should be investigated. More trials are needed to generate evidence for the treatment and prevention of heavy and painful menstruation associated with LNG IUD.

Migraine susceptibility is modulated by food triggers and analgesic overuse via sulfotransferase inhibition.

BACKGROUND/AIM: Certain constituents in migraine food triggers and non-steroidal anti-inflammatory drugs (NSAIDs) inhibit sulfotransferases (SULTs) that detoxify drugs/chemicals and play role in the metabolism of neurotransmitters. We aimed to dissect SULT1A1 modulation of CSD susceptibility and behavior in an in vivo experimental model using hesperidin, a SULT1A1 inhibitor found in citrus fruits (known migraine triggers) and mefenamic acid (SULT1A1 inhibitor), an NSAID to simulate medication overuse. METHODS: Hesperidin was used as SULT1A1 inhibitor found in citrus fruits, known migraine triggers and mefenamic acid (NSAID), another SULT1A1 inhibitor, was used to induce MO in rats. The groups were; 1) Hesperidin (ip) or its vehicle-DMSO (ip) 2) Chronic (4 weeks) mefenamic acid (ip) or its vehicle (ip) 3) Chronic mefenamic acid+hesperidin (ip) or DMSO (ip). CSD susceptibility was evaluated and behavioral testing was performed. SULT1A1 enzyme activity was measured in brain samples. RESULTS: Single-dose of hesperidin neither changed CSD susceptibility nor resulted in any behavioral change. Chronic mefenamic acid exposure resulted in increased CSD susceptibility, mechanical-thermal hypersensitivity, increased head shake, grooming and freezing and decreased locomotion. Single dose hesperidin administration after chronic mefenamic acid exposure resulted in increased CSD susceptibility and mechanical-thermal hypersensitivity, increased freezing and decreased locomotion. SULT1A1 enzyme activity was lower in mefenamic acid and mefenamic acid+hesperidin groups compared to their vehicles. CONCLUSION: Mefenamic acid and hesperidin have synergistic effect in modulating CSD susceptibility and pain behavior. Sulfotransferase inhibition may be the common mechanism by which food triggers and NSAIDs modulate migraine susceptibility. Further investigations regarding human provocation studies using hesperidin in migraine patients with medication overuse are needed.

Mefenamic acid as a promising therapeutic medicine against colon cancer in tumor-bearing mice.

Although radiotherapy is an effective strategy for cancer treatment, tumor resistance to ionizing radiation (IR) and its toxic effects on normal tissues are limiting its use. The aim of this study is to evaluate the anti-cancer effects of mefenamic acid (MEF), as an approved medicine, and its combination with IR against colon tumor cells in mice. Tumor-bearing mice were received MEF at a dose of 25 mg/kg for 6 successive days. The tumor size was measured. In the second experiment, after MEF treatment, tumor-bearing mice locally received an X-ray at dose 6 Gy. Tumor growth and biochemical, histological, and immunohistological assay (caspase-3) were performed. MEF significantly decreased tumor size in mice in comparison to the control group. IR and/or MEF treatment significantly reduced the tumor volume and inhibited tumor growth by 49%, 55%, and 67% by MEF, IR, and MEF + IR groups as compared with the control group. Administration of MEF in combination with radiation had a synergistic effect on enhanced histopathological changes in tumor tissues. MEF treatment in IR exposure mice showed a significant increase in the immunoreactivity of caspase-3 in the colon tumor tissue. MEF has an anti-tumor effect in colon tumor-bearing mice. MEF in combination with IR increased pathological changes and apoptosis in tumor tissues, suggesting that MEF might be clinically useful in the treatment of colon cancer.

Efficacy of the use of mefenamic acid combined with standard medical care vs. standard medical care alone for the treatment of COVID­19: A randomized double­blind placebo­controlled trial.

Mefenamic acid is a non­steroidal anti­inflammatory drug exhibiting a wide range of anti­inflammatory, antipyretic, analgesic and probable antiviral activities. The present study evaluated the efficacy of treatment with mefenamic acid combined with standard medical care vs. standard medical care plus a placebo in ambulatory patients with coronavirus disease 2019 (COVID­19; nasal/oropharyngeal swabs reverse transcription­PCR test results positive for severe acute respiratory syndrome coronavirus 2). The present study is a phase II prospective, two­arm, parallel­group, randomized, double­blind placebo­controlled clinical trial which analyzed 36 patients. Two aspects were evaluated during the 14­day follow­up period: i) The time for reaching a patient acceptable symptom state (PASS), and ii) the last day of each COVID­19 symptom presentation. Adverse effects were evaluated. The clinical severity for all the patients in the study was mild (88.9%) and moderate (11.1%). The control (placebo) group achieved PASS on day 8.0±1.3, compared with day 4.4±0.8 in the mefenamic acid group (P=0.020, Kaplan­Meier analyses using log­rank tests). Patients that received mefenamic acid plus standard medical care had a ~16­fold higher probability of achieving PASS on day 8 (adjusted RR, 15.57; 95% CI, 1.22­198.71; P=0.035), compared with the placebo plus standard medical care group. All symptoms lasted for fewer days in the mefenamic acid group, compared with the placebo group; however, only the symptoms of headache (P=0.008), retro­orbital eye pain (P=0.049), and sore throat (P=0.029) exhibited statistically significant differences. The experimental treatment produced no severe adverse effects. On the whole, the present study demonstrates that the administration of mefenamic acid markedly reduced the symptomatology and time to reach PASS in ambulatory patients with COVID­19. Due to its probable antiviral effects and potent anti­inflammatory mechanisms, mefenamic acid may prove to be useful in the treatment of COVID­19, in combination with other drugs, including the new antivirals (remdesivir, molnupiravir, or favipiravir). However, future studies are also required to confirm these findings.

Effect of fennel on primary dysmenorrhea: a systematic review and meta-analysis.

BACKGROUND: One of the most common complaints for women is dysmenorrhea. Several studies investigated the treatment effects of medicinal plants on primary dysmenorrhea. OBJECTIVES: This systematic review and meta-analysis investigates the effect of Foeniculum vulgare (Fennel) on pain in primary dysmenorrhea in comparison to non-steroidal anti-inflammatory drugs such as mefenamic acid. METHODS: PubMed, EMBASE, EBSCO Web of Science, Scopus, Cochrane library, Cochrane Central Register of Controlled Trials (CENTRAL), Science Direct, ProQuest, ISI Web of Science, Google Scholar, Magiran, SID, Iran Medex, and Irandoc were searched up to January 2019. Quality assessment of clinical trials was conducted using Jadad scoring system. Totally, 12 studies were entered in the meta-analysis. I 2 was calculated to determine heterogeneity. Fixed effects and/or random effects models were applied. RESULTS: Meta-analysis of these trials showed that F. vulgare intake decreased significantly the intensity of dysmenorrhea compared to the placebo (SMD -0.632; CI: -0.827 to -0.436; p<0.001; heterogeneity p=0.807; I 2=0%; fixed effect model; seven articles). However, the effect of Mefenamic acid with F. vulgare was not different from each other (SMD=-0.214; CI: -0.446 to 0.017; p=0.07; heterogeneity p=0.58; I 2=0%; fixed effect model; six trials). CONCLUSION: The F. vulgare alleviates dysmenorrhea. Regarding the same effect of F. vulgare with NSAIDs, it is highly recommend to the women suffered from dysmenorrhea specifically the ones who have high tendency toward herbal medicine.

Assessment of C-reactive Protein Level and Efficacy of Diclofenac Sodium and Mefenamic Acid in Relieving Pain in Mandibular Impacted Third Molar Surgery.

AIM: To compare the efficacy of diclofenac sodium and mefenamic acid in relieving pain in mandibular impacted third molar surgery and to assess the level of the C-reactive protein (CRP) level. MATERIALS AND METHODS: This study was conducted on 90 patients of impacted mandibular third molars. All patients were administered with 2% lignocaine with 1:80,000 adrenaline, and surgical removal of impacted third molar was done following the standardized surgical procedure by a single oral surgeon. Patients were divided into two groups of 45 each. In group I, patients were prescribed 50 mg diclofenac sodium and in group II patients were prescribed 500 mg mefenamic acid for three times a day for 3 days. The CRP level was again evaluated after 3 days of analgesics. Pain was assessed using the visual analog scale (VAS). RESULTS: The mean VAS was 2.58 in group I and 3.46 in group II, which was statistically considerable (p < 0.05). The mean CRP level postoperatively in group I was 15.7 and after 3 days was 27.2 in group I, whereas it was 25.1 postoperatively and 31.5 after 3 days in group II. CONCLUSION: Authors found that diclofenac sodium as useful as mefenamic acid. The CRP level was raised significantly following surgery, thus reflecting that it is an indicator of inflammation. CLINICAL SIGNIFICANCE: Diclofenac sodium can be used to relieve pain. The CRP level evaluation can be helpful to assess inflammation following surgery.

Randomized, double-blind, placebo-controlled clinical trial studying the effects of Turmeric in combination with mefenamic acid in patients with primary dysmenorrhoea.

Primary dysmenorrhea (PDM) is one of the common complaints in women. This study aimed to assess the effects of turmeric and mefenamic acid and a combination compared with placebo on PDM. This clinical trial was conducted on dormitory students with PDM. Subjects completed the visual analog scale (VAS) before randomization. One hundred twenty-eight patients, randomly assigned to one of following groups: Turmeric group (n=32), mefenamic acid group (n=32), turmeric and mefenamic acid group (n=32), and placebo group (n=32). Turmeric and mefenamic acid were administrated in 500mg and 250mg, respectively. Pain severity was assessed in the baseline and the end line by VAS. Statistical analysis was performed using SPSS software. The combination of turmeric and mefenamic acid, dramatically, alleviated pain in comparison to other groups. Our results illustrated that combination of turmeric and mefenamic acid would be better in pain alleviation in PDM.

Effects of Mefenamic Acid in Pain Control during Loop Electrical Excision Procedure:A Prospective Double-Blind Randomized Control Trial.

OBJECTIVE: To investigate the effectiveness of pre-procedural oral mefenamic acid compared with placebo in women undergoing Loop Electrosurgical Excision Procedure (LEEP) with intracervical lidocaine injection. STUDY DESIGNS: A prospective double-blinded randomized control trial. Materials, Setting, Methods: Women undergoing LEEP for any indications were asked to participate in the study. The participants were randomly allocated into two groups. In group 1 (oral mefenamic acid), the participants were offered oral mefenamic acid (500 mg) for 30 minutes before procedures. In group 2 (placebo), the patients were given oral placebo (identical tablet) for 30 minutes before operation. All participants received immediate 10 mL of 2% lidocaine with 1:100,000 of epinephrine intracervical injection before undergoing the LEEP. All participants were excised in one piece of LEEP. No top-hat excision in this study.  The patients graded their pain on a 10-cm visual analog scale (VAS) at different points during the procedure, including speculum insertion, at starting excision, and 30 minutes post excision. Primary outcomes revealed the difference of VAS during all steps of LEEP by generalized estimating equations procedure. RESULTS: Sixty participants (30 in mefenamic group and 30 in placebo group) participated in this study. The study did not find differences of VAS during all steps of LEEP and analgesic drug requirement at 30 minutes after LEEP procedure. All patients reported no immediate complications and no intervention-related adverse events were observed. CONCLUSION: Using pre-procedural oral mefenamic acid before LEEP procedure was not associated with pain reduction during all steps of excision.
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Interventions commonly available during pandemics for heavy menstrual bleeding: an overview of Cochrane Reviews.

BACKGROUND: Within the context of heavy menstrual bleeding, pandemics impact upon women's assessment and treatment by healthcare providers. OBJECTIVES: To summarise the evidence from Cochrane Reviews evaluating interventions for heavy menstrual bleeding that are commonly available during pandemics. METHODS: We sought published Cochrane Reviews, evaluating interventions that can continue during pandemics for women with heavy menstrual bleeding with no known underlying cause. We identified Cochrane Reviews by searching the Cochrane Database of Systematic Reviews in June 2020. The primary outcome was menstrual bleeding. Secondary outcomes included quality of life, patient satisfaction, side effects, and serious adverse events. We undertook the selection of systematic reviews, data extraction, and quality assessment in duplicate. We resolved any disagreements by discussion. We assessed review quality using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) 2 tool, and the certainty of the evidence for each outcome using GRADE methods. MAIN RESULTS: We included four Cochrane Reviews, with 11 comparisons, data from 44 randomised controlled trials (RCTs), and 3196 women. We assessed all the reviews to be high quality. Non-steroidal anti-inflammatory drugs (NSAIDs) NSAIDs may be more effective in reducing heavy menstrual bleeding than placebo (mean difference (MD) -124 mL per cycle, 95% confidence interval (CI) -186 to -62 mL per cycle; 1 RCT, 11 women; low-certainty evidence). Mefenamic acid may be similar to naproxen (MD 21 mL per cycle, 95% CI -6 to 48 mL per cycle; 2 RCTs, 61 women; low-certainty evidence), and NSAIDs may be similar to combined hormonal contraceptives for heavy menstrual bleeding (MD 25 mL per cycle, 95% CI -22 to 73 mL per cycle; 1 RCT, 26 women; low-certainty evidence). NSAIDs may be be less effective in reducing menstrual bleeding than antifibrinolytics (relative risk (RR) 0.70, 95% CI 0.58 to 0.85; 2 RCTs, 161 women; low-certainty evidence). We are uncertain whether NSAIDs reduce menstrual blood loss more than short-cycle progestogens (RR 0.80, 95% CI 0.49 to 1.32; 1 RCT 32 women; very low-certainty evidence). Antifibrinolytics Antifibrinolytics appear to be more effective in reducing heavy menstrual bleeding than placebo (MD -53 mL per cycle, 95% CI -63 to -44 mL per cycle; 4 RCTs, 565 women; moderate-certainty evidence). Antifibrinolytics may be similar to placebo on the incidence of side effects (RR 1.05, 95% CI 0.93 to 1.18; 1 RCT, 297 women; low-certainty evidence), and they are probably similar on the incidence of serious adverse events (thrombotic events; RR 0.10, 95% CI 0.00 to 2.46; 2 RCT, 468 women; moderate-certainty evidence). Antifibrinolytics may be more effective in reducing heavy menstrual bleeding than short-cycle progestogen (MD -111 mL per cycle, 95% CI -178 mL to -44 mL per cycle; 1 RCT, 46 women; low-certainty evidence). We are uncertain whether antifibrinolytics are similar to short-cycle progestogens on quality of life (RR 1.67, 95% CI 0.76 to 3.64; 1 RCT, 44 women; very low-certainty evidence), patient satisfaction (RR 0.91, 95% CI 0.59 to 1.39; 1 RCT, 42 women; very low-certainty evidence), or side effects (RR 0.85, 95% CI 0.65 to 1.12; 3 RCTs, 211 women; very low-certainty evidence). We are uncertain whether antifibrinolytics are more effective in reducing heavy menstrual bleeding when compared with long-cycle progestogen (MD -9 points per cycle, 95% CI -30 to 12 points per cycle; 2 RCTs, 184 women; low-certainty evidence). Antifibrinolytics may increase self-reported improvement in menstrual bleeding when compared with long-cycle medroxyprogesterone acetate (RR 1.32, 95% CI 1.08 to 1.61; 1 RCT, 94 women; low-certainty evidence). Antifibrinolytics may be similar to long-cycle progestogens on quality of life (MD 5, 95% CI -2.49 to 12.49; 1 RCT, 90 women; low-certainty evidence). We are uncertain whether antifibrinolytics are similar to long-cycle progestogens on side effects (RR 0.58, 95% CI 0.33 to 1.00; 2 RCTs, 184 women; very low-certainty evidence). There were no trials comparing antifibrinolytics to combined hormonal contraceptives. Combined hormonal contraceptives Combined hormonal contraceptives appear to be more effective for heavy menstrual bleeding than placebo or no treatment (RR 13.25, 95% CI 2.94 to 59.64; 2 RCTs, 363 women; moderate-certainty evidence). Combined hormonal contraceptives are probably similar to placebo on the incidence of side effects (RR 1.53, 95% CI 0.90 to 2.60; 2 RCTs, 411 women; moderate-certainty evidence). Progestogens There were no trials comparing progestogens to placebo. Limitations in the evidence included risk of bias in the primary RCTs, inconsistency between the primary RCTs, and imprecision in effect estimates. AUTHORS' CONCLUSIONS: There is moderate-certainty evidence that antifibrinolytics and combined hormonal contraceptives reduce heavy menstrual bleeding compared with placebo. There is low-certainty evidence that NSAIDs reduce heavy menstrual bleeding compared with placebo. There is low-certainty evidence that antifibrinolytics are more effective in reducing heavy menstrual bleeding when compared with NSAIDs and short-cycle progestogens, but we are unable to draw conclusions about the effects of antifibrinolytics compared to long-cycle progestogens, on low-certainty evidence.

Progestogen-releasing intrauterine systems for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) impacts the quality of life of otherwise healthy women. The perception of HMB is subjective and management depends upon, among other factors, the severity of the symptoms, a woman's age, her wish to get pregnant, and the presence of other pathologies. Heavy menstrual bleeding was classically defined as greater than or equal to 80 mL of blood loss per menstrual cycle. Currently the definition is based on the woman's perception of excessive bleeding which is affecting her quality of life. The intrauterine device was originally developed as a contraceptive but the addition of progestogens to these devices resulted in a large reduction in menstrual blood loss: users of the levonorgestrel-releasing intrauterine system (LNG-IUS) reported reductions of up to 90%. Insertion may, however, be regarded as invasive by some women, which affects its acceptability. OBJECTIVES: To determine the effectiveness, acceptability and safety of progestogen-releasing intrauterine devices in reducing heavy menstrual bleeding. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL (from inception to June 2019); and we searched grey literature and for unpublished trials in trial registers. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in women of reproductive age treated with LNG-IUS devices versus no treatment, placebo, or other medical or surgical therapy for heavy menstrual bleeding. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed risk of bias and conducted GRADE assessments of the certainty of evidence. MAIN RESULTS: We included 25 RCTs (2511 women). Limitations in the evidence included risk of attrition bias and low numbers of participants. The studies compared the following interventions. LNG-IUS versus other medical therapy The other medical therapies were norethisterone acetate, medroxyprogesterone acetate, oral contraceptive pill, mefenamic acid, tranexamic acid or usual medical treatment (where participants could choose the oral treatment that was most suitable). The LNG-IUS may improve HMB, lowering menstrual blood loss according to the alkaline haematin method (mean difference (MD) 66.91 mL, 95% confidence interval (CI) 42.61 to 91.20; 2 studies, 170 women; low-certainty evidence); and the Pictorial Bleeding Assessment Chart (MD 55.05, 95% CI 27.83 to 82.28; 3 studies, 335 women; low-certainty evidence). We are uncertain whether the LNG-IUS may have any effect on women's satisfaction up to one year (RR 1.28, 95% CI 1.01 to 1.63; 3 studies, 141 women; I² = 0%, very low-certainty evidence). The LNG-IUS probably leads to slightly higher quality of life measured with the SF-36 compared with other medical therapy if (MD 2.90, 95% CI 0.06 to 5.74; 1 study: 571 women; moderate-certainty evidence) or with the Menorrhagia Multi-Attribute Scale (MD 13.40, 95% CI 9.89 to 16.91; 1 trial, 571 women; moderate-certainty evidence). The LNG-IUS and other medical therapies probably give rise to similar numbers of women with serious adverse events (RR 0.91, 95% CI 0.63 to 1.30; 1 study, 571 women; moderate-certainty evidence). Women using other medical therapy are probably more likely to withdraw from treatment for any reason (RR 0.49, 95% CI 0.39 to 0.60; 1 study, 571 women, moderate-certainty evidence) and to experience treatment failure than women with LNG-IUS (RR 0.34, 95% CI 0.26 to 0.44; 6 studies, 535 women; moderate-certainty evidence). LNG-IUS versus endometrial resection or ablation (EA) Bleeding outcome results are inconsistent. We are uncertain of the effect of the LNG-IUS compared to EA on rates of amenorrhoea (RR 1.21, 95% CI 0.85 to 1.72; 8 studies, 431 women; I² = 21%; low-certainty evidence) and hypomenorrhoea (RR 0.98, 95% CI 0.73 to 1.33; 4 studies, 200 women; low-certainty evidence) and eumenorrhoea (RR 0.55, 95% CI 0.30 to 1.00; 3 studies, 160 women; very low-certainty evidence). We are uncertain whether both treatments may have similar rates of satisfaction with treatment at 12 months (RR 0.95, 95% CI 0.85 to 1.07; 5 studies, 317 women; low-certainty evidence). We are uncertain if the LNG-IUS compared to EA has any effect on quality of life, measured with SF-36 (MD -14.40, 95% CI -22.63 to -6.17; 1 study, 33 women; very low-certainty evidence). Women with the LNG-IUS compared with EA are probably more likely to have any adverse event (RR 2.06, 95% CI 1.44 to 2.94; 3 studies, 201 women; moderate-certainty evidence). Women with the LNG-IUS may experience more treatment failure compared to EA at one year follow up (persistent HMB or requirement of additional treatment) (RR 1.78, 95% CI 1.09 to 2.90; 5 studies, 320 women; low-certainty evidence); or requirement of hysterectomy may be higher at one year follow up (RR 2.56, 95% CI 1.48 to 4.42; 3 studies, 400 women; low-certainty evidence). LNG-IUS versus hysterectomy We are uncertain whether the LNG-IUS has any effect on HMB compared with hysterectomy (RR for amenorrhoea 0.52, 95% CI 0.39 to 0.70; 1 study, 75 women; very low-certainty evidence). We are uncertain whether there is difference between LNG-IUS and hysterectomy in satisfaction at five years (RR 1.01, 95% CI 0.94 to 1.08; 1 study, 232 women; low-certainty evidence) and quality of life (SF-36 MD 2.20, 95% CI -2.93 to 7.33; 1 study, 221 women; low-certainty evidence). Women in the LNG-IUS group may be more likely to have treatment failure requiring hysterectomy for HMB at 1-year follow-up compared to the hysterectomy group (RR 48.18, 95% CI 2.96 to 783.22; 1 study, 236 women; low-certainty evidence). None of the studies reported cost data suitable for meta-analysis. AUTHORS' CONCLUSIONS: The LNG-IUS may improve HMB and quality of life compared to other medical therapy; the LNG-IUS is probably similar for HMB compared to endometrial destruction techniques; and we are uncertain if it is better or worse than hysterectomy. The LNG-IUS probably has similar serious adverse events to other medical therapy and it is more likely to have any adverse events than EA.

Celecoxib versus mefenamic acid in the treatment of primary dysmenorrhea.

Background The objective was to compare the effectiveness and tolerability of mefenamic acid and celecoxib in women with primary dysmenorrhea (PD) and to compare the quality of life of study participants pre- and post-treatment. Materials and methods This was a randomized crossover clinical trial conducted among sexually inactive female adults aged 18-25 years with PD. Participants were asked to rate their pain score and answer a validated quality of life questionnaire (EQ-5D-3L) before and after consumption of each medication in two menstrual cycles. The effectiveness of celecoxib and mefenamic acid in treating PD was compared with regard to reduction in pain score and the need for medical leave and rescue therapy. Drug tolerability was determined by comparing the occurrence of side effects of both drugs. Quality of life scores pre- and post-intervention were measured and compared. Results Mefenamic acid had a comparable effect to celecoxib in relieving symptoms of PD. Both drugs were equally tolerable and showed similar impacts on quality of life. Conclusions This study demonstrated that mefenamic acid and celecoxib had similar effectiveness in improving pain score and quality of life in women with PD.

Mefenamic acid can attenuate depressive symptoms by suppressing microglia activation induced upon chronic stress.

BACKGROUND: Depression is the most debilitating neuropsychiatric disorder, and psychosocial stressors are major risk factors for the onset of depression. Depression is closely associated with chronic inflammation and microglia are the principal mediators of inflammation in the central nervous system (CNS). Mefenamic acid (MA) and celecoxib are nonselective and selective inhibitors of cyclooxygenase (COX), respectively. COX is a key enzyme in mediating inflammatory response in microglia. In this study, we examine the effects of inhibiting COX by MA on depressive-like behaviors and microglia activation in the hippocampus. METHODS: We evaluate the effect of MA on chronic mild stress (CMS) induced depressive-like behavior by sucrose preference and forced swimming tests. Effect of MA on microglia activation in dentate gyrus (DG) of hippocampus was examined by immunohistochemistry. In vitro experiments including western blotting and phagocytosis assay were used to investigate the effect of MA on microglia activation. RESULTS: Behavioral assays reveal MA and celecoxib ameliorate CMS-induced depressive-like behavior. Compared to the stressed mice, the number of activated/phagocytic microglia (Iba1+/CD68+) in DG of hippocampus significantly decreases in stressed mice treated with MA or celecoxib. MA and celecoxib play a role in inhibiting microglia activation by inhibiting of ERK1/2 and P38 MAPK activation and iNOS expression. MA or celecoxib also reduce the high phagocytic activity of activated microglia. CONCLUSION: MA inhibits microglia activation/phagocytosis induced upon chronic stress in the hippocampus, which might result in the improvement of depressive symptoms.

A double-blind controlled crossover study to investigate the efficacy of salix extract on primary dysmenorrhea.

OBJECTIVES: Primary dysmenorrhea in the absence of pelvic pathology is a common gynecologic disorder affecting the quality of life of women of reproductive age. This study evaluates the effect of salix extract on primary dysmenorrhea. DESIGN: This study was a randomized crossover clinical trial. SETTING: The study population included 96 female students with level two or three of primary dysmenorrhea: 48 students in the treatment group (sequence I) followed by control (sequence II) and 48 students in control group (sequence I) followed by treatment (sequence II). INTERVENTIONS: The intervention was salix capsule (400 mg daily) and the active control was mefenamic acid capsule (750 mg daily) as. MAIN OUTCOMES: Pain intensity, measured by the visual analog scale (VAS), amount of bleeding, and severity of dysmenorrhea symptoms were outcomes. Generalized estimating equations were used for data analysis. RESULTS: The demographic and menstrual characteristics of the students were homogenous between the groups. The results showed that the students in mefenamic acid group had a significantly higher level of VAS than the students in the salix group over time (1.61 ± 0.06, P < 0.001). The estimated odds of the bleeding level in the salix and mefenamic acid group were not significantly different (P = 0.31). In average, 77.39%±16.18 of the students in salix group showed no symptoms followed by 22.18%±14.08 of the students who experienced mild symptoms. Averagely, 44.58%±20.16 of the students in the mefenamic acid group had mild symptoms followed by moderate symptoms (28.12%±15.29). CONCLUSIONS: Salix extract significantly decreased dysmenorrhea in comparison to mefenamic acid, as the standard treatment of dysmenorrhea.

Combined hormonal contraceptives for heavy menstrual bleeding.

BACKGROUND: Menorrhagia or heavy menstrual bleeding (HMB) is an excessive blood loss that impairs a woman's quality of life, either physical, emotional, social or material. It is benign and not associated with pregnancy or any other gynaecological or systemic disease. Medical treatments used to reduce excessive menstrual blood loss (MBL) include prostaglandin synthetase inhibitors, antifibrinolytics, oral contraceptive pills, and other hormones. The combined oral contraceptive pill (COCP) is claimed to have a variety of beneficial effects, inducing a regular shedding of a thinner endometrium and inhibiting ovulation, thus having the effect of both treating HMB and providing contraception. More recently, a contraceptive vaginal ring (CVR) has been trialled to investigate whether this treatment can provide similar benefits to COCP while lessening hormonal systemic exposure. This review is an update of a review which originally focused on COCP alone. The scope of the review has been widened to consider other types of delivery of combined hormonal contraceptives for reduction of MBL. OBJECTIVES: To determine the efficacy of combined hormonal contraceptives (pills, vaginal ring or patch) compared with other medical therapies, placebo, or no therapy in the treatment of HMB. A secondary objective was to compare the COCP with the CVR. SEARCH METHODS: We searched the Gynecology and Fertility Group trials register, MEDLINE, Embase, CENTRAL, CINAHL and PsycINFO (search dates: Oct 1996, May 2002, June 2004, April 2006, June 2009, July 2017 and September 2018) for all randomised controlled trials (RCTs) of COCP and CVR for the treatment of HMB. We also searched trial registers and the reference lists of retrieved studies for additional trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of the use of COCP or CVR compared with no treatment, placebo, or other medical therapies for women with HMB and regular menstrual cycles. DATA COLLECTION AND ANALYSIS: All assessments of trial quality and data extraction were performed unblinded by at least two review authors. Our primary review outcomes were treatment success, menstrual bleeding (assessed objectively, semi-objectively or subjectively), and participant satisfaction with treatment. Secondary outcomes were adverse events, quality of life, and haemoglobin level. MAIN RESULTS: We identified eight RCTs involving 805 participants. Two trials comparing COCP with placebo were considered to be moderate quality and the remaining studies were low to very low quality, mainly because of serious risk of bias from lack of blinding and concerns over precision.COCP versus placeboCOCP, with a step-down oestrogen and step-up progestogen regimen, improved response to treatment (return to menstrual 'normality') (OR 22.12, 95% CI 4.40 to 111.12; 2 trials; 363 participants; I2 = 50%; moderate-quality evidence), and lowered MBL (OR 5.15, 95% CI 3.16 to 8.40; 2 trials; 339 participants; I2 = 0%; moderate-quality evidence) when compared to placebo. The results suggested that, if the chance of 'successful' treatment was 3% in women taking placebo, then COCP increased this chance from 12% to 77% in women with unacceptable HMB. Minor adverse events, in particular breast pain, were more common with COCP. No study in this comparison reported semi-objectively assessed MBL or participant satisfaction with treatment.COCP versus other medical treatmentsNon-steroidal anti-inflammatory drugs (NSAIDs)There was insufficient evidence to determine whether the COCP reduced MBL when compared to NSAIDs (mefenamic acid and naproxen). No study in this comparison reported semi-objectively assessed MBL, subjectively assessed MBL, participant satisfaction with treatment or adverse events.Levonorgestrel-releasing intrauterine system (LNG IUS)The LNG IUS was more effective than COCP in reducing MBL (OR 0.21, 95% CI 0.09 to 0.48; 2 trials; 151 participants; I2 = 0%; low-quality evidence) but it was not clear whether satisfaction with treatment or adverse effects varied according to which treatment was used. No study in this comparison reported semi-objectively assessed MBL or subjectively assessed MBL.Contraceptive vaginal ring (CVR) versus other medical treatmentsCOCP COCP was compared with CVR in two trials. There were discrepancies between some of the findings and there was no evidence of a benefit for one treatment compared to the other for response to treatment, MBL or participant satisfaction with treatment. There was a greater likelihood of nausea with COCP. No study in this comparison reported objectively assessed MBL or subjectively assessed MBL.ProgestogensCVR was compared to long course progestogens in one trial. It is possible that CVR increased the odds of satisfaction; but we are uncertain whether CVR improved MBL. The evidence was based on small numbers of participants and was very low quality, so definitive conclusions could not be reached. No study in this comparison reported objectively assessed MBL, subjectively assessed MBL, or adverse events. AUTHORS' CONCLUSIONS: Moderate-quality evidence suggests that the combined oral contraceptive pill over six months reduces HMB in women with unacceptable HMB from 12% to 77% (compared to 3% in women taking placebo). When compared with other medical options for HMB, COCP was less effective than the LNG IUS. Limited evidence suggested that COCP and CVR had similar effects. There was insufficient evidence to determine comparative efficacy of combined hormonal contraceptives with NSAIDs, or long course progestogens.

Mefenamic Acid Attenuates Chronic Alcohol Induced Cognitive Impairment in Zebrafish: Possible Role of Cholinergic Pathway.

Based on the scientific evidence supporting the neuroinflammatory response contributes the cognitive impairment associated with chronic alcoholism and the neuroprotective actions of mefenamic acid with reversal of memory loss and brain inflammation in mice, this study was designed to evaluate the effect of mefenamic acid against chronic alcohol induced cognitive impairment in zebrafish model. Zebrafish were grouped and subjected to normal behavioral analysis in light-dark chamber for 10 days. The preference to dark compartment was noted in zebrafish. Zebrafish were grouped and exposed to escalating doses of alcohol for 28 days with and without mefenamic acid exposure (100 and 200 µg/L) and subjected to a fear conditioning passive avoidance task from day 13 of 28. The cognitive evaluation was performed for 10 days and the brain tissue was isolated to estimate acetylcholinesterase activity. In cognitive evaluation study, the normal zebrafish retained the memory of the learned task and avoided the dark. The alcohol exposed zebrafish showed impairment in retaining the memory of learned task. Mefenamic acid exposed zebrafish showed a significant protection against cognitive impairment caused by alcohol and retained the memory of learned task with a significant decrease in AChE activity in brain homogenate compared to alcohol exposed zebrafish. The results of this study suggest that the memory enhancing activity of mefenamic acid might be due to activation of cholinergic transmission that has protected neuroinflammatory and neurodegenerative conditions caused by alcohol.

Effect on Risk of Stroke and Acute Myocardial Infarction of Nonselective Nonsteroidal Anti-Inflammatory Drugs in Patients With Rheumatoid Arthritis.

There are still debates on the association of increased cardiovascular risk with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with rheumatoid arthritis (RA) because of inconsistent results. Therefore, our study aims to evaluate the transient effects of selective and nonselective NSAIDs on the risk of stroke and acute myocardial infarction (AMI) in patients with RA. We conducted a case-crossover study of 5,921 stroke or AMI patients with co-morbidity of RA. All cases were identified from the Taiwan National Health Insurance Database between January 1, 2006, and December 31, 2011, according to the International Classification of Diseases, 9th Revision and Clinical Modification diagnosis codes from inpatient claims. The index date was defined as the date of hospitalization for stroke or AMI. Exposure to NSAIDs was compared during a case period (1 to 30 days before the index date) with a control period (91 to 120 days before the index date). The adjusted odds ratios (ORs) of stroke and AMI were estimated using conditional logistic regression models. Our results showed that overall NSAIDs use increased the risk of stroke by 1.40-fold (95% confidence interval [CI] 1.25 to 1.56) and risk of AMI by 1.73-fold (95% CI 1.29 to 2.32). After classifying NSAIDs into selective and nonselective groups, only nonselective NSAIDs use significantly increased the risks of stroke (adjusted OR 1.39; 95% CI 1.25 to 1.55) and AMI (adjusted OR 1.82; 95% CI 1.37 to 2.41), respectively. In conclusion, nonselective NSAIDs were associated with an increased risk of both stroke and AMI in patients with RA.

Comparison of the effect of honey and mefenamic acid on the severity of pain in women with primary dysmenorrhea.

BACKGROUND AND OBJECTIVE: Primary dysmenorrhea starts simultaneously with menstruation or before it and usually continues for 48-72 h. As a prevalence disorder, it affects about 80-97% of women in the reproductive age. The conventional treatment modalities of primary dysmenorrhea are associated with complications and side effects. In addition, there is a lack of knowledge of the effect of honey on the treatment of primary dysmenorrhea. The objective of this study is to investigate the effect of honey on the severity of pain in women with dysmenorrhea. METHODS: A randomized crossover clinical trial was conducted on 56 female students. Subjects were randomly assigned to two groups. Groups I and II received honey and mefenamic acid in the 'first treatment period', respectively. In the 'second treatment period', the intervention methods were reversed between the groups. Samples recorded the severity of pain during the first 3 days of menstruation. RESULTS: There were no significant differences in the most severe level of pain in the first and second months of the first treatment period, and the first and second months of the second treatment period between the groups. CONCLUSIONS: Honey and the mefenamic acid capsules led to the same amount of pain relief in women with primary dysmenorrhea. Honey is suggested to be used for pain relief due to its lower side effects and pharmacological complications.