Flufenamic Acid in Treatment of Primary Spasmodic Dysmenorrhœa

Kapadia, Lalit D.; Elder, M. G.

doi:10.1016/s0140-6736(78)91078-4

Cited by 36 publications

(14 citation statements)

References 11 publications

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“…Interestingly, doxorubicinol is highly cardiotoxic, and it is believed that doxorubicinol is responsible for the cardiotoxicity associated with doxorubicin chemotherapy [39,40]. Since the AKR inhibitor 5β-cholanic acid is a well-tolerated naturally occurring bile acid in humans, and since flufenamic acid has been used in clinical trials with manageable toxicities [41], there may be significant value in conducting clinical trials in which either 5β-cholanic acid or flufenamic acid are co-administered with doxorubicin during chemotherapy. Results in this study would suggest that these AKR inhibitors may increase tumour levels of doxorubicin and block cardiotoxicity induced by doxorubicin conversion to doxorubicinol.…”

Section: Discussionmentioning

confidence: 99%

Role of aldo-keto reductases and other doxorubicin pharmacokinetic genes in doxorubicin resistance, DNA binding, and subcellular localization

et al. 2012

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BackgroundSince proteins involved in chemotherapy drug pharmacokinetics and pharmacodynamics have a strong impact on the uptake, metabolism, and efflux of such drugs, they likely play critical roles in resistance to chemotherapy drugs in cancer patients.MethodsTo investigate this hypothesis, we conducted a whole genome microarray study to identify difference in the expression of genes between isogenic doxorubicin-sensitive and doxorubicin-resistant MCF-7 breast tumour cells. We then assessed the degree of over-representation of doxorubicin pharmacokinetic and pharmacodynamic genes in the dataset of doxorubicin resistance genes.ResultsOf 27,958 Entrez genes on the array, 7.4 per cent or 2,063 genes were differentially expressed by ≥ 2-fold between wildtype and doxorubicin-resistant cells. The false discovery rate was set at 0.01 and the minimum p value for significance for any gene within the “hit list” was 0.01. Seventeen and 43 per cent of doxorubicin pharmacokinetic genes were over-represented in the hit list, depending upon whether the gene name was identical or within the same gene family, respectively. The most over-represented genes were within the 1C and 1B families of aldo-keto reductases (AKRs), which convert doxorubicin to doxorubicinol. Other genes convert doxorubicin to other metabolites or affect the influx, efflux, or cytotoxicity of the drug. In further support of the role of AKRs in doxorubicin resistance, we observed that, in comparison to doxorubicin, doxorubincol exhibited dramatically reduced cytotoxicity, reduced DNA-binding activity, and strong localization to extra nuclear lysosomes. Pharmacologic inhibition of the above AKRs in doxorubicin-resistant cells increased cellular doxorubicin levels, restored doxorubicin cytotoxicity and re-established doxorubicin localization to the nucleus. The properties of doxorubicinol were unaffected.ConclusionsThese findings demonstrate the utility of using curated pharmacokinetic and pharmacodynamic knowledge bases to identify highly relevant genes associated with doxorubicin resistance. The induction of one or more of these genes was found to be correlated with changes in the drug’s properties, while inhibiting one specific class of these genes (the AKRs) increased cellular doxorubicin content and restored drug DNA binding, cytotoxicity, and subcellular localization.

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Section: Discussionmentioning

confidence: 99%

Role of aldo-keto reductases and other doxorubicin pharmacokinetic genes in doxorubicin resistance, DNA binding, and subcellular localization

et al. 2012

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“…Flufenamic acid (69,79,80), mefe namic acid (79,81,82,87), and tolfenamic acid (73) have been shown to be effective in dysmenorrhea. The fenamates have a PG-antagonistic prop erty on smooth muscles (83)(84)(85)(86)(87)(88) including the myometrium (86-88).…”

Section: The Fenamatesmentioning

confidence: 99%

Prostaglandins and Nonsteroidal Antiinflammatory Drugs in Dysmenorrhea

Çhan¹

1983

Annu. Rev. Pharmacol. Toxicol.

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INTRODUCTIONDysmenorrhea, commonly known as menstrual pain or cramps, is classifi ed into primary and secondary dysmenorrhea. Generally, primary dysmenorr hea has its inception at the onset of or soon after menarche and characteris tically has no identifiable macroscopical pathology. In contrast, secondary dysmenorrhea usually has its onset in adulthood and is associated with specific pelvic pathology. Some of the causes of secondary dysmenorrhea are endometriosis, uterine polyps, pelvic inflamm atory diseases, uterogeni tal anatomical anomaly, and intrauterine device. Primary dysmenorrhea is by far the more prevalent form.The incidence and prevalence of primary dysmenorrhea have not been established, but it has been estimated that as many as 50% of women of reproductive age, particularly nulliparas, suffer from dysmenorrhea at one time or other. In approximately 10% of these dysmenorrheic subjects, the symptoms are disabling enough to cause incapacitation for one to two days a month (1-4). Primary dysmenorrhea is the most common gynecologic complaint. Because of its cyclic recurring nature, the medical and socioeco nomic impact of dysmenorrhea is enormous. It is the greatest single cause of lost work hours and school days among women (5-8), with more than 140 million work hours estimated to be lost annually (4). With increasing numbers of women entering the work force, dysmenorrhea may cause an even greater economic loss to society. 131Annu. Rev. Pharmacol. Toxicol. 1983.23:131-149. Downloaded from www.annualreviews.org Access provided by University of California -Davis on 02/03/15. For personal use only. Quick links to online content Further ANNUAL REVIEWS 132 CHAN Despite the prevalence of dysmenorrhea, until very recently, medicine has made very little headway either toward the understanding of the patho physiology of dysmenorrhea or the discovery of a specifi c and effective therapy for this female malady. The introduction of oral contraceptives in the 19608 marked the advent of the first effective therapeutic agent for the treatment of primary dysmenorrhea. Oral contraceptives, however, are not specific agents for dysmenorrhea. Until that time, treatments for dys menorrhea were primarily symptomatic, involving strong analgesics, an tidepressants, alcohol, and a variety of home remedies. These therapeutic approaches have not been successful, because of either lack of efficacy or unacceptable side effects. The first rational therapy for dySmenorrhea ap peared on the medical scene as late as the mid 19708, when the relationship between prostaglandin (pG) and dysmenorrhea was recognized and the newer nonsteroidal anti-in1lamm atory drugs (NSAIDs) with PG synthetase inhibitory activity were being introduced to the general medical practice.This review focuses on the etiologic role of PO in primary dysmenorrhea and therapeutic suppression of uterine PG production as a specifi c therapy for dysmenorrhea. PATHOPHYSIOLOGY OF PRIMARY DYSMENORRHEAMany theories have been proposed for the cause of dysmenorrhea. These inc...

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“…P=.03). Of the 267 girls who responded to the disability items, 59% were clas¬ sified as mildly disabled when experiencing menstrual discomfort (total disability score range, 0-6) compared with 36% who were classified as moderately disabled (to¬ tal disability score range, 7-15) and 5% who were clas¬ sified as severely disabled (total disability score range,[16][17][18][19][20][21][22][23]. Symptom Severity Scale scores greater than or equal to 20 were considered mild discomfort; scores between 21 and 40, moderate dis¬ comfort; and scores between 41 and 60, severe discom¬ fort.…”

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confidence: 99%