Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the main causes of fixed drug eruption (FDE). Cross-sensitivity between chemically unrelated NSAIDs has been rarely described in FDE. We report herein two cases of NSAID-induced FDE confirmed by oral provocation test (OPT) with a literature review. Case 1 is a 49-year-old woman who took mefenamic, naproxen and acetaminophen for lumbago. On the second day, she noticed three erythematous plaques, located in the upper lip, chin and the right hand, which faded spontaneously, leaving residual patches. Three months later, she took mefenamic acid with reactivation of the same plaques. She received naproxen. On the same day, she exhibited a reactivation of lesions with the development of a new one. These lesions have disappeared leaving hyperpigmented sequelae. After negative patch test to naproxen, an OPT was performed with positive reaction, observed on the third day. To establish the cross-reactivity, she underwent OPTs, which gave positive results to indomethacin, ketoprofen and tiaprofenic acid. Case 2 is a 52-year-old woman who presented painful dusky-red macules, located in the right and left wrists, 24 hours after taking mefenamic acid. She described two similar events that occurred in the past with an undefined drug and piroxicam. Patch tests to lysine acetylsalicylate, mefenamic acid, piroxicam, naproxen and celecoxib were negative. OPTs to the same NSAIDs gave positive results to lysine acetylsalicylate, piroxicam and mefenamic acid. Thirteen case reports, seven case series and one retrospective analysis, including cases with confirmed cross-reactivity between NSAIDs, were reported in literature. Clinicians should be aware of such phenomenon.

BACKGROUND: One of the most common complaints for women is dysmenorrhea. Several studies investigated the treatment effects of medicinal plants on primary dysmenorrhea.
OBJECTIVE: 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).
CONCLUSIONS: 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.

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BACKGROUND: Mefenamic acid-induced enteropathy may be an under-recognized condition because few reported cases and no review of literature to comprehensively describe all reported cases exist. From inception until February 2017, a systematic literature search identified twenty original reports of cases of mefenamic acid-induced enteropathy. Additional five cases were identified at our hospital. All cases were included in the analyses.
UNASSIGNED: Most patients had been regularly taking therapeutic dosages of mefenamic acid for at least three months before symptoms developed. All patients presented with chronic diarrhea with significant weight loss. Approximately one-third of the cases had some degree of anemia and hypoalbuminemia.
UNASSIGNED: Endoscopic findings could range from very mild abnormalities, such as mild atrophic mucosa, to marked abnormalities, such as blunted villi with scalloping appearance in the small intestine and inflamed mucosa with a few superficial ulcers in the ileum and colon. Pathological findings included flattened small intestinal villi and mixed inflammatory infiltrates including eosinophils in lamina propria.
METHODS: After identifying history of prolong mefenamic acid exposure, all patients were prescribed to stop this medication. Nutritional support and substitutional treatment for mefenamic acid were provided as well.
RESULTS: All symptoms responded dramatically to drug withdrawal. Some patients could change to use other nonsteroidal anti-inflammatory drugs (NSAIDs) without symptoms reoccurring.
CONCLUSIONS: Unlike other traditional NSAIDs, mefenamic acid could induce intestinal villous atrophy. An adequate drug history is crucial to identifying the condition. Protracted diarrhea occurring during treatment should be the indication to cease the medicine promptly.

Menstrually related migraine (MRM) headache is common in women and associated with substantial disability. Compared to nonmenstrual migraine, MRM attacks are more severe, longer in duration, and have a poorer response to analgesics. The purpose of this guideline is to provide a systematic review and meta-analysis of the existing therapy trials for MRM and evidence-based recommendations for acute and short-term preventive treatment of MRM headache. Prospective, double-blind, randomized controlled trials of any pharmacologic agent for the symptomatic relief or prevention of MRM headache were included in the guideline. The main outcomes considered were the pain response and pain-free response at 2 hours for acute treatment trials, and the incidence of MRM or the number of days on which MRM attacks occurred for short-term prevention trials. Nineteen trials were included in the analysis. The US Preventive Services Task Force quality criteria were used to assess trial quality and to grade recommendations. Based on the evidence, grade B recommendations can be made for the use of sumatriptan 50 and 100 mg, mefenamic acid 500 mg, and rizatriptan 10 mg for the acute treatment of MRM. For the preventive treatment of MRM, there are grade B recommendations for the perimenstrual use of transcutaneous estrogen 1.5 mg, frovatriptan 2.5 mg twice daily, and naratriptan 1 mg twice daily. Choosing among treatment strategies must be based on clinical considerations.

There are no studies verifying that mefenamic acid is more effective than other NSAID (= non-steroidal anti-inflammatory drugs). However, there are several notions in the literature that this drug is less well-tolerated than other NSAID because over a prolonged period of application more lesions of the upper gastro-intestinal tract are induced as well as occasionally renal insufficiency. Compared to other NSAID the systemic toxicity starts already with relatively low doses above the maximal daily dose. Considering current knowledge there is no reason to prefer mefenamic acid to other NSAID.

Sulfotransferase catalyzes the transfer of sulfate, donated by 3\'-phosphoadenosine-5\'-phosphosulfate, to an acceptor substrate that may be a hydroxy group or an amine group. Man is exposed daily to drugs and dietary chemicals that can inhibit sulfotransferase activity. The aim of this study was to review the literature concerning the inhibition of sulfotransferases by drugs and dietary chemicals in the human liver and duodenum. The IC50 value of mefenamic acid for human liver phenol sulfotransferase (SULT 1A1) was 0.02 microM and for human liver catechol sulfotransferase (SULT1A3) 76 microM with a SULT 1A3/SULT1A1 ratio for the IC50 of 3,800. Mefenamic acid is therefore a potent and selective inhibitor of human liver SULT1A1. The IC50 values of mefenamic acid for the sulfation rates of (-)-salbutamol and (-)-apomorphine were 4 orders of magnitude greater in the human duodenum than in the liver. Salicylic acid inhibited the sulfation of (-)-apomorphine in human liver with an IC50 of 54 gM but did not inhibit the sulfation of (-)-apomorphine in human duodenum. Quercetin, a flavonoid present in edible fruit, vegetable and wine, was a potent inhibitor of human liver SULT1A1 and estrogen sulfotransferase (EST) activities and the sulfation of resveratrol. Quercetin inhibited the sulfation of dopamine, (-)-salbutamol, minoxidil and paracetamol and the IC50 values were 1 - 2 orders of magnitude greater in human duodenum than in the liver. In conclusion, mefenamic acid, salicylic acid and quercetin inhibit SULT1A1 whereas SULT1A3 is relatively resistant to the inhibition by these compounds. Under particular circumstances, human duodenum sulfotransferase is more resistant than liver sulfotransferase to the inhibition by mefenamic acid, salicylic acid and quercetin.

OBJECTIVE: To quantify the efficacy and safety of naproxen, ibuprofen, mefenamic acid, aspirin and acetaminophen (paracetamol) in the treatment of primary dysmenorrhoea through a systemic overview of randomised controlled trials.
METHODS: MEDLINE, EMBASE and the Science Citation Index were searched for randomised controlled trials. Efficacy was assessed by measurement of pain relief, requirement for rescue analgesics, restriction of daily life and absence from work or school. The rate ratios of side effects were used to assess safety.
RESULTS: Fifty-six trials describing 55 comparisons of analgesics with placebo and 12 direct comparisons with other analgesics met our inclusion criteria. Women taking naproxen were over three times more likely to have at least moderate pain relief than those taking placebo. Ibuprofen, mefenamic acid and aspirin were also superior to placebo but acetaminophen was not. The requirement for rescue analgesics, restriction of daily life and absence from work or school were less frequent with naproxen and ibuprofen than placebo but not with aspirin or acetaminophen. Direct comparisons did not show any difference between naproxen and ibuprofen. Side effects occurred more frequently only with naproxen when compared with placebo.
CONCLUSIONS: Naproxen, ibuprofen, mefenamic acid and aspirin are all effective in primary dysmenorrhoea. Ibuprofen appears to have the most favourable risk-benefit ratio. Acetaminophen appears to be less effective than nonsteroidal anti-inflammatory drugs, but there was only one trial meeting our inclusion criteria and further studies are required.

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