Effect of oral co-administration of frozen-dried grapefruit juice on pharmacokinetics of tramadol in dogs

Summary Tramadol is a centrally acting analgesic drug extensively metabolized in animal species. Its clinical response is mainly due to the M1 metabolite, poorly produced in dogs. Grapefruit-juice can inhibit the metabolism of different drugs in animals and humans. The aim of the present study was to evaluate the pharmacokinetics of tramadol and its major metabolites after co-administration of tramadol and frozen-dried grapefruit-juice. A balanced cross-over study was used involving six male Beagle dogs. They were administered with tramadol alone (5 mg/kg) or with tramadol (5 mg/kg) plus frozen-dried grapefruit-juice (10 g). The plasma concentration vs time curves showed significant differences during the first 4 h following drug administration. Tmax was at 1.33 and 1.70 h following tramadol and tramadol plus frozen-dried grapefruit-juice treatment, respectively. Significant differences were also shown in Cmax (490 vs 270 ng/ml) and AUC (11,610 vs 5,890 h·h·ng/ml). Significant differences between the treatments were shown in all the M1 parameters reported. M2 and M5 did not show significant differences after both administrations. In conclusion, the frozen-dried grapefruit-juice was shown to affect the plasma concentrations of M1, despite them being well below those reported in humans

Tyrosol-Enriched Tomatoes by Diffusion across the Fruit Peel from a Chitosan Coating: A Proposal of Functional Food

Chitosan is receiving increasing attention from the food industry for being a biodegradable, non-toxic, antimicrobial biopolymer able to extend the shelf life of, and preserve the quality of, fresh food. However, few studies have investigated the ability of chitosan-based coatings to allow the diffusion of bioactive compounds into the food matrix to improve its nutraceutical quality. This research is aimed at testing whether a hydrophilic molecule (tyrosol) could diffuse from the chitosan-tyrosol coating and cross the tomato peel. To this end, in vitro permeation tests using excised tomato peel and an in vivo application of chitosan-tyrosol coating on tomato fruit, followed by tyrosol quantification in intact fruit, peel and flesh during a seven-day storage at room temperature, were performed. Both approaches demonstrated the ability of tyrosol to permeate across the fruit peel. Along with a decreased tyrosol content in the peel, its concentration within the flesh was increased, indicating an active transfer of tyrosol into this tissue. This finding, together with the maintenance of constant tyrosol levels during the seven-day storage period, is very promising for the use of chitosan formulations to produce functional tomato fruit

Design, synthesis and biological evaluation of novel orthosteric-allosteric ligands of the cannabinoid receptor type 2 (CB2R)

It is well known that G protein–coupled receptors (GPCRs) assume multiple active states. Orthosteric ligands and/or allosteric modulators can preferentially stabilize specific conformations, giving rise to pathway-biased signaling. One of the most promising strategies to expand the repertoire of signaling-selective GPCR activators consists of dualsteric agents, which are hybrid compounds consisting of orthosteric and allosteric pharmacophoric units. This approach proved to be very promising showing several advantages over monovalent targeting strategies, including an increased affinity or selectivity, a bias in signaling pathway activation, reduced off-target activity and therapeutic resistance. Our study focused on the cannabinoid receptor type 2 (CB2R), considered a clinically promising target for the control of brain damage in neurodegenerative disorders. Indeed, CB2R was found highly expressed in microglial cells, astrocytes, and even in some neuron subpopulations. Here, we describe the design, synthesis, and biological evaluation of two new classes of potential dualsteric (bitopic) CB2R ligands. The new compounds were obtained by connecting, through different linkers, the pharmacophoric portion of the CB2R positive allosteric modulator (PAM), EC21a, with that of the CB2R selective orthosteric agonist LV62, both developed in our laboratories. A preliminary screening enabled us to identify compound JR64a as the most promising of the series. Indeed, functional examination highlighted a signaling ‘bias’ in favor of G protein activation over βarrestin2 recruitment, combined with high affinity for CB2R and the ability to efficiently prevent inflammation in human microglial cells (HMC3) exposed to LPS/TNFα stimulation, thus demonstrating great promise for the treatment of neurodegenerative diseases

Synthesis and In Vitro Characterization of Selective Cannabinoid CB2 Receptor Agonists: Biological Evaluation against Neuroblastoma Cancer Cells

1,8-naphthyridine-3-carboxamide structures were previously identified as a promising scaffold from which to obtain CB2R agonists with anticancer and anti-inflammatory activity. This work describes the synthesis and functional characterization of new 1,8-naphthyridin-2(1H)-one-3-carboxamides with high affinity and selectivity for CB2R. The new compounds were able to pharmacologically modulate the cAMP response without modulating CB2R-dependent beta-arrestin2 recruitment. These structures were also evaluated for their anti-cancer activity against SH-SY5Y and SK-N-BE cells. They were able to reduce the cell viability of both neuroblastoma cancer cell lines with micromolar potency (IC50 of FG158a = 11.8 mu M and FG160a = 13.2 mu M in SH-SY5Y cells) by a CB2R-mediated mechanism. Finally, in SH-SY5Y cells one of the newly synthesized compounds, FG158a, was able to modulate ERK1/2 expression by a CB2R-mediated effect, thus suggesting that this signaling pathway might be involved in its potential anti-cancer effect

Application of An Improved HPLC-FL Method to Screen Serine Palmitoyl Transferase Inhibitors

In this work, we reported the application and validation of an improved high-performance liquid chromatography method coupled with a fluorimetric detector (HPLC-FL) to screen the activity of two heterocyclic derivatives reported as serine palmitoyl transferase (SPT) inhibitors. The analytical conditions were optimized in terms of the derivatization procedure, chromatographic condition, extraction procedure, and method validation according to EMEA guidelines. Once fully optimized, the method was applied to assess the SPT-inhibitory activity of the above-mentioned derivatives and of the reference inhibitor myriocin. The obtained results, expressed as a percentage of residual SPT activity, were compared to those obtained with the reference radio immune assay (RIA). The good correlation between the two types of assay demonstrated that the improved HPLC-FL method is suitable for a preliminary and rapid screening of potential SPT-inhibitors

Design, Synthesis, and Biological Activity of New CB2 Receptor Ligands: from Orthosteric and Allosteric Modulators to Dualsteric/Bitopic Ligands

The design of dualsteric/bitopic agents as single chemical entities able to simultaneously interact with both the orthosteric and an allosteric binding site represents a novel approach in medicinal chemistry. Biased dualsteric/bitopic agents could enhance certain signaling pathways while diminishing the others that cause unwanted side effects. We have designed, synthesized, and functionally characterized the first CB2R heterobivalent bitopic ligands. In contrast to the parent orthosteric compound, our bitopic ligands selectively target CB2R versus CB1R and show a functional selectivity for the cAMP signaling pathway versus βarrestin2 recruitment. Moreover, the most promising bitopic ligand FD-22a displayed anti-inflammatory activity in a human microglial cell inflammatory model and antinociceptive activity in vivo in an experimental mouse model of neuropathic pain. Finally, computational studies clarified the binding mode of these compounds inside the CB2R, further confirming their bitopic nature

The Political Economy of Reducing the United States Dollar’s Role as a Global Reserve Currency

Many have argued that the major source of the existing global macroeconomic imbalances are the twin deficits of the United States (US). However, there is still a debate about whether the global imbalances indeed pose a significant threat to the world economy. This matter is settled by arguing that the global imbalances acted as a handmaiden to the 2008 financial crisis. One way to reduce global imbalances is to reform the international monetary system and reduce the role of the US dollar as a reserve currency. Robert Triffin was one of those critical of this exorbitant privilege granted to the US, which makes it both a system maker and privilege taker. The Triffin Dilemma captures the fundamental instability that underlies the dollar reserve system. However, there are major obstacles to this proposal. Some analysts including Triffin cited the US security umbrella as the primary reason the US and its major allies would want to retain the role of the dollar in global trade and finance despite the underlying inequities in the system. This is related to the imbalance in global governance which is largely US-centric. The imbalance in global governance is also reflected in the dominance of the US financial system brought about by the first-mover advantage. Because of the inertia brought about by the imbalance in global governance, economic arguments to reform the international monetary system are likely to be trumped by political reality. The paper analyzes whether current efforts in East Asia in terms of financial and monetary cooperation and rebalancing of economic growth could significantly mitigate the adverse impacts of a global system that will still be dominated by the US dollar in the foreseeable future. It also explains why the People's Republic of China (PRC) is unlikely to make significant unilateral adjustments to reduce global macroeconomic imbalances

PHARMACOKINETICS OF TRAMADOL AFTER EPIDURAL ADMINISTRATION IN HORSES

Tramadol is a centrally acting analgesic structurally related to codeine and morphine. The aim of the present study was to evaluate the pharmacokinetic of tramadol and its major metabolites after caudal epidural administration in the horse. Six gelding male adult horses were assigned to receive epidural administration of tramadol at 2 mg/kg. Plasma substances detection was achieved using a HPLC-FL method. Tramadol was detectable after 5 minutes up to 8 hours after epidural administration. Metabolites plasma concentrations were found under the limit of quantification of the method; however negligible amounts of M2 was detected from 30 min up to 1 hour in three subjects. In conclusion, this study shows that tramadol administered by caudal route in horses produces plasma concentrations within the extrapolated therapeutic range from humans for sufficient time to provide analgesia. Further study of the drug's safety and efficacy for the treatment of pain in horses is warranted