Exacerbation of Celecoxib-Induced Renal Injury by Concomitant Administration of Misoprostol in Rats

Nonsteroidal anti-inflammatory drugs (NSAIDs) can produce adverse effects by inhibiting prostaglandin (PG) synthesis. A PGE1 analogue, misoprostol, is often utilized to alleviate NSAID-related gastrointestinal side effects. This study examined the effect of misoprostol on celecoxib renal toxicity. Additionally, the effects of these drugs on cardiovascular parameters were evaluated. Four randomized rat groups were orally gavaged for 9 days, two groups receiving vehicle and two groups receiving misoprostol (100 μg/kg) twice daily. Celecoxib (40 mg/kg) was co-administered once daily to one vehicle and one misoprostol group from days 3 to 9. Urine and blood samples were collected and blood pressure parameters were measured during the study period. Hearts and kidneys were harvested on final day. Day 2 urinary electrolyte samples revealed significant reductions in sodium excretion in misoprostol (0.12±0.05 μmol/min/100 g) and misoprostol+celecoxib groups (0.07±0.02 μmol/min/100 g). At day 3, all treatment groups showed significantly reduced sodium excretion. Potassium excretion diminished significantly in vehicle+celecoxib and misoprostol+celecoxib groups from day 3 onward. Urinary kidney injury molecule-1 levels were significantly increased in vehicle+celecoxib (0.65±0.02 vs. 0.35±0.07 ng/mL, p = 0.0002) and misoprostol+celecoxib (0.61±0.06 vs. 0.37±0.06 ng/mL, p = 0.0015) groups when compared to baseline; while plasma levels of cardiac troponin I increased significantly in vehicle+celecoxib (p = 0.0040) and misoprostol+misoprostol (p = 0.0078) groups when compared to vehicle+vehicle. Blood pressure parameters increased significantly in all misoprostol treated groups. Significant elevation in diastolic (p = 0.0071) and mean blood pressure (p = 0.0153) was noted in misoprostol+celecoxib compared to vehicle+celecoxib. All treatments produced significant tubular dilatation/necrosis compared to control. No significant myocardial changes were noticed; however, three animals presented with pericarditis. Kidney, heart, and plasma celecoxib levels revealed no significant change between vehicle+celecoxib and misoprostol+celecoxib. Concomitant misoprostol administration did not prevent celecoxib renal toxicity, and instead exacerbated renal side effects. Misoprostol did not alter plasma or tissue celecoxib concentrations suggesting no pharmacokinetic interaction between celecoxib and misoprostol

Does Human Nature Conflict with Itself?: Human Form and the Harmony of the Virtues

Does possessing some human virtues make it impossible for a person to possess other human virtues? Isaiah Berlin and Bernard Williams both answered “yes” to this question, and they argued that to hold otherwise—to accept the harmony of the virtues—required a blinkered and unrealistic view of “what it is to be human.” In this essay, I have two goals: (1) to show how the harmony of the virtues is best interpreted, and what is at stake in affirming or denying it; and (2) to provide a partial defense of the harmony of the virtues. More specifically, I show how the harmony of the virtues can be interpreted and defended within the kind of Aristotelian naturalism developed by philosophers such as Philippa Foot, Rosalind Hursthouse, and Michael Thompson. I argue that far from being an embarrassing liability for Aristotelianism—based in an “archaic metaphysical biology”—the harmony thesis is an interesting and plausible claim about human excellences, supported by a sophisticated account of the representation of life, and fully compatible with a realistic view of our human situation

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Nanoparticles in Drug Delivery: Mechanism of Action, Formulation and Clinical Application Towards Reduction in Drug-Associated Nephrotoxicity

Introduction: Over the past few decades, nanoparticles (NPs) have gained immeasurable interest in the field of drug delivery. Various NP formulations have been disseminated in drug development in an attempt to increase efficacy, safety and tolerability of incorporated drugs. In this context, NP formulations that increase solubility, control release, and/or affect the in vivo disposition of drugs, were developed to improve the pharmacokinetic and pharmacodynamic properties of encapsulated drugs.Areas covered: In this article, important properties related to NP function such as particle size, surface charge and shape are disseminated. Also, the current understanding of how NP characteristics affect particle uptake and targeted delivery is elucidated. Selected NP systems currently used in delivery of drugs in biological systems and their production methods are discussed as well. Emphasis is placed on current NP formulations that are shown to reduce drug-induced adverse renal complications.Expert opinion: Formulation designs utilizing NP-encapsulated drugs offer alternative pharmacotherapy options with improved safety profiles for current and emerging drugs. NPs have been shown to increase the therapeutic index of several entrapped drugs mostly by decreasing drug localization and side effects on organs. Recent studies on NP-encapsulated chemotherapeutic and antibiotic medications show enhanced therapeutic outcomes by altering drug degradation, increasing systemic circulation and/or enhancing cell specific targeting. They may also reduce the distribution of encapsulated drugs into the kidneys and attenuate drug-associated adverse renal complications. The usefulness of NP formulation in reducing the nephrotoxicity of nonsteroidal anti-inflammatory drugs is an underexplored territory that deserves more attention

Risk and Tradeoffs

The orthodox theory of instrumental rationality, expected utility (EU) theory, severely restricts the way in which risk-considerations can figure into a rational individual's preferences. It is argued here that this is because EU theory neglects an important component of instrumental rationality. This paper presents a more general theory of decision-making, risk-weighted expected utility (REU) theory, of which expected utility maximization is a special case. According to REU theory, the weight that each outcome gets in decision-making is not the subjective probability of that outcome; rather, the weight each outcome gets depends on both its subjective probability and its position in the gamble. Furthermore, the individual's utility function, her subjective probability function, and a function that measures her attitude towards risk can be separately derived from her preferences via a Representation Theorem. This theorem illuminates the role that each of these entities plays in preferences, and shows how REU theory explicates the components of instrumental rationality

On Cognitive and Moral Enhancement: A Reply to Savulescu and Persson

In a series of recent works, Julian Savulescu and Ingmar Persson insist that, given the ease by which irreversible destruction is achievable by a morally wicked minority, (i) strictly cognitive bio-enhancement is currently too risky, while (ii) moral bio-enhancement is plausibly morally mandatory (and urgently so). This article aims to show that the proposal Savulescu and Persson advance relies on several problematic assumptions about the separability of cognitive and moral enhancement as distinct aims. Specifically, we propose that the underpinnings of Savulescu's and Persson's normative argument unravel once it is suitably clear how aiming to cognitively enhance an individual will in part require that one aim to bring about certain moral goods we show to be essential to cognitive flourishing; conversely, aiming to bring about moral enhancement in an individual must involve aiming to improve certain cognitive capacities we show to be essential to moral flourishing. After developing these points in some detail, and their implication for Savulescu's & Persson's proposal, we conclude by outlining some positive suggestions

Cross section (40X) of normal cardiac myocytes from vehicle+vehicle group.

<p>(A), vehicle+celecoxib group showing a mild organizing pericarditis (*) and adjacent normal cardiac myocytes (arrow) (B), normal cardiac myocytes from misoprostol+misoprostol group (C), misoprostol+celecoxib group showing a severe organizing pericarditis (*), and adjacent normal cardiac myocytes (arrow) (D).</p

NKCC2 immunohistochemistry consisting of an isotype control, then one section from each group (vehicle+vehicle (A); vehicle+celecoxib (B); misoprostol+misoprostol (C); misoprostol+celecoxib (D)) showing the presence of NKCC2 (arrows).

<p>40x magnification and insert at 100x.</p

Effect of treatment with vehicle+vehicle (VEH+VEH), vehicle+celecoxib (VEH+CEL), misoprostol+misoprostol (MISO+MISO), or misoprostol+celecoxib (MISO+CEL) on sodium excretion rate.

<p>*p<0.05, significantly different from baseline. ^¶p<0.05, significantly different from day 2. ^#p<0.05, significantly different from VEH+VEH. ⁺p<0.05, comparison of VEH+CEL group with MISO+CEL group.</p