Effects of JWH015 in cytokine secretion in primary human keratinocytes and fibroblasts and its suitability for topical/transdermal delivery.

Background JWH015 is a cannabinoid (CB) receptor type 2 agonist that produces immunomodulatory effects. Since skin cells play a key role in inflammatory conditions and tissue repair, we investigated the ability of JWH015 to promote an anti-inflammatory and pro-wound healing phenotype in human primary skin cells. Methods Human primary keratinocytes and fibroblasts were stimulated with lipopolysaccharide. The mRNA expression of cannabinoid receptors was determined using RT-PCR. The effects of JWH015 (0.05, 0.1, 0.5, and 1 µM) in pro- and anti-inflammatory factors were tested in lipopolysaccharide-stimulated cells. A scratch assay, using a co-culture of keratinocytes and fibroblasts, was used to test the effects of JWH015 in wound healing. In addition, the topical and transdermal penetration of JWH015 was studied in Franz diffusion cells using porcine skin and LC-MS. Results The expression of CB1 and CB2 receptors (mRNA) and the production of pro- and anti-inflammatory factors enhanced in keratinocytes and fibroblasts following lipopolysaccharide stimulation. JWH015 reduced the concentration of major pro-inflammatory factors (IL-6 and MCP-1) and increased the concentration of a major anti-inflammatory factor (TGF-ß) in lipopolysaccharide-stimulated cells. JWH015 induced a faster scratch gap closure. These JWH015'seffects were mainly modulated through both CB1 and CB2 receptors. Topically administered JWH015 was mostly retained in the skin and displayed a sustained and low level of transdermal permeation. Conclusions Our findings suggest that targeting keratinocytes and fibroblasts with cannabinoid drugs could represent a therapeutic strategy to resolve peripheral inflammation and promote tissue repair.

Impact of COVID-19 on Pharmacy Education and Practice: Strategies to Boost Advocacy and Unity among Health Care Organizations.

The global COVID-19 pandemic impacted pharmacy education and changed the pharmacists' scope of practice at the federal and state levels. Based on the Amended Public Readiness and Emergency Preparedness Act, pharmacists were authorized to provide essential services, including testing, treatments, and immunizations at various practice settings. Specifically, the United States Food and Drug Administration issued emergency use authorization for several medications, vaccines, and medical devices. The pandemic also affected the regulatory landscape for pharmacists, pharmacy education, access to care, and delivery of pharmacy services in-person and through telehealth. The pandemic's specific impact on pharmacy education heightened awareness of the well-being of the Academy. This commentary will highlight the impact of COVID-19 on both pharmacy education and practice. It will also provide strategies that educators, researchers, and practitioners can take into future research and action to help promote advocacy and unity among pharmacy organizations.

Novel l-adenosine analogs as cardioprotective agents.

Two l-nucleosides, l-3'-amino-3'-deoxy-N(6)-dimethyladenosine (l-3'-ADMdA) 1, previously synthesized in our laboratory, and the novel l-3'-amino-3'-deoxy-N(6)-methyladenosine-5'-N-methyluronamide (l-3'-AM-MECA) 2 were evaluated in an ischemia/reperfusion model on Langendorff perfused mouse heart. l-3'-ADMdA 1 was found to enhance functional recovery from ischemia (32.2+/-3.7cm H(2)O/s % rate pressure product, compared to 21.3+/-1.4 for the control and 30.7+/-3.4 for adenosine) and increase the time to onset of ischemic contracture (14.5+/-0.9min, compared to 10.5+/-1.0min for the control and 13.6+/-0.6min for adenosine) comparable to adenosine. Consistent with the functional recovery data, decreased infarction area was seen in the case of 1 (19.1+/-8.4, compared to 40.5+/-7.2% for the control and 11.5+/-2.1% for adenosine). In contrast, l-3'-AM-MECA 2 did not show significant functional recovery, increased onset of contracture, nor decreased infarction area compared to control. Unlike adenosine, neither 1 nor 2 induced cardiac standstill in mouse heart.

Recent Advances in Drug Repurposing for Parkinson's Disease.

As a long-term degenerative disorder of the central nervous system that mostly affects older people, Parkinson's disease is a growing health threat to our ever-aging population. Despite remarkable advances in our understanding of this disease, all therapeutics currently available only act to improve symptoms but cannot stop the disease progression. Therefore, it is essential that more effective drug discovery methods and approaches are developed, validated, and used for the discovery of disease-modifying treatments for Parkinson's disease. Drug repurposing, also known as drug repositioning, or the process of finding new uses for existing or abandoned pharmaceuticals, has been recognized as a cost-effective and timeefficient way to develop new drugs, being equally promising as de novo drug discovery in the field of neurodegeneration and, more specifically for Parkinson's disease. The availability of several established libraries of clinical drugs and fast evolvement in disease biology, genomics and bioinformatics has stimulated the momentums of both in silico and activity-based drug repurposing. With the successful clinical introduction of several repurposed drugs for Parkinson's disease, drug repurposing has now become a robust alternative approach to the discovery and development of novel drugs for this disease. In this review, recent advances in drug repurposing for Parkinson's disease will be discussed.

Sulfonamide Allergies.

As one of the earliest developed antimicrobial classes, sulfonamides remain important therapeutic options for the empiric and definitive treatment of various infectious diseases. In the general population, approximately 3-8% of patients are reported to experience a sulfonamide allergy. Sulfonamide allergies can result in various physical manifestations; however, rash is reported as the most frequently observed. In patients with human immunodeficiency virus (HIV), dermatologic reactions to sulfonamide antimicrobial agents occur 10 to 20 times more frequently compared to immunocompetent patients. This article describes the incidence, manifestations, and risk factors associated with sulfonamide allergies. The potential for cross-reactivity of allergies to sulfonamide antimicrobials with nonantimicrobial sulfonamide medications is also reviewed. Data suggest that substitutions at the N1 and N4 positions are the primary determinants of drug allergy instead of the common sulfonamide moiety. For patients with an indication for a sulfonamide antimicrobial with a listed allergy, it is important for healthcare practitioners to adequately assess the allergic reaction to determine appropriate management. Rechallenge and desensitization strategies may be appropriate for patients with delayed maculopapular eruptions, while alternative treatment options may be prudent for more severe reactions. Available data suggests a low risk of cross-allergenicity between sulfonamide antimicrobial and nonantimicrobial agents.

Synthesis, stereochemical characterization, and antimicrobial evaluation of a potentially nonnephrotoxic 3'-C-acethydrazide puromycin analog.

Puromycin is a peptidyl nucleoside endowed with significant antibiotic and anticancer properties, but also with an unfortunate nephrotoxic character that has hampered its use as a chemotherapeutic agent. Since hydrolysis of puromycin's amide to puromycin aminonucleoside is the first metabolic step leading to nephrotoxicity, we designed a 3'-C-hydrazide analog where the nitrogen and carbon functionality around the amide carbonyl of puromycin are inverted. The title compound, synthesized in 11 steps from D-xylose, cannot be metabolized to the nephrotoxic aminonucleoside. Evaluation of the title compound on Staphylococcus epidermidis and multi-drug resistance Staphylococcus aureus did not show significant antimicrobial activity up to a 400 µM concentration.

Recent Advances in the Rational Design and Optimization of Antibacterial Agents.

This review discusses next-generation antibacterial agents developed using rational, or targeted, drug design strategies. The focus of this review is on small-molecule compounds that have been designed to bypass developing bacterial resistance, improve the antibacterial spectrum of activity, and/or to optimize other properties, including physicochemical and pharmacokinetic properties. Agents are discussed that affect known antibacterial targets, such as the bacterial ribosome, nucleic acid binding proteins, and proteins involved in cell-wall biosynthesis; as well as some affecting novel bacterial targets which do not have currently marketed agents. The discussion of the agents focuses on the rational design strategies employed and the synthetic medicinal chemistry and structure-based design techniques utilized by the scientists involved in the discoveries, including such methods as ligand- and structure-based strategies, structure-activity relationship (SAR) expansion strategies, and novel synthetic organic chemistry methods. As such, the discussion is limited to small-molecule therapeutics that have confirmed macromolecular targets and encompasses only a fraction of all antibacterial agents recently approved or in late-stage clinical trials. The antibacterial agents selected have been recently approved for use on the U.S. or European markets or have shown promising results in phase 2 or phase 3 U.S.

L-nucleosides: antiviral activity and molecular mechanism.

Drug discovery for antiviral chemotherapy has provided the effective treatment of numerous viral diseases. Among antiviral agents used in therapy, nucleoside analogues have been particularly useful. In fact, almost twenty nucleosides are currently used in antiviral therapy, seven of which are for the treatment of HIV infection. In the search for new and effective agents within this class, the focus has recently expanded on L-analogues, characterized by opposite configuration compared to the natural D-nucleosides. The interest in L-nucleosides has risen since the discovery of 3TC, one of the most important drugs used in the treatment of AIDS and hepatitis B infection. This review will discuss the latest advances in L-nucleosides as antiviral agents with a particular focus on the synthesis and molecular mechanism as well as metabolic differences between L- and D-nucleosides.

Structure-activity relationships of 2'-fluoro-2',3'-unsaturated D-nucleosides as anti-HIV-1 agents.

We studied the structure-activity relationships of a series of 2'-fluoro-2',3'-unsaturated D-nucleosides against HIV-1 in human peripheral blood mononuclear (PBM) cells. The target compounds 10-21 and 28-33 were prepared by N-glycosylation of the acetate 4, which was readily prepared from 2,3-O-isopropylidene-D-glyceraldehyde in five steps. Among the newly synthesized nucleosides, 2-amino-6-chloropurine (11), adenine (14), inosine (16), guanine (18), 2,6-diaminopurine (20), and 5-fluorocytosine (30) derivatives were found to exhibit interesting anti-HIV activities with EC(50) values of 4.3, 0.44, 1.0, 2.6, 3.0, and 0.82 microM, respectively. The implications for drug resistance of the titled nucleosides with respect to lamivudine-resistant variants (M184V) were also examined, and no significant cross-resistance with the variants was observed with the D-series.

Synthesis, structure-activity relationships, and drug resistance of beta-d-3'-fluoro-2',3'-unsaturated nucleosides as anti-HIV Agents.

Our recent studies demonstrated that d- and l-2'-fluoro-2',3'-unsaturated nucleosides (d- and l-2'-F-d4Ns) display moderate to potent antiviral activities against HIV-1 and HBV. As an extension of these findings, beta-d-3'-fluoro-2',3'-unsaturated nucleosides were synthesized as potential antiviral agents. The key intermediate (2S)-5-(1,3-dioxolan)-1-benzoyloxy-3,3-difluoropentan-2-ol 6 was prepared from 2,3-O-isopropylidene-d-glyceraldehyde 1, which was converted to 5-O-benzoxy-d-2-deoxy-3,3-difluoropentofuranosyl acetate 7 by the ring-closure reaction under acidic conditions. The acetate 7 was condensed with silylated purine and pyrimidine bases, which produced the alpha and beta isomers. The 3',3'-difluoro nucleosides were then treated with t-BuOK to give the desired 3'-fluoro-unsaturated nucleosides. We studied the structure-activity relationships of d-3'-fluoro-2',3'-unsaturated nucleosides against HIV-1 in human peripheral blood mononuclear cells, from which we found that the cytosine derivative 26 was the most potent among the synthesized compounds. To understand the mode of action and drug resistance profile, with particular regard to the role of fluorine, we performed the molecular modeling studies of the cytidine analogue d-3'F-d4C and found a good correlation between calculated relative binding energies and activity/resistance data. Our model also shows interactions of the 3'-fluorine and the 2',3' double bond, which can be correlated to the observed biological data. Differences between fluorine substitution at the 3' and 2' positions may account for the higher cross-resistance with lamivudine observed in the 2'-fluorinated series.

l-2',3'-Didehydro-2',3'-dideoxy-3'-fluoronucleosides: synthesis, anti-HIV activity, chemical and enzymatic stability, and mechanism of resistance.

As antiviral nucleosides containing a 2',3'-unsaturated sugar moiety with 2'-fluoro substitution are endowed with increased stabilization of the glycosyl bond, it was of interest to investigate the influence of the fluorine atom at the 3'-position. Various pyrimidine and purine L-3'-fluoro-2',3'-unsaturated nucleosides were synthesized from their precursors, L-3',3'-difluoro-2',3'-dideoxy nucleosides, by elimination of hydrogen fluoride. In the L-3',3'-difluoro-2',3'-dideoxy nucleoside series, cytidine 16 and 5-fluorocytidine 18 analogues showed modest antiviral activity (EC(50) 11.5 and 8.8 microM, respectively) when evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells. In the 2',3'-unsaturated series, L-3'-fluoro-2',3'-didehydro-2',3'-dideoxycytidine 24 and 5-fluorocytidine 26 showed highly potent antiviral activity (EC(50) 0.089 and 0.018 microM, respectively) without significant cytotoxicity. The guanosine analogue 48 showed only marginal anti-HIV activity with some cytotoxicity (EC(50) 38.5 microM, and IC(50) 17.4, 58.4, 36.5 microM in PBM, CEM, and Vero cells, respectively). The cytidine 24 and 5-fluorocytidine 26 analogues, however, showed significantly decreased antiviral activity against the clinically important lamivudine-resistant variants (HIV-1(M184V)). Molecular modeling studies demonstrated that the 3'-fluoro atom of the L-3'-fluoro-2',3'-unsaturated nucleoside is within the hydrogen bonding distance with the amide backbone of Asp185, which favors the binding of the nucleoside triphosphate to the wild-type RT. This favorable binding mode, however, cannot be maintained when the triphosphate of 3'-fluoro 2',3'-unsaturated nucleoside binds to the active site of M184V RT because the bulky side chain of Val184 occupies the space needed for the nucleotide. The biological results suggest that, in addition to the sugar conformation, the base moiety may also play a role in their interaction with the M184V RT.

Synthesis of L-oxetanocin.

[reaction: see text] Hitherto unknown L-oxetanocin has been synthesized from L-xylose in 16 steps via a ribonolactone derivative.

Synthesis of novel spiro[2.3]hexane carbocyclic nucleosides via enzymatic resolution.

[reaction: see text] Novel R- and S-spiro[2.3]hexane nucleosides have been synthesized. The key step involved the Pseudomonas cepacia lipase catalyzed resolution of racemic compound 2, synthesized in seven steps starting from diethoxyketene and diethyl fumarate, to give (+)-acetate 3 and (-)-alcohol 13. (+)-Acetate 3 and (-)-acetate 14 were converted to R- and S-9-(6-hydroxymethylspiro[2.3]hexane)-4-adenine, respectively.

Synthesis of 2'-substituted inosine analogs via unusual masking of the 6-hydroxyl group.

2'-Modified inosine analogs have been synthesized from 6-chloropurine riboside via 6-dimethylaminopurine or 6-benzyloxypurine intermediates. The dimethylaminopurine intermediate was obtained via an unusually facile dimethylamine transfer from dimethylformamide. Graphical Abstract:

Structure-activity relationships of eugenol derivatives against Aedes aegypti (Diptera: Culicidae) larvae.

BACKGROUND: Dengue fever is a severe public health problem for several countries. In order to find effective larvicides to aid control programs, the structure-activity relationships of eugenol derivatives against Aedes aegypti (Diptera: Culicidae) larvae were evaluated. Additionally, the composition and larvicidal activity of Syzygium aromaticum essential oil was assessed. RESULTS: Four compounds representing 99.05% of S. aromaticum essential oil have been identified. The essential oil was active against Ae. aegypti larvae (LC(50) = 62.3 and 77.0 ppm, field-collected and Rockefeller larvae respectively). The larvicidal activity of eugenol, the major compound of the essential oil, was further evaluated (LC(50) = 93.3 and 71.9 ppm, field-collected and Rockefeller larvae respectively). The larvicidal activity and structure-activity relationships of synthetic derivatives of eugenol were also assessed. The larvicidal activity of the derivatives varied between 62.3 and 1614.9 ppm. Oxidation of eugenol allylic bond to a primary alcohol and removal of the phenolic proton resulted in decreased potency. However, oxidation of the same double bond in 1-benzoate-2-methoxy-4-(2-propen-1-yl)-phenol resulted in increased potency. CONCLUSION: Structural characteristics were identified that may contribute to the understanding of the larvicidal activity of phenylpropanoids. The present approach may help future work in the search for larvicidal compounds.

Pharmacokinetics of the antiviral agent beta-L-3'-fluoro-2',3'-didehydro-2',3'-dideoxycytidine in rhesus monkeys.

beta-L-3'-Fluoro-2',3'-didehydro-2',3'-dideoxycytidine (L-3'-Fd4C) is a potent and selective antiretroviral nucleoside with activity against lamivudine-resistant human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV) in vitro. The pharmacokinetics of L-3'-Fd4C were characterized in three rhesus monkeys given single intravenous and oral doses. A two-compartment open model was fitted to the plasma and urine data. Plasma concentrations declined in a biexponential fashion with an average beta half-life of 12.45 h and central and steady-state volumes of distribution of 0.43 and 1.90 liters/kg, respectively. The average systemic and renal clearance values were 0.23 and 0.08 liters/kg, respectively, and the apparent mean terminal half-life of the oral dose was 12.5 h. The serum concentrations exceeded the 90% effective concentration value for lamivudine-resistant and wild-type HIV-1 after oral administrations. A large variation was observed in the oral bioavailability, which ranged from 15 to 31%. To determine whether the bioavailability may be improved by using a basic buffer solution, the oral dose was repeated to the same animals in a sodium bicarbonate solution. The bioavailability of L-3'-Fd4C administered with sodium bicarbonate was not significantly different from the bioavailability when the oral dose was administered in the absence of buffer (P = 0.49), suggesting that further development of this compound may warrant other approaches, such as development of a prodrug to improve its oral absorption.