Effect of micronized cellulose powder on the efficacy of topical oxymetazoline in allergic rhinitis.

BACKGROUND: Defective nasal barrier function is implicated in allergic rhinitis, which results in persistent inflammation and clinical symptoms, among which congestion plays a prominent role. In searching ways to improve the efficacy of nasally applied drugs in this condition, we tested the hypothesis that hydroxypropylmethylcellulose (HPMC), known as a mucoprotective agent, could enhance the efficacy of a decongestant (oxymetazoline nasal spray, 0.05%) by "sealing" it to the mucosa. METHODS: This double-blind placebo-controlled study was conducted with 40 patients (mean age, 35 years; 23 women) with persistent allergic rhinitis. The patients were randomized to receive 1 puff of oxymetazoline, followed by 1 puff of either HPMC or lactose powder (placebo) twice a day for 7 days and then only oxymetazoline rescue medication for another week. Peak inspiratory nasal flow (PNIF) was measured for 360 minutes after oxymetazoline and HPMC or placebo insufflation on days 1 and 8, and at a single point on day 15. Symptoms assessments involve visual analog scales and total nasal symptom scores. RESULTS: HPMC significantly enhanced oxymetazoline-increased PNIF at days 1 (p = 0.042) and 8 (p = 0.006). Baseline PNIF was greater in the HPMC group at day 15 (p = 0.014), indicative of further reduced nasal congestion. All nasal symptoms improved in both groups at day 8, but only the HPMC group showed further amelioration at day 15. Rescue medication was smaller in the HPMC group between days 8 and 15. CONCLUSION: HPMC enhances decongestion through mucoadhesion but may also be augmenting the mucosal barrier in allergic rhinitis, which explains the carryover efficacy of oxymetazoline for a week after its discontinuation. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01986582.

WR1065 conjugated to thiol-PEG polymers as novel anticancer prodrugs: broad spectrum efficacy, synergism, and drug resistance reversal.

The lack of anticancer agents that overcome innate/acquired drug resistance is the single biggest barrier to achieving a durable complete response to cancer therapy. To address this issue, a new drug family was developed for intracellular delivery of the bioactive aminothiol WR1065 by conjugating it to discrete thiol-PEG polymers: 4-star-PEG-S-S-WR1065 (4SP65) delivers four WR1065s/molecule and m-PEG6-S-S-WR1065 (1LP65) delivers one. Infrequently, WR1065 has exhibited anticancer effects when delivered via the FDA-approved cytoprotectant amifostine, which provides one WR1065/molecule extracellularly. The relative anticancer effectiveness of 4SP65, 1LP65, and amifostine was evaluated in a panel of 15 human cancer cell lines derived from seven tissues. Additional experiments assessed the capacity of 4SP65 co-treatments to potentiate the anticancer effectiveness and overcome drug resistance to cisplatin, a chemotherapeutic, or gefitinib, a tyrosine kinase inhibitor (TKI) targeting oncogenic EGFR mutations. The CyQUANT®-NF proliferation assay was used to assess cell viability after 48-h drug treatments, with the National Cancer Institute COMPARE methodology employed to characterize dose-response metrics. In normal human epithelial cells, 4SP65 or 1LP65 enhanced or inhibited cell growth but was not cytotoxic. In cancer cell lines, 4SP65 and 1LP65 induced dose-dependent cytostasis and cytolysis achieving 99% cell death at drug concentrations of 11.2 ± 1.2 µM and 126 ± 15.8 µM, respectively. Amifostine had limited cytostatic effects in 11/14 cancer cell lines and no cytolytic effects. Binary pairs of 4SP65 plus cisplatin or gefitinib increased the efficacy of each partner drug and surmounted resistance to cytolysis by cisplatin and gefitinib in relevant cancer cell lines. 4SP65 and 1LP65 were significantly more effective against TP53-mutant than TP53-wild-type cell lines, consistent with WR1065-mediated reactivation of mutant p53. Thus, 4SP65 and 1LP65 represent a unique prodrug family for innovative applications as broad-spectrum anticancer agents that target p53 and synergize with a chemotherapeutic and an EGFR-TKI to prevent or overcome drug resistance.

Synthesis and biological evaluation of novel cyclosporin a analogues: potential soft drugs for the treatment of autoimmune diseases.

Cyclosporin A is effective in the treatment of asthma patients, but its chronic use is limited by toxicity. Novel cyclosporin A analogues were synthesized utilizing the olefin metathesis reaction and evaluated in a calcineurin A inhibition assay. The novel analogues demonstrated activity comparable to activity of the parent molecule and are potential soft drugs.

Synthesis of new 14-membered macrolide antibiotics via a novel ring contraction metathesis.

[reaction: see text] A novel ring opening ring closing metathesis (ROM-RCM) was demonstrated for cyclic conjugated dienes, effecting the excision of a C(2)H(2) unit and a net ring contraction. Applying the ring contraction metathesis, new 14-membered ring macrolide antibiotics were synthesized in a single step from existing 16-membered ring macrolides. This new class of macrolide antibiotics will provide access to new therapeutics for the treatment of macrolide-resistant bacterial infections.

Synthesis and in vitro biological evaluation of aryl boronic acids as potential inhibitors of factor XIa.

A series of functionalized aryl boronic acids were synthesized and evaluated as potential inhibitors of factor XIa. Crystal structures of the protein-inhibitor complexes led to the design and synthesis of second generation compounds showing single digit micromolar inhibition against FXIa and selectivity against thrombin, trypsin, and FXa.

Synthesis, SAR exploration, and X-ray crystal structures of factor XIa inhibitors containing an alpha-ketothiazole arginine.

Using an alpha-ketothiazole arginine moiety as a key recognition element, a series of small peptidomimetic molecules was designed and synthesized, and their co-crystal structures with factor XIa were studied in an effort to develop smaller, less peptidic inhibitors as antithrombotic agents.