Multimodal Clinical Pathway With Adductor Canal Block Decreases Hospital Length of Stay, Improves Pain Control, and Reduces Opioid Consumption in Total Knee Arthroplasty Patients: A Retrospective Review.

BACKGROUND: Total knee arthroplasty volume is increasing significantly in the United States. Reducing hospital length of stay may represent the best method for accommodating expanding volume and reducing costs. We hypothesized that tailoring a clinical pathway to facilitate early ambulation would decrease costs and resource utilization. METHODS: We conducted a sequential before-and-after study of total knee arthroplasty patients after a phased implementation of a clinical pathway that includes multimodal oral analgesic protocols, adductor canal nerve block, and standardized day of surgery ambulation protocols. Primary outcomes measured were hospital length of stay, total opioid consumption, total antiemetic use, and perioperative pain scores. RESULTS: Two hundred ninety-five patients were divided into 3 sequential cohorts. Cohort 1 received spinal anesthesia, femoral nerve block, and was not placed into postop day 0 ambulation therapy. Cohort 2 received spinal anesthesia, adductor canal block, and postop day 0 ambulation therapy. Cohort 3 received spinal anesthesia, adductor canal block, postop day 0 ambulation therapy, and standardized oral multimodal analgesic protocol. Cohort 3 had significantly reduced hospital length of stay. Cohorts 2 and 3 had significantly less opioid consumption. Cohort 3 had significantly less total ondansetron consumption compared with cohort 1. Cohort 3 had significantly reduced average pain scores compared with cohort 1. CONCLUSION: The data demonstrate that tailored clinical pathways designed to facilitate early ambulation can reduce hospital length of stay, reduce opioid consumption, reduce antiemetic use, and improve pain control. The results establish that refined clinical pathways can assist in improving care while increasing value to patients, providers, and systems.

Access to 4-alkylaminopyridazine derivatives via nitrogen-assisted regioselective Pd-catalyzed reactions.

3-Substituted, 6-substituted, and unsymmetrical 3,6-disubstituted 4-alkylaminopyridazines were prepared from a sequence of three chemo- and regioselective reactions combining amination and palladium-catalyzed cross-coupling reactions, such as reductive dehalogenation and Suzuki-Miyaura reactions. Extension of the methodology to Sonogashira reaction yielded a novel class of 3-substituted pyrrolopyridazines.

Paths to improve voluntary blood donation in mixed public/private blood donation systems such as in Lebanon?

BACKGROUND: The World Health Organization advocates for the achievement of 100% voluntary non-remunerated blood donation (VNRD) globally by the year 2020. However, until today, little was known in Lebanon regarding its actual rate or influencing factors, particularly donor motivations and behaviors. Therefore, the aim of this study was to assess the knowledge, attitudes, and practices of blood donors in Lebanon. The ultimate goals were to retain first-time donors, encourage them to become regular ones, and facilitate the transition from replacement donation to VNRD. MATERIALS AND METHODS: A multi-centric cross-sectional study was carried across the five governorates in Lebanon. A self-administered and structured questionnaire was used in this survey. Results were presented in terms of odds ratios, with statistical significance defined at a P value of 0.05 and a 95% confidence interval. Additionally, a benchmarking analysis of the situation of blood donation in Lebanon was also conducted, identifying several areas for improvement. RESULTS: A total of 620 blood donors participated in this study, with 21.3% being first-time donors and 78.7% repeat donors. While the latter were primarily motivated by self-esteem, solidarity or returning a favor (89%, 77.9% and 78.1%), the main obstacle for becoming regular donors was a lack of initiative (34.6%). Female donors (9.9% of the total) exhibited better knowledge (OR = 2.20, p = 0.011) and were more inclined to donate voluntarily (OR = 1.52, p = 0.048). Conversely, male donors were more likely to be repeat donors, often through replacement donation (OR = 2.95, p = 0.001). CONCLUSION: There is a significant disparity between the low rate of voluntary donation in Lebanon (22.2%) and the relatively high proportion of donors with adequate knowledge of the donation process (60.5%). Therefore, urgent action by public authorities, based on the evidence based strategies outlined in this article, is crucial to enhancing the voluntary donation rate in Lebanon.

N-Heteroarylation of chiral α-aminoesters by means of palladium-catalyzed Buchwald-Hartwig reaction.

N-Heteroaryl-α-amino acid derivatives are valuable pharmacological agents as peptidomimetics. Classical SNAr methods using acid catalysis and elevated temperatures could not be extended to various α-amino acids and fairly electrophilic heterocyclic partners. Here, we report a mild and versatile method of N-heteroarylation of chiral α-aminoesters without racemization, involving Buchwald-Hartwig conditions. It could be extended to various α-amino acids and azines. This efficient N-heteroarylation leads to (i) a chemical library of putative peptidomimetics combining diverse azaheterocycles with the chiral α-aminoesters and their corresponding derivatives (amides, alcohols, etc.) and (ii) arginine derivatives designed as NPFF receptor ligands.

Direct guanidinylation of aryl and heteroaryl halides via copper-catalyzed cross-coupling reaction.

A modified Ullmann reaction using p-methoxybenzyl (PMB) guanidine as guanidinylation agent yielded various aryl and heteroaryl guanidines in good yields.

Heteroarylguanidines as Allosteric Modulators of ASIC1a and ASIC3 Channels.

Acid-sensing ion channels (ASICs) are neuronal Na+-selective ion channels that open in response to extracellular acidification. They are involved in pain, fear, learning, and neurodegeneration after ischemic stroke. 2-Guanidine-4-methylquinazoline (GMQ) was recently discovered as the first nonproton activator of ASIC3. GMQ is of interest as a gating modifier and pore blocker of ASICs. It has however a low potency, and exerts opposite effects on ASIC1a and ASIC3. To further explore the molecular mechanisms of GMQ action, we have used the guanidinium moiety of GMQ as a scaffold and tested the effects of different GMQ derivatives on the ASIC pH dependence and maximal current. We report that GMQ derivatives containing quinazoline and quinoline induced, as GMQ, an alkaline shift of the pH dependence of activation in ASIC3 and an acidic shift in ASIC1a. Another group of 2-guanidinopyridines shifted the pH dependence of both ASIC1a and ASIC3 to more acidic values. Several compounds induced an alkaline shift of the pH dependence of ASIC1a/2a and ASIC2a/3 heteromers. Compared to GMQ, guanidinopyridines showed a 20-fold decrease in the IC50 for ASIC1a and ASIC3 current inhibition at pH 5. Strikingly, 2-guanidino-quinolines and -pyridines showed a concentration-dependent biphasic effect that resulted at higher concentrations in ASIC1a and ASIC3 inhibition (IC50 > 100 µM), while causing at lower concentration a potentiation of ASIC1a, but not ASIC3 currents (EC50 ≈ 10 µM). In conclusion, we describe a new family of small molecules as ASIC ligands and identify an ASIC subtype-specific potentiation by a subgroup of these compounds.

Targeting prohibitin with small molecules to promote melanogenesis and apoptosis in melanoma cells.

Prohibitins 1 and 2 (PHB1/2) are scaffold proteins that are involved in both melanogenesis and oncogenic pathways. We hypothesized that a PHB1 ligand, melanogenin, may display anti-cancer effects in addition to its known melanogenic activity in melanocytes. Here, we disclose a convenient synthesis of melanogenin, and its analogs. We found that, among 57 new melanogenin analogs, two (Mel9 and Mel41) significantly promoted both melanogenesis in melanocytes by activating one of the PHB2-interacting proteins, microtubule-associated protein light chain 3 (LC3), and upregulating the expression of microphthalmia associated transcription factor (MITF). These analogs also activate ERK. Besides, in addition to their promelanogenic activities, we uncovered that melanogenin and its active analogs induce apoptosis in several cancer cell lines, including melanoma cells, and that this effect is caused by an inhibition of AKT survival pathway. Our findings present a new putative function for PHBs as regulators of LC3/ERK/MITF melanogenic signaling, and suggest that Mel9 and Mel41 may provide the basis for the development of new drugs candidates to treat melanoma and other types of cancers.

Aminoguanidine Hydrazone Derivatives as Nonpeptide NPFF1 Receptor Antagonists Reverse Opioid Induced Hyperalgesia.

Neuropeptide FF receptors (NPFF1R and NPFF2R) and their endogenous ligand neuropeptide FF have been shown previously to display antiopioid properties and to play a critical role in the adverse effects associated with chronic administrations of opiates including the development of opioid-induced hyperalgesia and analgesic tolerance. In this work, we sought to identify novel NPFF receptors ligands by focusing our interest in a series of heterocycles as rigidified nonpeptide NPFF receptor ligands, starting from already described aminoguanidine hydrazones (AGHs). Binding experiments and functional assays highlighted AGH 1n and its rigidified analogue 2-amino-dihydropyrimidine 22e for in vivo experiments. As shown earlier with the prototypical dipeptide antagonist RF9, both 1n and 22e reduced significantly the long lasting fentanyl-induced hyperalgesia in rodents. Altogether these data indicate that AGH rigidification maintains nanomolar affinities for both NPFF receptors, while improving antagonist character toward NPFF1R.

Neuropeptide FF receptors as novel targets for limbic seizure attenuation.

Neuropeptide Y (NPY) is a well established anticonvulsant and first-in-class antiepileptic neuropeptide. In this study, the controversial role of NPY1 receptors in epilepsy was reassessed by testing two highly selective NPY1 receptor ligands and a mixed NPY1/NPFF receptor antagonist BIBP3226 in a rat model for limbic seizures. While BIBP3226 significantly attenuated the pilocarpine-induced seizures, neither of the highly selective NPY1 receptor ligands altered the seizure severity. Administration of the NPFF1/NPFF2 receptor antagonist RF9 also significantly attenuated limbic seizure activity. To further prove the involvement of NPFF receptors in these seizure-modulating effects, low and high affinity antagonists for the NPFF receptors were tested. We observed that the low affinity ligand failed to exhibit anticonvulsant properties while the two high affinity ligands significantly attenuated the seizures. Continuous NPFF1 receptor agonist administration also inhibited limbic seizures whereas bolus administration of the NPFF1 receptor agonist was without effect. This suggests that continuous agonist perfusion could result in NPFF1 receptor desensitization and mimic NPFF1 receptor antagonist administration. Our data unveil for the first time the involvement of the NPFF system in the management of limbic seizures.

Structure-activity relationship study around guanabenz identifies two derivatives retaining antiprion activity but having lost α2-adrenergic receptor agonistic activity.

Guanabenz (GA) is an orally active α2-adrenergic agonist that has been used for many years for the treatment of hypertension. We recently described that GA is also active against both yeast and mammalian prions in an α2-adrenergic receptor-independent manner. These data suggest that this side-activity of GA could be explored for the treatment of prion-based diseases and other amyloid-based disorders. In this perspective, the potent antihypertensive activity of GA happens to be an annoying side-effect that could limit its use. In order to get rid of GA agonist activity at α2-adrenergic receptors, we performed a structure-activity relationship study around GA based on changes of the chlorine positions on the benzene moiety and then on the modifications of the guanidine group. Hence, we identified the two derivatives 6 and 7 that still possess a potent antiprion activity but were totally devoid of any agonist activity at α2-adrenergic receptors. Similarly to GA, 6 and 7 were also able to inhibit the protein folding activity of the ribosome (PFAR) which has been suggested to be involved in prion appearance/maintenance. Therefore, these two GA derivatives are worth being considered as drug candidates.