Formulation and in Vitro Evaluation of Niacinloaded Nanoparticles to Reduce Prostaglandin Mediated Vasodilatory Flushing

OBJECTIVE: Niacin, activating G-protein coupled receptor (GPR) 109A, stimulates release of vasodilatory prostaglandins (PGs) such as PGE2 which can elicit niacin-associated flushing side effects. Poly-lactic-coglycolic acid (PLGA) and poly-lactic acid (PLA) are used in nanoparticle (NP) drug delivery to reduce adverse effects and modulate drug release. Our study evaluated the in vitro effects of niacin-loaded PLGA or PLA-NPs on PGE2 expression in whole human blood as a model for niacin-induced flushing. MATERIALS AND METHODS: NPs were formulated using a solvent evaporation process and characterized by size, polydispersity, zeta potential, drug entrapment, morphology, and drug release. NP in vitro effects on PGE2 release were measured via ELISA analysis. RESULTS: PLGA-NPs demonstrated the lowest NP size (66.7 ± 0.21 nm) with the highest zeta potential and percent drug entrapment (42.00 ± 1.62 mV and 69.09 ± 0.29%, respectively) when compared to PLA-NPs (130.4 ± 0.66 nm, 27.96 ± 0.18 mV, 69.63 ± 0.03 %, respectively). In vitro release studies showed that PLGA-NPs underwent significant reductions in cumulative drug release when compared to PLA-NPs (p \u3c 0.05). Furthermore, when compared to plain niacin, PLGA-NPs significantly reduced in vitro PGE2 release (p \u3c 0.05). CONCLUSIONS: These results support the use of PLGA-NPs as a novel method of delivery for reducing niacin-associated flushing

Celecoxib or Diclofenac Hepatic Status in the Presence or Absence of Rebamipide

OBJECTIVE: Utilization of nonsteroidal anti-inflammatory drugs (NSAIDs), such as diclofenac, can produce gastrointestinal ulceration. Thus, cyclooxygenase-2-selective inhibitors, such as celecoxib, and protective agents (e.g. rebamipide) have been employed to alleviate harmful NSAID effects. This study sought to explore the influence of rebamipide on the hepatic outcomes following administration of two commonly prescribed NSAIDs. MATERIALS AND METHODS: Rats were given either vehicle or rebamipide (30 mg/kg) orally twice daily for two days, then on the third day respective groups were dosed with either vehicle, celecoxib (40 mg/kg), or diclofenac (10 mg/kg) in addition to a respective dose of vehicle or rebamipide. Livers were collected on day 4 following euthanasia. Hepatic tissue was examined via histopathology and assayed for oxidative stress and specific NSAID concentration. RESULTS: The liver sections were found to be free from structural changes. Oxidative stress biomarkers, reduced glutathione and malondialdehyde, were discovered to be unaltered among the groups tested. The hepatic NSAID concentrations were not significantly affected by the presence of rebamipide. CONCLUSIONS: The concomitant administration of rebamipide does not influence the hepatic condition of rats administered either celecoxib or diclofenac at the dosages and over the time course examined

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

Iontophoresis of Dexamethasone-Phosphate Into the Equine Tibiotarsal Joint

In human rehabilitation medicine, dexamethasone-phosphate is theoretically iontophoresed to localized subcutaneous tissue where conversion to dexamethasone occurs. This delivery system has recently been introduced into veterinary medicine for the same purpose. However, the pharmacokinetic justification for parenteral delivery of this prodrug remains undocumented. Utilizing iontophoretic methods that are relevant to both human and veterinary clinical practice, the present investigation compared injection and iontophoresis of dexamethasone-phosphate into the equine tibiotarsal joint, also known as the tarsocrual joint. The tibiotarsal joints of seven horses were injected with 4 mL of 6 mg/mL dexamethasone-phosphate. With a similar drug concentration and over the same application site, six different horses underwent simultaneous cathodic iontophoresis (4 mA, 40 min) or passive application (0 mA, 40 min) on contralateral limbs. Following all applications, tibiotarsal joint synovium was collected. Local venous blood samples were also collected from the iontophoretic and passive application sites for analysis of plasma drug concentrations. Because of the potential for conversion of dexamethasone-phosphate to dexamethasone, an extraction and analysis protocol was developed for both chemicals. The technique demonstrated a linear range of detection (0.39-12 μg/mL) and a capability for measuring both chemicals in plasma and synovium. Conversion of dexamethasone-phosphate to dexamethasone occurred during synovial incubation (37 °C) and following freeze-thaw cycles. In contrast to the measurable synovial concentrations of dexamethasone-phosphate (2.3±0.96 mg/mL) and dexamethasone (0.27±0.07 mg/mL) following injection, neither drug was detected in the synovium or the local venous blood following iontophoretic or passive applications. In conclusion, these results do not confirm iontophoretic or passive delivery of measurable dexamethasone-phosphate into the tibiotarsal joint using current clinical methods

Examination of the Pharmacodynamics and Pharmacokinetics of a Diclofenac Poly(Lactic-Co-Glycolic) Acid Nanoparticle Formulation in the Rat

OBJECTIVE: Nonsteroidal anti-inflammatory drugs (NSAIDs) are assembled into two categories; cyclooxygenase (COX-1) sparing inhibitors of COX-2 and non-selective NSAIDs. Diclofenac (DICLO) is a non-selective NSAID that has been linked to serious side effects including gastric ulcers and renal injury. In this study, we examine the effect of poly(lactic-co-glycolic) acid nanoformulation on DICLO-associated adverse events and pharmacokinetics using a nanoparticle (NP) formulation previously developed in our laboratory.MATERIALS AND METHODS: Rats were administered a single dose of methylcellulose (VEH), blank NP, DICLO (10 mg/kg), or a DICLO-NP suspension equivalent to the DICLO dose. Urinary and blood parameters were measured at baseline and following treatment. Duodenal and gastric prostaglandin E2 (PGE2) and duodenal myeloperoxidase (MPO) were collected to assess inflammation at 24 hrs post-treatment.RESULTS: The mean percent change from baseline in sodium excretion rate (µmol/min/100 g body weight) differed significantly from VEH in the NP (p \u3c 0.0001), DICLO (p \u3c 0.0001), and DICLO-NP (p = 0.0001) groups. The differences among groups did not reach significance for plasma sodium or potassium concentrations, potassium excretion rate, gastric PGE2, or intestinal biomarker concentrations. Regarding renal histopathology, DICLO produced considerably more necrosis compared to VEH; while DICLO-NP did not elicit notable differences from VEH.CONCLUSIONS: Our results suggest that over the duration and dosage examined, DICLO-NP may reduce renal necrosis without influencing other side effects or drug characteristics