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Microbial dysbiosis has long been postulated to be associated with the pathogenesis of inflammatory bowel disease (IBD). Although evidence supporting the anti-colitic effects of melatonin have been accumulating, it is not clear how melatonin affects the microbiota. Herein, we investigated the effects of melatonin on the microbiome in colitis and identified involvement of Toll-like receptor (TLR) 4 signalling in the effects. Melatonin improved dextran sulfate sodium (DSS)-induced colitis and reverted microbial dysbiosis in wild-type (WT) mice but not in TLR4 knockout (KO) mice. Induction of goblet cells was observed with melatonin administration, which was accompanied by suppression of Il1b and Il17a and induction of melatonin receptor and Reg3β, an antimicrobial peptide (AMP) against Gram-negative bacteria. In vitro, melatonin treatment of HT-29 intestinal epithelial cells promotes mucin and wound healing and inhibits growth of Escherichia coli. Herein, we showed that melatonin significantly increases goblet cells, Reg3β, and the ratio of Firmicutes to Bacteriodetes by suppressing Gram-negative bacteria through TLR4 signalling. Our study suggests that sensing of bacteria through TLR4 and regulation of bacteria through altered goblet cells and AMPs is involved in the anti-colitic effects of melatonin. Melatonin may have use in therapeutics for iBD.

These findings suggest that the pharmacokinetics of the newly developed FDC tablet of amlodipine and valsartan did not differ significantly from the conventional FDC tablet in these healthy Korean male subjects. Both formulations were well tolerated, with no serious adverse events observed. ClinicalTrials.gov identifier: NCT01823913.

Telmisartan, an angiotensin receptor blocker (ARB), is indicated for the treatment of essential hypertension. This study aimed to develop a mechanistic model of telmisartan drug effect in human beings using non-invasive markers. Data were acquired from a previous study where telmisartan 80 mg was given once daily for 6 days. Systolic (SBP) and diastolic blood pressure (DBP) and heart rate (HR) were measured before dosing for days 1-5 and serially after the last dose. Mean arterial pressure (MAP) and pulse pressure (PP) were calculated from SBP and DBP. Relationships between MAP, PP, HR and total peripheral resistance (TPR) were developed. Circadian variation was incorporated into PP and HR, and TPR was assumed to adjust itself in response to changes in PP and HR based on baroreflex mechanism. Drug effects were then described as lowering the set point of MAP through TPR with a physiological feedback effect stimulating HR and PP. Drug concentrations were described by a two-compartment disposition model with first-order absorption and lag time, and first-order elimination. Circadian variation was described by cosine functions, having periods of 12 and 24 hr. A log-linear model was used to describe drug effect, with estimated drug effect parameter of 0.051/hr. Estimated fractional turnover rate of PP, HR and TPR was 11.2 hr. The model successfully described the time courses of these cardiovascular variables. This work demonstrated the feasibility of using non-invasive cardiovascular measurements to derive a mechanistic model for telmisartan in human beings. The model may be suitable for other ARBs.Telmisartan is an antagonist of the angiotensin II type 1 (AT1) receptor that is used for the treatment of hypertension. It selectively inhibits stimulation of the AT1 receptor by angiotensin II. It has a high volume of distribution and is eliminated mainly by the kidneys which results in a long terminal elimination half-life. The compound is not metabolized by cytochrome P450 isoenzymes and has a low risk for P450-based drug interactions [1,2].The action of telmisartan is known to lead to inhibition of aldosterone secretion and reduced vasoconstriction. The time course of its effect involves both rapid and slow responses. The rapid response is mainly due to antagonizing angiotensin II vasoconstriction. The slow response is due to antagonizing angiotensin-mediated aldosterone secretion which leads to a natriuretic effect, followed by decreased plasma volume and consequent decrease in cardiac stroke volume. Both the rapid and slow effects contribute to lowering of blood pressure [1].A population pharmacokinetic (PK) model for telmisartan was first published in 2003 [3] and reported that a two-compartment disposition model with first-order absorption and elimination described the data. A PKPD model of telmisartan has been published [4] in spontaneously hypertensive rats. To the authors' knowledge, no PKPD model of telmisartan has been published in human beings. Previous PKPD models used either an empirical modelli...

AIMSThe objective of this study was to develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model to quantitatively describe the antihypertensive effect of combined therapy with amlodipine and valsartan. METHODSPK modelling was used with data collected from 48 healthy volunteers receiving a single dose of combined formulation of 10 mg amlodipine and 160 mg valsartan. Systolic (SBP) and diastolic blood pressure (DBP) were recorded during combined administration. SBP and DBP data for each drug alone were gathered from the literature. PKPD models of each drug and for combined administration were built with NONMEM 7.3. RESULTSA two-compartment model with zero order absorption best described the PK data of both drugs. Amlodipine and valsartan monotherapy effects on SBP and DBP were best described by an I max model with an effect compartment delay. Combined therapy was described using a proportional interaction term as follows:. D 1 and D 2 are the predicted drug effects of amlodipine and valsartan monotherapy respectively. ALPHA is the interaction term for combined therapy. Quantitative estimates of ALPHA were À0.171 (95% CI: À0.218, À0.143) for SBP and À0.0312 (95% CI: À0.07739, À0.00283) for DBP. These infra-additive interaction terms for both SBP and DBP were consistent with literature results for combined administration of drugs in these classes. CONCLUSIONPKPD models for SBP and DBP successfully described the time course of the antihypertensive effects of amlodipine and valsartan. An infra-additive interaction between amlodipine and valsartan when used in combined administration was confirmed and quantified. British Journal of Clinical Pharmacology WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Due to differences in their mechanisms of action, amlodipine (CCB) and valsartan (ARB) are often used in combination to reduce blood pressure.• Combination therapy is known to be less effective than expected from adding two independent monotherapies (infra-additive effect). WHAT THIS STUDY ADDS• Predicted BP changes in healthy population from PKPD modelling are consistent with BP changes reported in patient population.• It is confirmed and quantitatively estimated that the interaction of combined administration leads to an infra-additive effect. Tables of Links