Nezulcitinib (TD-0903), a lung-selective pan-Janus-associated kinase (JAK) inhibitor designed for inhaled delivery, is under development for treatment of acute lung injury associated with coronavirus disease 2019 (COVID-19). This two-part, double-blind, randomized, placebo-controlled, single ascending dose (part A) and multiple ascending dose (part B) phase I study evaluated the safety, tolerability, and pharmacokinetics (PK) of nezulcitinib in healthy participants. Part A included three cohorts randomized 6:2 to receive a single inhaled dose of nezulcitinib (1, 3, or 10 mg) or matching placebo. Part B included three cohorts randomized 8:2 to receive inhaled nezulcitinib (1, 3, or 10 mg) or matching placebo for 7 days. The primary outcome was nezulcitinib safety and tolerability assessed from treatment-emergent adverse events (TEAEs). The secondary outcome was nezulcitinib PK. All participants completed the study. All TEAEs were mild or moderate in severity, and none led to treatment discontinuation. Overall (area under the plasma concentration-time curve) and peak (maximal plasma concentration) plasma exposures of nezulcitinib were low and increased in a dose-proportional manner from 1 to 10 mg in both parts, with no suggestion of clinically meaningful drug accumulation. Maximal plasma exposures were below levels expected to result in systemic target engagement, consistent with a lung-selective profile. No reductions in natural killer cell counts were observed, consistent with the lack of a systemic pharmacological effect and the observed PK. In summary, single and multiple doses of inhaled nezulcitinib at 1, 3, and 10 mg were well-tolerated in healthy participants, with dose-proportional PK supporting once-daily administration.

Background: Janus kinases (JAKs) play a central role in signaling the pro-inflammatory effects of multiple cytokines. TD-8236 is an inhaled, lung selective pan-JAK inhibitor being evaluated for the treatment of asthma. Objective: This study evaluated the safety, tolerability, and plasma pharmacokinetics of TD-8236 following inhaled administration in healthy participants and those with mild asthma. Pharmacodynamics were assessed by evaluating fractional exhaled nitric oxide (FeNO) in participants with mild asthma. Methods: This was a Phase 1, randomized, double-blinded, placebo-controlled study. Single ascending doses were evaluated in 39 healthy participants at doses ranging from 50 μg to 4500 μg. Multiple ascending doses were evaluated in 31 participants with mild asthma at doses of 150 μg, 500 μg, 1500 μg, and 4000 μg once daily for 7 days. Results: All adverse events were mild or moderate in severity, and none led to discontinuation of treatment. No clinically significant changes were noted in vital signs, ECGs, or laboratory parameters. TD-8236 plasma concentrations were low and approximately proportional across the observed range of single and multiple ascending doses. Placebo-corrected reductions in FeNO were observed in daily measurements taken 6 and 24 hours after dosing over 7 days in participants with mild asthma at dose levels ≥500 mg. Conclusions: TD-8236 was generally well tolerated in healthy participants and those with mild asthma. TD-8236 administration resulted in dose-dependent target engagement in the lung as demonstrated by reductions in FeNO with minimal systemic exposure.

Introduction: TD-0714 is an orally active, potent, and selective inhibitor of human neprilysin (NEP) in development for the treatment of a range of cardiorenal diseases including chronic heart failure (CHF) and chronic kidney disease (CKD). A significant population of these patients exhibit moderate to severe renal impairment. NEP inhibitors exhibiting non-renal excretion and a once-daily dosing regimen may provide optimal therapy for such patients. A multiple dose, double–blind, placebo–controlled, dose–escalation study in healthy subjects was conducted to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of TD–0714. Methods: Forty healthy adult subjects (n = 10/group) were randomized to one of four cohorts and received a daily oral dose of TD–0714 (10 to 200 mg) or placebo in a 4:1 ratio for 14 days. In addition, ten elderly healthy subjects were randomized to receive either 100 mg TD-0714 or placebo in a 4:1 ratio. Safety and tolerability were evaluated by monitoring treatment-emergent adverse events (TEAE), ECG, vital signs and laboratory parameters. PK and corresponding PD response (cGMP and ANP), were assessed. Results: TD-0714 was generally well tolerated up to the highest dose level tested (200 mg). No SAEs were reported. No clinically significant effects on vital signs or ECG parameters were observed. One subject at the lowest dose level (10 mg) exhibited an asymptomatic increase in liver enzymes (ALT, AST). This subject was subsequently rechallenged at the same dose level (10 mg QD for 14days) and no elevations in liver enzymes were observed upon rechallenge. No clinically relevant changes in laboratory parameters were observed in any other subjects during the study. PK (Cmax and AUC) of TD-0714 was dose–proportional from 10 mg to 200 mg, no accumulation was observed from day 1 to day 14 and renal excretion remained low at <1% of the administered dose. In addition, PK of TD-0714 was similar in elderly vs adult subjects. Dose-dependent increases in plasma and urine cGMP levels were observed. The increases in cGMP were sustained for 24 hr after a single dose and remained significantly above the baseline for the entire 24 hr interval on day 14 indicating that sustained cGMP elevations are achieved at steady state. Maximal PD effects were observed at doses of ≥50 mg based on plasma cGMP on day 14. Conclusions: Multiple doses of TD-0714 from 10 to 200 mg were generally well tolerated. PK was dose-proportional with negligible renal elimination. PD effects consistent with NEP target engagement were sustained for and remained significantly over baseline during the entire dosing interval at steady state. The TD-0714 PK and PD profiles continue to support the potential for once-daily administration and predictable exposure in patients with cardiorenal diseases across all levels of renal function.

Introduction: TD-0714 is an orally active, potent, and selective inhibitor of human neprilysin (NEP) in development for the treatment of a range of cardiorenal diseases including chronic heart fail...

The evidence provided by both human and animal studies on chronic Chagas' heart disease suggests that the development of the chronic fibrosing myocarditis is related to progressive and additive focal cellular necrosis with associated inflammatory lymphomononuclear infiltrate, reactive and reparative myocardial fibrosis, surrounding myocyte hypertrophy. These processes may be initiated and perpetuated by alterations in the myocardial microcirculation and by autoimmune factors. These findings could foster future therapeutic strategies in the management of chronic chagasic patients to optimize the medical treatment and hopefully to improve prognosis.

Objectives: The present study was designed to evaluate a novel bioerodible sol-gel film coated paclitaxel-eluting stent (sol-gel-PES, 3 mu g per stent) in a porcine coronary artery model.Background: Although current polymer-based PES decrease restenosis, the permanent polymer and bound drug have raised concerns regarding delayed vessel healing and late stent thrombosis.Methods: Polymer-based PES (poly-PES, n= 8), sol-gel-PES ( n= 15), bare metal (BMS, n= 14), and sol-gel film only ( sham, n= 12), stents were implanted in 17 juvenile pigs. Animals were terminated 28 days post-implant for angiographic restudy and complete histopathologic and histomorphometric analyses.Results: Angiographic late loss was equally reduced for both poly-PES and sol-gel-PES (0.51 +/- 0.64 and 0.61 +/- 0.52 mm, respectively) compared to both BMS and sham (0.98 +/- 0.74 and 1.25 +/- 0.72 mm, p<0.05). Similarly beneficial results were observed for histomorphometric parameters of neointimal thickness and area, yielding reductions of in-stent stenosis by 43% and 48% for poly-PES, as well as 31% and 37% for sol-gel-PES, vs. BMS and sham, respectively (p<0.05). Re-endothelialization was complete in all groups. Although the inflammatory cell infiltration and intramural thrombus scores were no different between poly-and sol-gel-PES, medial necrosis was increased for poly-PES (p<0.05 vs. all others).Conclusions: A novel bioerodible sol-gel film coated with low-dose paclitaxel demonstrates less toxicity to the coronary tunica media, while retaining effective inhibition of neointimal formation at 28 days. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

The uremic solutes p-cresol and indoxyl sulfate inhibit endothelial proliferation and wound repair.Cardiovascular diseases are the major causes of mortality in uremic patients, and the vascular endothelium is dysfunctional in uremia. We hypothesized that uremic retention solutes may be among the factors involved in this endothelial dysfunction. We therefore investigated the in vitro effect of a large panel of uremic retention solutes (guanidino compounds, polyamines, oxalate, myoinositol, urea, uric acid, creatinine, indoxyl sulfate, indole-3-acetic acid, p-cresol, hippuric acid, and homocysteine) on endothelial proliferation. In addition, we tested the effect of uremic solutes that altered proliferation on endothelial wound repair.Human umbilical vein endothelial cells (HUVEC) were incubated with uremic retention solutes at concentrations in the range found in uremic patients. Protein-bound uremic solutes were also tested in the presence of 4% human albumin. Then, we determined the effect of each uremic solute on endothelial proliferation by a 5-bromo-2-deoxy-uridine (BrdU) labeling assay. In addition, confluent endothelial monolayers were injured, incubated with uremic solutes that altered endothelial proliferation, and the surface of the wound was measured at different intervals by image analysis.Endothelial proliferation was inhibited by two protein-bound uremic retention solutes: p-cresol and indoxyl-sulfate. Inhibition of endothelial proliferation by p-cresol was dose-dependent. Moreover, p-cresol and indoxyl sulfate decreased endothelial wound repair. The presence of albumin did not affect the inhibitory effect of these solutes on endothelial proliferation, but the decrease in endothelial wound repair was less marked in the presence of albumin.We demonstrated that both p-cresol and indoxyl sulfate decrease endothelial proliferation and wound repair. These solutes could play a role in endothelial dysfunction observed in uremic patients.

Coronary stent fracture can be a potentially serious complication to stenting leading to various complications, such as restenosis, and even occlusion. We reported multiple stent fracture of overlapping paclitaxel and sirolimus-eluting stent. Although an overwhelming majority of stent fracture was reported from sirolimus-eluting stent, our case showed that fracture of paclitaxel-eluting stent could occur by similar mechanisms as in sirolimus-eluting stent. So angiographic follow-up with intravascular ultrasound should be performed to elucidate the clinical significance of stent fracture of DES regardless of DES type.