Efficacy and Tolerability Evaluation of a Nutraceutical Composition Containing Vitex agnus-castus Extract (EVX40™), Pyridoxine, and Magnesium in Premenstrual Syndrome: A Real-World, Interventional, Comparative Study.

Background Pre-menstrual syndrome (PMS) is a condition associated with altered hormone levels during the menstrual phase of females and is characterised by physical, emotional, and behavioural symptoms that have a negative impact on the quality of life of females. The symptoms of PMS may vary between individuals, but the major complication is pain, especially during menstrual days. The current treatment strategy involves the use of hormonal therapies and analgesics for symptomatic relief, but these therapies have a risk of potential side effects. The use of herbal and nutraceutical supplements in PMS conditions is increasing due to their long-term safety and proven efficacy. The current real-world study aimed to evaluate the efficacy and tolerability of Ezedayz® tablets containing Vitex agnus-castus extract (EVX40™), vitamin B6, and magnesium in PMS subjects. Methodology A real-world, open-label study was conducted involving 64 participants with varied severity of PMS symptoms. Participants were categorised into Group A (N=23) receiving standard therapies, Group B (N=20) receiving Ezedayz® tablets, or Group C (N=21) receiving standard and Ezedayz® therapy. Standard therapies were provided as per physician supervision, and Ezedayz® tablets were given for 90 days. All subjects were evaluated on core symptoms of PMS like menstrual backache, menstrual cramps, joint or muscle pain, and headache using the numerical rating scale (NRS), and quality-of-life (QoL) was evaluated using a QoL questionnaire. A spontaneous reporting methodology was used to evaluate the tolerability of the therapies provided. Statistical analysis was performed as per the statistical plan. A p-value of <0.05 was considered statistically significant. Results Out of 64 participants, five were lost to follow-up, and the data of 59 participants were included in the final analysis. All groups showed improvement in all evaluated parameters, but Group B and Group C showed greater improvement at the end of the study in all evaluated parameters. The quality-of-life assessment revealed greater improvement in Group B and Group C participants compared to Group C in all evaluated QoL parameters. No serious side effects were observed in any subjects. Conclusion The results of the current study conclude that the nutraceutical composition of Vitex agnus-castus extract, vitamin B6, and magnesium is effective in reducing the severity of PMS symptoms and improving the quality of life of PMS subjects. The nutraceutical therapy provided greater relief from PMS symptoms compared to standard therapy alone, and this effect was augmented when the nutraceutical therapy was provided in combination with standard therapies. Similarly, the improvement in quality-of-life parameters was greater in subjects treated with nutraceuticals alone or in combination therapy. Despite the limitations of the study, the results of the current study are promising, and the nutraceutical composition (Ezedayz®) can be effectively used in clinical settings to control symptoms and improve the quality of life of PMS patients.

Hepatoprotective and antioxidant effect of Adiantum lunulatum Burm. F. leaf in alcohol-induced rat model.

Background Adiantum lunulatum Burm. F. leaf (AL) and its related species have been used traditionally for the treatment of various diseases. Objective The present study evaluated the hepatoprotective, and antioxidant activities of ethanolic extract of AL. Methodology and Result The hepatoprotective effect of AL was evaluated against ethanol-induced hepatotoxicity in rats. Administration of ethanol (2 g/kg) showed a significant biochemical and histological deterioration in the liver of experimental animals. Pretreatment with ethanolic extract of AL (250 and 500 mg/kg b.wt. p.o) significantly reduced the elevated levels of serum enzymes like serum glutamic-oxaloacetic transaminase (AST), serum glutamic-pyruvic transaminase (ALT), alkaline phosphatase (ALP), total protein, total bilirubin and reversed the hepatic damage in the liver which evidenced the hepatoprotective activity. The superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) level notably increased due to doses of AL. Conclusion The results of the present study demonstrate that the ethanolic extract of AL possesses hepatoprotective and antioxidant activities. Graphical Abstract.

Differential effects of dexamethasone and rosiglitazone in a sephadex-induced model of lung inflammation in rats: possible role of tissue inhibitor of metalloproteinase-3.

OBJECTIVES: To study the effects of two different classes of drugs in sephadex-induced lung inflammation using rats and explore the potential mechanism (s). MATERIALS AND METHODS: Effects of dexamethasone (0.3 mg/kg, p.o.) and rosiglitazone (10 mg/kg, p.o.) treatments were evaluated up to 3 days in sephadex challenged rats. 72 h postsephadex administration, broncho-alveolar lavage fluid (BALF) was collected for cell count and cytokine estimation. Lung tissues were harvested for gene expression and histopathology. RESULTS: Dexamethasone treatment resulted in significant inhibition of lymphocytes, monocytes, eosinophils and neutrophils, whereas rosiglitazone inhibited eosinophils and neutrophils only. Further, dexamethasone reduced the elevated levels of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) after sephadex challenge while rosiglitazone significantly reduced the PGE2 levels without altering LTB4 in the BALF. Hydroxyproline content in rat lung homogenate was significantly reduced with dexamethasone treatment but not with rosiglitazone. Both the drugs were found to suppress matrix metallo proteinase 9, whereas only dexamethasone showed inhibition of tumor necrosis factor-alpha and up-regulation of tissue inhibitor of metalloproteinase 3 (TIMP-3) expression and preserved the broncho-alveolar microstructure. CONCLUSIONS: Our results revealed that up-regulation of TIMP-3 corroborated well with dexamethasone mediated inhibition of collagen degradation and restoration of alveolar micro-architecture.

Chemopreventive effect of a novel, selective TACE inhibitor on DMBA- and TPA-induced skin carcinogenesis.

UNLABELLED: Abstract Context: Tumor necrosis factor (TNF)-α, a potent proinflammatory cytokine, plays a major role in the pathogenesis of cancer. TNF-α converting enzyme (TACE) mediates processing and release of biologically active TNF-α. OBJECTIVE: We aimed to investigate the effect of a novel, selective TACE inhibitor (compound 11p) on skin inflammation and associated tumorigenesis in mice. METHODS: Skin edema was induced in mice by dermal application 12-O-tetradecanoylphorbol-13-acetate (TPA) solution in acetone on to the ear and the effect of post-treatment of compound 11p (topical application) was evaluated. Edema and inflammation was assessed by measuring ear thickness, weight of skin punch and cytokine levels. Skin cancer in mice was initiated by single topical application of 7,12-dimethylbenz[a]anthracene (DMBA) and promoted by repeated TPA application for 20 weeks. The effect of compound 11p on papilloma incidence and multiplicity was evaluated. RESULTS: Treatment with compound 11p strongly suppressed TPA-induced elevation in skin thickness and weight. A dose-dependent suppression in TPA-mediated TNF-α, IL-6, IFN-γ, IL-17 and PGE2 levels which was associated with a decrease in infiltration of inflammatory cells was also observed with the treatment. Moreover, compound 11p treatment delayed the onset, markedly reduced the papilloma incidence and multiplicity persuaded by DMBA and TPA. DISCUSSION AND CONCLUSION: These findings suggest that selective blockade of TACE suppresses TPA-induced epidermal hyperplasia, inflammatory cell infiltration and cytokine level. Inhibition of inflammatory events related to tumor growth might have led to the anti-tumor effect in mouse skin cancer model induced by DMBA and TPA.

Assessment of demographics, treatment strategies, and evidence-based medicine use among diabetic and non-diabetic patients with acute coronary syndrome: A cohort study.

OBJECTIVES: To evaluate and compare clinical and epidemiological characteristics, treatment strategies, and utilization of evidence-based medicine (EBM) among coronary artery disease (CAD) patients with or without diabetes. MATERIALS AND METHODS: Prospective observational cohort study from a tertiary care hospital in India among patients with CAD (myocardial infarction, unstable angina, or chronic stable angina). Data included demographic information, vital signs, personal particulars, risk factors for CAD, treatment strategies, and discharge medications. We evaluated epidemiologic characteristics and treatment strategies for diabetic and non-diabetic patients. RESULTS: Of 1,073 patients who underwent angiography, 960 patients (30% diabetic) had CAD. Proportion of hypertensive patients was higher among diabetic patients (58 vs 35% non-diabetic, P < 0.001). Similar proportion of patients received medical management in diabetic vs non-diabetic CAD patients (35 vs 34%, P = 0.091); in diabetics the use of surgical procedure was higher (22 vs 17%, P = 0.0230) than interventional strategy (percutaneous transluminal coronary angioplasty, 43 vs 49%, P = 0.0445). Key medications (antiplatelet agents, angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB), beta-blockers, and ahtihyperlipidemic agents) were prescribed in 95, 53/12, 67, and 91% diabetic (n = 252) and 96, 51/8, 67, and 94% non-diabetic (n = 673) patients, respectively on discharge. CONCLUSIONS: Clustering of several risk factors at presentation, typically diabetes and hypertension, is common in CAD patients. Though diabetic patients are managed more conservatively, utilization of EBM for diabetic and non-diabetic patients is consistent with the recommendations.

Involvement of TACE in colon inflammation: a novel mechanism of regulation via SIRT-1 activation.

TNF-α converting enzyme (TACE) processes the membrane TNF-α to release the bioactive soluble TNF-α. Several evidences suggest the involvement of TNF-α and TACE in inflammatory bowel disease (IBD). Tissue inhibitor of metalloproteinase (TIMP)-3, an endogenous inhibitor of TACE, is positively associated with silent information regulator (SIRT)-1. We aimed to study the expression of TACE, TIMP-3 and SIRT-1 at different stages of colitis and how TACE is regulated in response to SIRT-1 activation. Acute colitis was induced by 3.5% dextran sulfate sodium (DSS) in drinking water for 5days and levels of cytokines and mRNA expression of TACE, TIMP-3 and SIRT-1 were measured in colon at different time intervals. Next, the effect of SIRT-1 activator (resveratrol) or a selective TACE inhibitor (compound 11p) treatment was evaluated. Elevated levels of TNF-α, interleukin (IL)-6, IL-1ß, interferon (IFN)-γ and IL-17 were observed during DSS exposure phase which restored to the normal level after DSS removal. A significant increase in TACE and suppression in TIMP-3 and SIRT-1 mRNA level was observed during DSS exposure phase which reverts back to normal towards the remission phase. Treatment with resveratrol significantly elevated SIRT-1 and TIMP-3 and suppressed TACE mRNA expression and was associated with amelioration of disease. Furthermore, treatment with selective TACE inhibitor significantly suppressed body weight loss, disease activity index, colonic myeloperoxidase activity and the elevated levels of cytokines after DSS challenge. These results strongly emphasize the involvement of TACE in colon inflammation and inhibition of TACE directly or indirectly via SIRT-1 activation ameliorates colitis.

Anti-nociceptive and anti-allodynic activity of aliskiren in various pain models.

In the present study, we have investigated the anti-nociceptive and anti-allodynic activity of the renin inhibitor, aliskiren, in various pain models. The anti-nociceptive activity of aliskiren was investigated in chemically-induced pain, orofacial pain and centrally mediated pain models. Anti-allodynic activity was evaluated in post-operative and neuropathic pain models. The levels of TNF-α and IL-6 were measured in homogenates of hind paw as markers of inflammation in formalin injected mice. Intraperitoneal administration of aliskiren (1-50mg/kg) showed anti-nociceptive activity in the writhing test, formalin hind paw test, capsaicin induced pain, and orofacial pain tests in ICR mice in a dose dependent manner. Aliskiren (50mg/kg, i.p.) reduced levels of TNF-α and IL-6 in hind paw homogenates of formalin-injected mice. Aliskiren (50mg/kg, i.p.) did not show any analgesic activity in hot-plate and tail-flick tests, indicating the absence of centrally mediated anti-nociceptive effects. On the other hand, intra-plantar administration of aliskiren (0.1, 0.5 and 1mg) showed analgesic activity in rat formalin tests, indicating a locally mediated effect. Aliskiren (30-100mg/kg, i.p.) showed anti-allodynic activity in post-operative pain and chronic constriction injury-induced neuropathic pain in Sprague Dawley rats. This data suggests that aliskiren may have the potential to be used as an anti-nociceptive and anti-allodynic agent.

Blockade of tumor necrosis factor-α converting enzyme (TACE) enhances IL-1ß and IFN-γ via caspase-1 activation: a probable cause for loss of efficacy of TACE inhibitors in humans?

TNF-α converting enzyme (TACE) is a member of the ADAM (a disintegrin and metalloproteinase) family and is known as ADAM17, which processes precursor TNF-α in order to release soluble TNF-α (sTNF-α). Inhibition of TACE has been effective as a strategy to inhibit arthritis in animal models; however, it has not been translated in the clinic due to lack of efficacy or toxicity. We hypothesized that inhibition of TACE may activate a different pro-inflammatory pathway in human. To investigate this, we studied the effect of TACE inhibitor DPC-333 on cytokine levels in concanavalin A (Con A) activated human peripheral blood mononuclear cells (hPBMC). We have also studied the effects of DPC-333 on Con A induced cytokine levels in mice in vivo or in vitro in whole blood assay. DPC-333 treatment significantly up-regulated IL-1ß and IFN-γ in Con A activated hPBMC. In contrast, pre-treatment with DPC-333 effectively suppressed IL-1ß and IFN-γ in mice in vivo or in vitro. Interestingly, DPC-333 was found to up-regulate mRNA expression of caspase-1 in hPBMC in a dose dependent fashion and selective caspase-1 inhibitor completely restored DPC-333 induced IL-1ß and IFN-γ. Furthermore, selective IL-1ß receptor antagonist (anakinra) prevented DPC-333 induced IFN-γ. In conclusion, our data demonstrates that blockade of TACE enhances IL-1ß in a caspase-1 dependent manner in vitro in hPBMC and the elevation of IFN-γ is secondarily mediated via IL-1ß. This novel finding might explain the possible cause behind the loss of efficacy of TACE inhibitors in human.

Linagliptin: a novel xanthine-based dipeptidyl peptidase-4 inhibitor for treatment of type II diabetes mellitus.

Type 2 diabetes mellitus causes significant morbidity and mortality on account of its progressive nature and results in considerable burden on healthcare resources. Current treatment strategies have only limited long-term efficacy and tolerability given the progressive nature of the disease leading to inadequate glycemic control and are also associated with undesirable side effects such as weight gain, hypoglycemia and gastrointestinal distress. In the light of these existing limitations, exploring new treatment targets and new therapies have become the need of the hour at present. The incretin pathway, in particular, glucagon-like peptide (GLP-1), plays an important pathological role in the development of type 2 diabetes mellitus, and treatments targeting the incretin system have recently generated surmount interest. These can mainly be categorized into two broad classes; GLP-1 agonists/analogs (exenatide, liraglutide), and dipeptidyl peptidase- 4 inhibitors (sitagliptin, vildagliptin). The gliptins act by prolonging the action of incretins, the gut hormones which can boost insulin levels. Linagliptin is the latest dipeptidyl peptidase-4 inhibitor to complete pivotal phase III trials, which have demonstrated its superiority to its competitors based on its low therapeutic dose, long-lasting inhibition of DPP-4 activity and a good safety/tolerability profile. One of the unique characteristics of linagliptin is its primarily non-renal route of excretion. The drug has recently been approved by the US Food and Drug Administration and has been portrayed as a promising treatment option for patients in whom metformin and the other DPP-4 inhibitors are either contraindicated or require dose adjustment because of moderate to severe renal impairment.

Alogliptin: a novel molecule for improving glycemic control in type II diabetes mellitus.

Type 2 diabetes mellitus causes significant morbidity and mortality on account of its progressive nature and results in considerable burden on healthcare resources. It is characterized by high circulating levels of glucose resulting from insulin resistance and impaired insulin secretion. Current treatment strategies have only limited long-term efficacy and tolerability given the progressive nature of the disease leading to inadequate glycemic control and are also associated with undesirable side effects such as weight gain, hypoglycemia and gastrointestinal distress. In the light of these existing limitations, exploring new treatment targets and new therapies have become the need of the hour at present. The incretin pathway, in particular, glucagon-like peptide (GLP-1), plays an important pathological role in the development of type 2 diabetes mellitus, and treatments targeting the incretin system have recently generated surmount interest. These can mainly be categorized into two broad classes; GLP-1 agonists/analogs (exenatide, liraglutide), and dipeptidyl peptidase- 4 inhibitors (sitagliptin, vildagliptin). The gliptins act by prolonging the action of incretins, the gut hormones which can boost insulin levels. Alogliptin is a potent, highly selective dipeptidyl peptidase-4 inhibitor now undergoing clinical testing to support a new drug application for the treatment of type 2 diabetes. The results of Phase II and Phase III human studies, upon evaluation for clinical efficacy, safety and tolerability in patients with type 2 diabetes, have demonstrated that Alogliptin is effective and well tolerated as a treatment for type 2 diabetes, either as monotherapy or in combination with metformin, thiazolidinediones, sulfonylureas and insulin, with an excellent safety profile.