Unraveling Prostaglandin and NLRP3 Inflammasomemediated Pathways of Primary Dysmenorrhea and the Role of Mefenamic Acid and Its Combinations

Painful menstrual cramps during or around the time of the monthly cycle are known as dysmenorrhea. The estimated global prevalence in women of reproductive age ranges from 45% to 95%. It has a significant negative impact on regular activities and productivity at work. However, despite the severe consequences on quality of life, primary dysmenorrhea (PD) is underdiagnosed. Dysmenorrhea has complex pathogenesis. It involves the release of prostaglandins and activation of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome and also includes the involvement of other mediators such as bradykinin, histamine and acetylcholine. Even though nonsteroidal anti-inflammatory drugs (NSAIDs) remain the most common type of pain medication, the question of which one should be the most preferred is still open to debate. The current review examines the existing evidence for the pathogenesis of PD and makes evidence based and clinical experience based recommendations for the use of mefenamic acid and its combination in the treatment of dysmenorrhea. Mefenamic acid alleviates PD by inhibiting endometrial prostaglandin formation, restoring normal uterine activity, and reducing the inflammatory response by inhibiting the NLRP3 inflammasome and reducing the release of cytokines such as interleukin (IL)-1?. It is also known to have bradykinin antagonist activity. Dicyclomine has a dual action of blocking the muscarinic action of acetylcholine in postganglionic parasympathetic effect or regions and acting directly on uterine smooth muscle by blocking bradykinin and histamine receptors to relieve spasms. According to the experts, mefenamic acid and dicyclomine act synergistically by acting on the different pathways of dysmenorrhea by blocking multifactorial agents attributed to the cause of dysmenorrhea. Hence, the combination of mefenamic acid and dicyclomine should be the preferred treatment option for dysmenorrhea.

NLRP3 Inflammasome in the Pathogenesis of Dysmenorrhea and Role of Mefenamic Acid as its Inhibitor

While the role of prostaglandin as a trigger in dysmenorrhea is well known, not many are aware that inflammation and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome are also implicated in primary dysmenorrhea (PD). Inhibition of NLRP3 inflammasome and inflammation pathways is an important approach to treating dysmenorrhea and also the symptoms of premenstrual syndrome. Mefenamic acid is an effective and selective inhibitor of the NLRP3 inflammasome, which can be considered the most important option for PD treatment owing to its action via various pathways. In this article, the authors have reviewed the role of inflammation and NLRP3 inflammasome in causing PD, how inhibitors of NLRP3 inflammasome can treat dysmenorrhea and the mechanism of action of mefenamic acid as NLRP3 inflammasome inhibitor and its role in PD.

Losartan: Benefits Beyond Hypertension

Losartan was the first angiotensin AT1 receptor blocker (ARB) approved by US Food and Drug Administration (FDA) for the treatment of hypertension. In addition to its established antihypertensive and end organ effects, several benefits of losartan beyond its antihypertensive effect have been demonstrated in clinical trials. Apart from its class effects of ARBs, losartan has pharmacokinetic and pharmacodynamic properties that are unique to it. It has shown considerable benefits as uricosuric agent, in erectile dysfunction and in prevention of stroke in hypertension patients with left ventricular hypertrophy. This review presents the benefits of losartan beyond being a hypertensive agent and associated clinical outcomes.

Role of Prostaglandins in Pathogenesis of Dysmenorrhea and Place of Mefenamic Acid and Dicyclomine in its Management

Despite being one of the most common gynecological issues faced by women of reproductive age, dysmenorrhea largely remains an ignored, underdiagnosed and untreated condition. It continues to be a public health issue and has a significant impact on the quality of life of the affected women in terms of inability to lead routine activities, absenteeism from academic activities or work and reduced social activities. Currently, existing evidence correlates and implicates the excessive synthesis of prostaglandins with the menstrual pain. Hence, treatment approaches that can inhibit prostaglandins' production or already formed prostaglandins can provide relief in dysmenorrhea. In this review, the impact of dysmenorrhea on the quality of life of women, the role of prostaglandins in the pathogenesis of dysmenorrhea, and how nonsteroidal anti-inflammatory drugs (NSAIDs) like mefenamic acid can be safe and effective in managing dysmenorrhea are discussed.

Inflammasome, Inflammation, Infection and Mefenamic Acid

Nucleotide-binding oligomerization domain like receptors (NLRs) –intracellular proteins, are a recently discovered class of innate immune receptors that play a crucial role in initiating the inflammatory response following pathogen recognition. The dysregulation of NLRP3 inflammasome can cause uncontrolled inflammation and drive the development of a wide variety of human diseases. Mefenamic acid which belongs to fenamate group inhibits the NLRP3 inflammasome by inhibiting efflux of chloride ions and influx of calcium ions through blocking VRAC and TRPM2 respectively. Thus, Mefenamic acid provides a potentially practical pharmacological approach for treating NLRP3- driven diseases

Dapagliflozin in the Landscape of Type 2 Diabetes Management

As per current statistics, India accounts for more than 74 million individuals living with diabetes. Many of these individuals have associated cardiovascular disease (CVD) and chronic kidney disease (CKD) comorbidities. Optimal glycemic management is important because uncontrolled glycemia may accelerate the macrovascular and microvascular complications, further aggravating the comorbid conditions. Metformin is used as the first-line therapy in most persons. However, there are some who do not tolerate metformin, are unable to achieve required glycemic targets or require greater efforts for cardiovascular (CV) risk reduction. These patients require an alternative hypoglycemic agent to be used as either monotherapy or as combination treatment with metformin, respectively. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are one such novel class of drugs that can be used as either monotherapy or as part of two drug (dual) or three drug (triple) combinations with other oral hypoglycemic agents or insulin. Dapagliflozin is a promising option for managing type 2 diabetes with CV and renal benefits, weight and blood pressure reducing properties. A low risk of hypoglycemia and drug-drug interactions are the added advantages. In this article, the authors have reviewed the existing clinical evidences on dapagliflozin and highlighted its place in the diabetes management landscape