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Aims: PUR0200 is a tiotropium bromide formulation engineered with the iSPERSE dry powder delivery technology. PUR0200 is being developed as a bioequivalent alternative to tiotropium bromide, delivered using Spiriva® HandiHaler® (HH). We investigated the bronchodilator effects, pharmacokinetics and safety of PUR0200 in patients with chronic obstructive pulmonary disease (COPD)., Methods: This was a randomized, placebo-controlled, crossover study using different PUR0200 doses and the comparator tiotropium HH. In vitro aerodynamic particle size distribution (aPSD) characterization of PUR0200 and tiotropium HH are presented. The main endpoints included forced expiratory volume in 1 s (FEV 1 ) trough and (0-24 h) and pharmacokinetic parameters., Results: The increased fine-particle fraction of PUR0200 demonstrated by testing using the next-generation impactor increased the proportion of drug available for lung deposition compared with the tiotropium HH. There was a numerical dose-response effect for PUR0200 on FEV 1 , with 3 μg demonstrating a lower effect than higher doses. The placebo-adjusted mean (95% confidence interval) increases from baseline at 24 h postdose were 150 ml (100-200), 210 ml (160-270) and 200 ml (140-250) for 3 μg, 6 μg and 9 μg doses of PUR0200, respectively. Tiotropium HH (18 μg) caused a mean 169 ml (standard deviation 157ml) improvement in trough FEV 1 , which was not significantly different to the PUR0200 effects at any of the tested doses., Conclusions: PUR0200 treatment caused bronchodilation in COPD patients that was similar in magnitude to that caused by tiotropium HH. This enabled a similar clinical effect on lung function to be achieved with PUR0200 using a lower metered dose of tiotropium compared with tiotropium HH., (© 2018 The British Pharmacological Society.)

NDI-010976, an allosteric inhibitor of acetyl-coenzyme A carboxylases (ACC) ACC1 and ACC2, reduces hepatic de novo lipogenesis (DNL) and favorably affects steatosis, inflammation, and fibrosis in animal models of fatty liver disease. This study was a randomized, double-blind, placebo-controlled, crossover trial evaluating the pharmacodynamic effects of a single oral dose of NDI-010976 on hepatic DNL in overweight and/or obese but otherwise healthy adult male subjects. Subjects were randomized to receive either NDI-010976 (20, 50, or 200 mg) or matching placebo in period 1, followed by the alternate treatment in period 2; and hepatic lipogenesis was stimulated with oral fructose administration. Fractional DNL was quantified by infusing a stable isotope tracer, [1- 13 C]acetate, and monitoring 13 C incorporation into palmitate of circulating very low-density lipoprotein triglyceride. Single-dose administration of NDI-010976 was well tolerated at doses up to and including 200 mg. Fructose administration over a 10-hour period stimulated hepatic fractional DNL an average of 30.9 ± 6.7% (mean ± standard deviation) above fasting DNL values in placebo-treated subjects. Subjects administered single doses of NDI-010976 at 20, 50, or 200 mg had significant inhibition of DNL compared to placebo (mean inhibition relative to placebo was 70%, 85%, and 104%, respectively). An inverse relationship between fractional DNL and NDI-010976 exposure was observed with >90% inhibition of fractional DNL associated with plasma concentrations of NDI-010976 >4 ng/mL., Conclusion: ACC inhibition with a single dose of NDI-010976 is well tolerated and results in a profound dose-dependent inhibition of hepatic DNL in overweight adult male subjects. Therefore, NDI-010976 could contribute considerable value to the treatment algorithm of metabolic disorders characterized by dysregulated fatty acid metabolism, including nonalcoholic steatohepatitis. (Hepatology 2017;66:324-334)., (© 2017 Nimbus Discovery, Inc. Hepatology published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.)

Background: Hereditary angioedema (HAE) is a rare, autosomal-dominant disorder caused by C1 inhibitor gene mutation. Patients with HAE experience intermittent attacks of edema affecting the oropharynx, abdomen, gastrointestinal tract, and limbs. C1 inhibitor is the primary endogenous inhibitor of the kallikrein-kinin (contact) cascade. Unregulated kallikrein activation generates bradykinin, the likely mediator of the swelling and pain characterizing HAE attacks. Ecallantide, a novel, recombinant protein, potently inhibits kallikrein. This is the first placebo-controlled assessment in human beings of a therapeutic intervention to improve symptoms of HAE attacks under the hypothesis that the contact cascade is the putative pathway responsible for HAE pathology., Objective: To determine the safety and efficacy of ecallantide in patients with HAE., Methods: This double-blind, placebo-controlled, ascending-dose study assessed efficacy and tolerability of ecallantide (5, 10, 20, or 40 mg/m(2) intravenously) in individuals experiencing acute HAE attacks (N = 49). Twelve patients were assigned to each dose level: 10 to ecallantide and 2 to placebo, per cohort., Results: Ecallantide treatment ameliorated the symptoms of HAE attacks: 72.5% (29/40) of patients treated with ecallantide versus 25.0% (2/8) of placebo patients reported significant improvement in symptoms within 4 hours (P = .0169). Ecallantide was well tolerated at all doses., Conclusion: Ecallantide, a potent, specific inhibitor of plasma kallikrein, significantly improved HAE symptoms over placebo. The trial provides strong support for the role of the kallikrein-kinin cascade and its end product, bradykinin, in the pathophysiology of HAE. Further clinical trials are underway., Clinical Implications: Ecallantide is a promising new therapy for HAE attacks.

Unlabelled: CPG 10101 (ACTILON) is a novel potent and selective unmethylated cytidine-phosphate-guanosine (CpG)-containing oligodeoxynucleotide agonist of Toll-like receptor 9 (TLR9) being developed for the treatment of chronic infections such as HCV., Objectives and Methods: In this randomized, double-blind, placebo-controlled Phase I study in 48 normal volunteers, we investigated the safety, pharmacokinetic parameters and immune effects of subcutaneous administration of CPG 10101. Five sequential escalating doses from 0.25 to 20 mg were administered twice, 14 days apart. In addition, a 4 mg dose was administered twice weekly for four weeks., Results: A maximum tolerated dose was not reached and the adverse event profile was consistent with the known immunostimulatory effects of TLR9 agonists, mostly consisting of injection site reactions or flu-like symptoms that were generally mild in intensity. CPG 10101 induced interferons, cytokines and chemokines in a pattern consistent with the biology of TLR9. The most sensitive marker was IP-10/CXCL10, whose induction was detected in some subjects even at the 0.25 mg dose. Some cytokines showed transient circulating levels, while the levels of others such as the antiviral cytokine 2',5'-oligoadenylate synthetase were sustained for several days., Conclusion: This study warrants further investigation of CPG 10101 for the treatment of chronic infections such as HCV.

Diethyldithiocarbamate (DDTC) is an investigational agent used to ameliorate chemotherapy- or radiotherapy-induced myelosuppression. We studied the effects of DDTC on the regulation of hematopoietic cytokine production in human myeloid cells. The results demonstrated that DDTC decreases proliferation of human HL-60 promyelocytic leukemia cells in a concentration-dependent manner. DDTC treatment also increased interleukin-alpha (IL-1 alpha), IL-1 beta, and tumor necrosis factor (TNF) expression in these cells. Similar findings were obtained in normal human peripheral blood monocytes. Peak induction of these cytokines occurred 6-12 hr after exposure to DDTC; levels returned to those in control cells by 24-48 hr in HL-60 cells. This effect was specific for IL-1 and TNF in that there was no detectable increase in IL-3, macrophage colony-stimulating factor or granulocyte/macrophage colony-stimulating factor RNA expression. Transcriptional run-on analysis demonstrated that exposure to DDTC increased the rate of TNF gene transcription in HL-60 cells. These data suggest that the myeloprotective effects of DDTC may be mediated, at least in part, by the induction of TNF, IL-1 alpha, and IL-1 beta.

Sodium diethyldithiocarbamate (DDTC) has been shown to modulate the myelosuppression that commonly occurs following treatment with anticancer drugs in mice. In order to investigate the mechanism of action of this myeloprotector, murine long-term bone marrow cultures were treated with DDTC alone or were preceded by the anticancer drug cis-diammine(cyclobutanedicarboxylato)platinum(II) (CBDCA), and the granulocyte/macrophage colony-stimulating activity of the supernatants was measured. The supernatants harvested from DDTC-treated cultures enhanced proliferation of granulocyte/macrophage progenitor cells almost 4-fold compared to cultures treated with no drug or with CBDCA alone. Pretreatment of cultures with CBDCA neither enhanced nor inhibited DDTC-induced colony-stimulating activity. Similar results were obtained by using marrow stromal cell cultures free of hematopoietic cells. Thus, DDTC may hasten bone marrow recovery by augmenting stromal cell production of a factor(s) with hematopoietic colony-stimulating activity.

The effect of diethyldithiocarbamate (DDTC) on myelotoxicity induced by 1,3-bis(2-chloroethyl)-1-nitrosourea, Adriamycin, or mitomycin C in C57BL/6J x DBA/2J mice is reported here. All drugs were administered i.v. Myelotoxicity was assessed, 24 h after administration of the myelotoxic drug, using bone marrow stem cell (spleen colony-forming unit) and granulocyte/macrophage progenitor cell (granulocyte/macrophage colony-forming unit in culture) clonogenic assays. Administration of DDTC alone had no effect on spleen colony-forming units or granulocyte/macrophage colony-forming units in culture. 1,3-Bis(2-chloroethyl)-1-nitrosourea showed a dose-dependent toxicity for both cell types, and subsequent treatment with DDTC (300 mg/kg i.v. 3 h after 1,3-bis(2-chloroethyl)-1-nitrosourea) ameliorated this toxicity. The same dosing regimen of DDTC ameliorated Adriamycin-induced toxicity to bone marrow stem cells at the two higher doses tested. However, the myelosuppressive effects of mitomycin C were not altered by DDTC administration (300 mg/kg i.v. 3 h after or 30 min before mitomycin C). These results demonstrate that DDTC ameliorates myelotoxicity induced by several, but not all, chemotherapeutic agents and suggest a broad role for DDTC in cancer chemotherapy.

Diethyldithiocarbamate (DDTC) has been shown to ameliorate the myelosuppression induced by the platinum cancer chemotherapeutic drugs in mice. Optimal drug scheduling for DDTC and cis-diammine(cyclobutanedicarboxylato)platinum(II) (CBDCA) has been determined in C57BL/6 x DBA/2 F1 mice, using the pluripotent stem cell assay to assess hematological toxicity. DDTC, at doses of 0.3 to 300 mg/kg given 3 h after 60 mg/kg CBDCA, tripled the number of proliferating spleen colony-forming units compared to treatment with CBDCA alone. No significant difference in efficacy was noted among these doses. DDTC, at the lowest myeloprotective dose (0.3 mg/kg), was most active when administered from 1 to 3 h after CBDCA. The combination of DDTC with CBDCA in vivo did not alter the clonogenic survival of L1210 cells compared to CBDCA alone. CBDCA depressed both bone marrow and tumor cell DNA synthesis. DDTC given 3 h after CBDCA hastened the recovery of DNA synthesis only in marrow cells; the addition of DDTC to CBDCA did not alter DNA synthesis in tumor cells. DDTC alone did not significantly affect DNA synthesis in either normal or tumor cells. These results suggest that the mechanism of DDTC myeloprotection involves stimulation of bone marrow cell proliferation and that the selectivity of DDTC is based upon the absence of stimulation in tumor cells.