An Autophagy Modulator Peptide Prevents Lung Function Decrease and Corrects Established Inflammation in Murine Models of Airway Allergy

The involvement of autophagy and its dysfunction in asthma is still poorly documented. By using a murine model of chronic house dust mite (HDM)-induced airway inflammation, we tested the expression of several autophagy markers in the lung and spleen of asthma-like animals. Compared to control mice, in HDM-sensitized and challenged mice, the expression of sequestosome-1/p62, a multifunctional adaptor protein that plays an important role in the autophagy machinery, was raised in the splenocytes. In contrast, its expression was decreased in the neutrophils recovered from the bronchoalveolar fluid, indicating that autophagy was independently regulated in these two compartments. In a strategy of drug repositioning, we treated allergen-sensitized mice with the therapeutic peptide P140 known to target chaperone-mediated autophagy. A single intravenous administration of P140 in these mice resulted in a significant reduction in airway resistance and elastance, and a reduction in the number of neutrophils and eosinophils present in the bronchoalveolar fluid. It corrected the autophagic alteration without showing any suppressive effect in the production of IgG1 and IgE. Collectively, these findings show that autophagy processes are altered in allergic airway inflammation. This cellular pathway may represent a potential therapeutic target for treating selected patients with asthma.

Toxicity Profile of Artesunate in Rats and Dogs

OBJECTIVES: The objectives of these studies were to investigate the toxicity, safety and toxicokinetics of single and multiple doses of artesunate for injection in rats and dogs. METHODS: Sprague-Dawley rats and Beagle dogs were treated intravenously or intramuscularly for 28 consecutive days with doses of up to 30 mg/kg artesunate, evaluating toxicity, kinetics, genotoxicity, and cardiovascular and central nervous safety parameters after single and 4-week repeated administrations. Furthermore, respiratory parameters were evaluated after a single intravenous administration in rats. RESULTS: Artesunate was well tolerated with no mortality and only minor effects on clinical pathology parameters. CONCLUSIONS: The results obtained in these studies support the safe use of intravenous and intramuscular artesunate in humans.

Targeting brain metastases with ultrasmall theranostic nanoparticles, a first-in-human trial from an MRI perspective

The use of radiosensitizing nanoparticles with both imaging and therapeutic properties on the same nano-object is regarded as a major and promising approach to improve the effectiveness of radiotherapy. Here, we report the MRI findings of a phase 1 clinical trial with a single intravenous administration of Gd-based AGuIX nanoparticles, conducted in 15 patients with four types of brain metastases (melanoma, lung, colon, and breast). The nanoparticles were found to accumulate and to increase image contrast in all types of brain metastases with MRI enhancements equivalent to that of a clinically used contrast agent. The presence of nanoparticles in metastases was monitored and quantified with MRI and was noticed up to 1 week after their administration. To take advantage of the radiosensitizing property of the nanoparticles, patients underwent radiotherapy sessions following their administration. This protocol has been extended to a multicentric phase 2 clinical trial including 100 patients.

Biological Safety and Biodistribution of Chitosan Nanoparticles

The effect of unmodified chitosan nanoparticles with a size of ~100 nm and a weakly positive charge on blood coagulation, metabolic activity of cultured cardiomyocytes, general toxicity, biodistribution, and reactive changes in rat organs in response to their single intravenous administration at doses of 1, 2, and 4 mg/kg was studied. Chitosan nanoparticles (CNPs) have a small cytotoxic effect and have a weak antiplatelet and anticoagulant effect. Intravenous administration of CNPs does not cause significant hemodynamic changes, and 30 min after the CNPs administration, they mainly accumulate in the liver and lungs, without causing hemolysis and leukocytosis. The toxicity of chitosan nanoparticles was manifested in a dose-dependent short-term delay in weight gain with subsequent recovery, while in the 2-week observation period no signs of pain and distress were observed in rats. Granulomas found in the lungs and liver indicate slow biodegradation of chitosan nanoparticles. In general, the obtained results indicate a good tolerance of intravenous administration of an unmodified chitosan suspension in the studied dose range.

P278 Pharmacokinetics, pharmacodynamics and efficacy of OPC-61815, prodrug of tolvaptan for intravenous administration, in patients with congestive heart failure

Funding Acknowledgements Otsuka Pharmaceutical Co. Ltd. On Behalf OPC-61815 phase II investigators Background/Introduction: Tolvaptan, a vasopression V2-receptor antagonist, is effective for congestion in patients with congestive heart failure (CHF), and hyponatremia in patients with CHF and SIADH. But, this drug is not readily soluble in water and not suited for development as an injection. OPC-61815, a prodrug of tolvaptan having improved water solubility, is suitable for intravenous administration. Purpose The phase-II clinical study (ClinicalTrials.gov Identifier: NCT03254108) was conducted to investigate the dose for intravenous administration of OPC-61815 achieving tolvaptan exposure equivalent to that for oral administration of tolvaptan 15-mg tablet in CHF patients. Methods This study was a multicenter, a double-blind, randomized, active-controlled, parallel-group comparison clinical pharmacology trial. Sixty patients aged between 20 and 85 years with CHF with volume overload despite the use of conventional diuretics were randomly assigned to four treatment cohorts to receive OPC-61815 at doses of 2, 4, 8, 16 mg (i.v.) or tolvaptan at 15 mg (p.o.). Both drugs were administered once a day for 5 days. The primary endpoint was to assess the dose of OPC-61815 equivalent to tolvaptan at 15 mg using Cmax and AUC24h values after the first administration. Pharmacodynamics (urine volume, urine osmolality, serum electrolyte concentration, biomarkers), efficacy (body weight change, congestive symptoms) and safety were also evaluated. Results The mean Cmax and AUC of the metabolite tolvaptan increased dose-dependently following single intravenous administration of OPC-61815 at 2, 4, 8, and 16 mg. Tolvaptan exposure (Cmax and AUC24h) on Day 1 following single intravenous administration of OPC-61815 at 16 mg was the closest and similar to that following single administration of tolvaptan 15-mg tablet. OPC-61815 increased urine volume from baseline, leading to decrease in body weight and improvement of lower limb edema. The incidence of treatment-emergent adverse events was 54.2% (26/48 subjects) in the OPC-61815 2 to 16-mg, and 83.3% (10/12 subjects) in the tolvaptan 15-mg groups. No clinically relevant changes from baseline were found in laboratory parameters, vital signs, or ECG findings. Conclusions Tolvaptan exposure on Day 1 following single intravenous administration of OPC-61815 at 16 mg was the most similar to that following single administration of tolvaptan 15-mg tablet. There was no marked difference in tolerability between OPC-61815 at 16 mg and tolvaptan 15-mg tablet, and no clinically significant problems were observed.

NI-11 PATHOLOGICAL ASSESSMENT IN THE IMPACT OF ONE-SHOT BEVACIZUMAB ON UPTAKE OF 11C-METHIONINE

BACKGROUND This study aimed to clarify how one-time administration of bevacizumab (BEV) changes histological features in glioblastoma, and how histological changes affect the uptake of 11C-methyl-L-methionine (11C-met) as an amino-acid tracer. MATERIALS AND METHODS Subjects were 18 patients with newly diagnosed glioblastoma who were assigned to 2 groups: BEV group, single intravenous administration of BEV before surgical tumor removal; and control group, surgical tumor removal alone. After surgery, we compared the densities of tumor cells and microvessels, and microvascular structures including vascular pericytes and L-type amino acid transporter-1 (LAT1), between the BEV and control groups. Correlations between 11C-met uptake on positron emission tomography before surgery, microvascular density, and LAT1 expression were assessed in each group. RESULTS BEV induced significant reductions in microvascular density, while tumor cell density and proliferation were retained in the BEV group. Percentages of vessels with pericytes and vascular endothelium with LAT1 expression were lower in the BEV group than in controls. Uptake of 11C-met correlated significantly with microvascular density in the BEV group, but not with LAT1expression. CONCLUSIONS The present study showed that even one course of BEV administration induced reductions in microvessels, vascular pericytes, and LAT1 expression in glioblastomas. One course of BEV therapy also reduced 11C-met uptake, which might have been largely attributed to reductions in microvessels rather than reductions in LAT1 expression, in addition to reduction of vascular permeability.