716. In vitro and In vivo Nonclinical Efficacy of AR-501 (Gallium Citrate)

Abstract Background Gallium nitrate citrate exhibits strong antibacterial activity and was recently shown to be safe and efficacious when intravenously administered to cystic fibrosis patients in a Phase 2 clinical study conducted by the University of Washington. We are developing an inhaled formulation of gallium citrate (AR-501), which is being tested in a Phase 1/2a clinical study. The in vitro antimicrobial activities, drug resistance profile, activities in combination with selected antibiotics, and in vivo animal efficacy if the inhaled vs. IV formulation is being presented. Methods MIC tests were performed on strains using the CLSI susceptibility test standards. Resistance testing exposed bacteria to 20 cycles at ranges above and below the MIC level of the drug used.SPF mice (C57BL/6J, 7–9 weeks) were inoculated intranasally with P. aeruginosa under ketamine/xylazine anesthesia. Inhalation of AR-501 used an Aeroneb Solo nebulizer. Gallium levels were determined by elemental analysis using atomic absorption spectroscopy. CFU levels were measured by enumeration of bacterial colonies following serial dilution of tissue homogenates. Results In vitro efficacy: MIC testing demonstrates the efficacy of AR-501 against gram (−), gram (+) and several species of mycobacteria of clinical isolates and the comparative antibacterial response with antibiotics. Resistance testing showed that AR-501 exhibited lower propensity to develop resistance than the antibiotics tested. In vivo efficacy: AR-501 Inhalation also increased the median survival time compared with IV dosing in the murine model. Bacterial clearance was increased when Tobramycin and AR-501 are co-administered. Comparative analysis of AR-501 after IH route demonstrate increased gallium levels in BAL and reduced levels in the kidney in contrast to IV route. Conclusion In vitro studies demonstrate the susceptibility of gram (−), gram (+) and mycobacteria pathogens and the dose range of AR-501 compared with SOC antibiotics. In vivo studies confirm the therapeutic efficacy of AR-501 in bacterial pneumonia by IH delivery and demonstrate that bacterial clearance is enhanced when SOC antibiotics are used in combination with AR-501. Disclosures All authors: No reported disclosures.

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Early formulation development of CKD-519, a new CETP inhibitor, for phase 1 clinical study based on in vitro and in vivo evaluation

International Journal of Pharmaceutics ◽

10.1016/j.ijpharm.2018.08.012 ◽

2018 ◽

Vol 549 (1-2) ◽

pp. 388-396 ◽

Cited By ~ 4

Author(s):

Shin Jung Park ◽

Prakash Thapa ◽

Hye-Jin Seo ◽

Eun Seok Park ◽

Seong Hoon Jeong

Keyword(s):

Clinical Study ◽

Phase 1 ◽

Formulation Development ◽

In Vivo Evaluation ◽

Cetp Inhibitor ◽

Early Formulation

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Antimicrobial, Antioxidant, and Immunomodulatory Properties of Essential Oils: A Systematic Review

Nutrients ◽

10.3390/nu11112786 ◽

2019 ◽

Vol 11 (11) ◽

pp. 2786 ◽

Cited By ~ 25

Author(s):

Magdalena Valdivieso-Ugarte ◽

Carolina Gomez-Llorente ◽

Julio Plaza-Díaz ◽

Ángel Gil

Keyword(s):

Essential Oils ◽

Animal Feed ◽

Antioxidant Activities ◽

Dose Range ◽

Food Preservation ◽

In Vivo Studies ◽

Resistant Bacteria ◽

Immunomodulatory Properties

Essential oils (EOs) are a mixture of natural, volatile, and aromatic compounds obtained from plants. In recent years, several studies have shown that some of their benefits can be attributed to their antimicrobial, antioxidant, anti-inflammatory, and also immunomodulatory properties. Therefore, EOs have been proposed as a natural alternative to antibiotics or for use in combination with antibiotics against multidrug-resistant bacteria in animal feed and food preservation. Most of the results come from in vitro and in vivo studies; however, very little is known about their use in clinical studies. A systematic and comprehensive literature search was conducted in PubMed, Embase®, and Scopus from December 2014 to April 2019 using different combinations of the following keywords: essential oils, volatile oils, antimicrobial, antioxidant, immunomodulation, and microbiota. Some EOs have demonstrated their efficacy against several foodborne pathogens in vitro and model food systems; namely, the inhibition of S. aureus, V. cholerae, and C. albicans has been observed. EOs have shown remarkable antioxidant activities when used at a dose range of 0.01 to 10 mg/mL in cell models, which can be attributed to their richness in phenolic compounds. Moreover, selected EOs exhibit immunomodulatory activities that have been mainly attributed to their ability to modify the secretion of cytokines.

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Xanthohumol, a Prenylated Chalcone Derived from Hops, Inhibits Growth and Metastasis of Melanoma Cells

Cancers ◽

10.3390/cancers13030511 ◽

2021 ◽

Vol 13 (3) ◽

pp. 511

Author(s):

Tatjana Seitz ◽

Christina Hackl ◽

Kim Freese ◽

Peter Dietrich ◽

Abdo Mahli ◽

...

Keyword(s):

Hepatic Metastasis ◽

Dose Range ◽

Melanoma Cells ◽

In Vivo Studies ◽

Melanoma Metastasis ◽

Anticancer Activities ◽

Prenylated Chalcone ◽

The Impact

Melanoma is one of the most aggressive and lethal cancers worldwide. Despite recent progress in melanoma therapy, the prognosis for metastasized melanoma continues to be poor. Xanthohumol (XN), a prenylated chalcone derived from hop cones, is known to possess a broad spectrum of chemopreventive and anticancer activities. However, few studies have analyzed functional XN effects on melanoma cells and there have been no previous in vivo studies of its effects on metastasis. The aim of this study was to investigate the impact of XN on the tumorigenic and liver metastatic activity of melanoma cells. XN exhibited dose-dependent cytotoxic effects on human melanoma cell lines (Mel Ju; Mel Im) in vitro. Functional analysis in the subtoxic dose-range revealed that XN dose-dependently inhibited proliferation, colony formation, and migratory activity of melanoma cells. Subtoxic XN doses also induced markers of endoplasmic reticulum stress but inhibited the phosphorylation of the protumorigenic c-Jun N-terminal kinases (JNK). Furthermore, XN effects on hepatic metastasis were analyzed in a syngeneic murine model (splenic injection of murine B16 melanoma cells in C57/BL6 mice). Here, XN significantly reduced the formation of hepatic metastasis. Metastases formed in the liver of XN-treated mice revealed significantly larger areas of central necrosis and lower Ki67 expression scores compared to that of control mice. In conclusion, XN inhibits tumorigenicity of melanoma cells in vitro and significantly reduced hepatic metastasis of melanoma cells in mice. These data, in conjunction with an excellent safety profile that has been confirmed in previous studies, indicate XN as a promising novel agent for the treatment of hepatic (melanoma) metastasis.

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A Phase 1 and Correlative Biological Study of CSL360 (anti-CD123 mAb) in AML

Blood ◽

10.1182/blood.v112.11.2956.2956 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2956-2956 ◽

Cited By ~ 5

Author(s):

Andrew W. Roberts ◽

Simon He ◽

Kenneth F Bradstock ◽

Mark S Hertzberg ◽

Simon T S Durrant ◽

...

Keyword(s):

Adverse Events ◽

Dose Level ◽

De Novo ◽

Biological Effects ◽

Phase 1 ◽

Dose Range ◽

Clinical Signs ◽

Biological Study

Abstract CD123 (IL-3Rα) is a phenotypic marker of putative leukemic stem cells (LSC) in AML (Jordan, Leukemia2000;14:1777). We and others have found that CD34+38− cells from AML patients (pts) express high levels of CD123, in contrast to absence of expression on CD34+38− cells in normal individuals. Binding of CD123 by monoclonal antibody (mAb) 7G3 inhibits IL-3-dependent signalling and proliferation in vitro. In a NOD-SCID xenograft model 7G3 inhibits human AML engraftment, but not normal human hematopoiesis (Lock ASH2007; Abs161). CSL360, a recombinant chimeric IgG1 mAb derived from 7G3, binds the same epitope. CSL360 concentrations ≥ 0.1μg/mL in vitro inhibited 90% AML cell growth in the presence of supraphysiological IL-3 levels. Preclinical toxicology studies with doses up to 100 mg/kg weekly × 4 in cynomolgus monkeys showed no CSL360-related effects in clinical signs, hematology, chemistry, urinalysis, gross pathology or histopathology. A Phase 1 study of safety, pharmacokinetics (PK) and bioactivity of CSL360 in relapsed, refractory or high risk AML began in March 2007. Pts receive 12 weekly iv infusions if not withdrawn early due to treatment-related toxicity or disease progression. Additional treatments may be given to pts who achieve a response. Bone marrow aspirates/trephine samples are obtained at screening, after dose 3 and before doses 5 and 11. More than 180 infusions have been administered to 26 AML pts (21 M, 5 F; 17 de novo, 8 MDS-related, 1 treatment-related AML) in 5 dose level cohorts: 0.1, 0.3, 1.0, 3.0 and 10 mg/kg. There is no intra-patient dose escalation. PK parameters over the dose range, estimated in 19 pts over 7 days after doses 1 and 4, were linear with dose-proportional increases in the AUC and Cmax; dose 1 Cmax ranged from 0.62 – 287.33 μg/mL and dose 4 Cmax from 1.02 – 178.22 μg/mL. CSL360 mean plasma half-life (dose 1, 83 ± 33 h; dose 4, 117 ± 59 h) appears to be independent of dose and treatment number. Dose 1 systemic clearance (0.21 ± 0.16 L/h) and volume of distribution (0.39 ± 0.22 L/kg) were relatively low, consistent with this size IgG. In all pre-treatment samples anti-CSL360 antibody titers were negative, determined by enzyme immunoassay. Anti-CSL360 antibodies were detected post-treatment in 8/12 pts; these antibodies have not been fully quantified or characterised. CSL360 has been well tolerated; a MTD has not been defined. Seven pts received all 12 doses, 13 pts were withdrawn due to progressive disease or investigator’s decision, 3 pts were withdrawn in association with infections, 2 pts withdrew consent, and 1 pt is ongoing. Three serious adverse events have been considered possibly related or related to CSL360: 1 invasive fungal infection (Gr 5), and 2 infusion reactions (Gr 2; hospitalised). Other adverse events are consistent with expectations for the disease population. Of 8 pts in the 3 mg/kg and 10 mg/kg cohorts who are evaluable for response after ≥ 4 doses, 1 complete response (CR) has been observed. A 22 yr old male, de novo FAB M1 cytogenetically normal AML, who had relapsed post-2 allogeneic SCT, achieved a morphologic leukemia free state after 3 doses (3.0 mg/kg) and CR after 12 doses, sustained for > 9 weeks. The pt received 17 doses before withdrawal to treat co-morbidities. Flow cytometry studies with anti-CD123 antibodies demonstrated dose-dependent CSL360 coating of both AML blasts and LSC. Saturation of target antigen on marrow and blood cells was observed 1 day after dosing at 0.3mg/kg, associated with decreased expression of CD123 detected by an antibody to a different epitope. At higher dose levels saturation of CD123 was maintained 7 days post dosing, associated with ongoing reduction in surface CD123 expression. In a representative sample, plasma from a pt treated at 10 mg/kg specifically inhibited IL-3-induced proliferation of AML blasts ex vivo, indicating sufficient circulating concentration of CSL360 to inhibit IL-3 mediated effects in vivo. Effects of CSL360 on proliferation and apoptosis of AML cells in treated patients are being investigated. These preliminary results show anti-CD123 mAb therapy with CSL360 is safe and tolerable; biological effects have been demonstrated; a sustained CR was achieved in 1 advanced, refractory AML pt. The study is continuing, with 20 evaluable patients to be accrued and treated at 10 mg/kg weekly; at this dose level the PK and correlative assays predict that complete blockade of IL-3 signalling through CD123 can be achieved in vivo.

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BMS-936564/MDX-1338: A Fully Human Anti-CXCR4 Antibody Induces Apoptosis In Vitro and Shows Anti Tumor Activity In Vivo

Blood ◽

10.1182/blood.v118.21.1543.1543 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1543-1543

Author(s):

Michelle R. Kuhne ◽

Tanya Mulvey ◽

Sharline Chen ◽

Chin Pan ◽

Colin Chong ◽

...

Keyword(s):

Phase 1 ◽

Human Monoclonal Antibody ◽

Prognostic Indicator ◽

Hematologic Malignancies ◽

Calcium Flux ◽

In Vivo Studies ◽

Tumor Growth Inhibition ◽

Anti Tumor Activity

Abstract Abstract 1543 BMS-936564/MDX-1338 is a fully human monoclonal antibody that specifically recognizes human CXCR4 and is currently in phase 1 studies in patients with relapsed/refractory acute myeloid leukemia (AML) and multiple myeloma (MM). CXCR4 has been identified as a prognostic indicator for AML and other malignancies, in which greater expression of CXCR4 correlates with disease severity. CXCR4 is a seven-transmembrane, G-protein-coupled receptor in the CXC chemokine receptor family. In response to stimulation by its ligand, the chemokine CXCL12, CXCR4 activates calcium flux, chemotaxis and mediates directional migration of hematopoietic cells. In healthy adults, the receptor is predominantly expressed on B and T cells, monocytes, macrophages, NK and dendritic cells, as well as lymphoid and myeloid precursor cells. Expression of CXCR4 is elevated in a variety of cancers and the interaction of CXCR4 on tumor cells with CXCL12 in the bone marrow promotes tumor cell survival and growth. An antagonist of this pathway is predicted to be efficacious in a variety of hematologic malignancies. In vitro studies demonstrate that BMS-936564/MDX-1338 binds to CXCR4expressing cells with low nanomolar affinity. The antibody blocks CXCL12 binding to CXCR4 expressing cells and inhibits CXCL12 induced migration and calcium flux with low nanomolar EC50 values. When given as monotherapy on established tumors, the antibody exhibits anti-tumor activity in multiple AML, NHL and MM xenograft models. BMS-936564/MDX-1338 is an IgG4 and thus does not elicit complement dependent cytotoxicity (CDC) or antibody dependent cell mediated cytotoxicity (ADCC). In vitro and in vivo studies suggest that BMS-936564/MDX-1338 induces apoptosis as one mechanism of tumor growth inhibition. Here we describe the in vitro and in vivo characterization and activities of BMS-936564/MDX-1338. Disclosures: Kuhne: Bristol-Myers Squibb: Employment. Mulvey:Bristol-Myers Squibb: Employment. Chen:Bristol-Myers Squibb: Employment. Pan:Bristol-Myers Squibb: Employment. Chong:Bristol-Myers Squibb: Employment. Niekro:Bristol-Myers Squibb: Employment. Kempe:Bristol-Myers Squibb: Employment. Henning:Bristol-Myers Squibb: Employment. Cohen:Bristol-Myers Squibb: Employment. Korman:Bristol-Myers Squibb: Employment. Cardarelli:Bristol-Myers Squibb: Employment.

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Phase I trial of a novel epothilone, KOS-1584, using a weekly dosing schedule

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.2041 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 2041-2041 ◽

Cited By ~ 9

Author(s):

A. Stopeck ◽

E. Thomas ◽

S. Jones ◽

J. Cohen ◽

G. Cropp ◽

...

Keyword(s):

Phase 1 ◽

Dose Range ◽

Optimal Dose ◽

Pharmacokinetic Profile ◽

In Vitro Cytotoxicity ◽

Epothilone D ◽

Ecog Ps ◽

Dose Levels

2041 Background: Several epothilones are progressing through phase 1–3 clinical trials treating solid tumor malignancies. KOS-1584 is a 3rd generation epothilone with 3–12 fold increased potency compared to Epothilone D (as measured by in vitro cytotoxicity, in vivo xenografts or induction of G2/M arrest by flow cytometry) and improved pharmacologic/pharmacokinetic profile (enhanced tumor tissue penetration and reduced exposure to the CNS). This dose-escalation trial explores a weekly administration schedule of KOS-1584. Methods: Define the MTD, toxicity profile and PK of KOS-1584 when administered to patients with advanced solid malignancies via 1-hour infusion on Days 1, 8 and 15 every 4 weeks. Plasma PK and pharmacodynamics (serial sampling of PBMCs for soluble and polymerized microtubules by immunoblot) were assessed. Results: 12 pts (7 F; median age 60; median ECOG PS 1; median prior regimens 4, range 2–13) enrolled in 5 dose levels (0.8, 1.5, 2.5, 5.0 and 7.5 mg/m2). To date, no Cycle 1 DLT has been seen; one Grade 3 episode of arthritis occurred in Cycle 2. Drug-related toxicities, all Grade 1 or 2 in severity: fatigue (n=3), anorexia (n=2) and individual patients with constipation, nausea, mucositis, dehydration, headache and pruritus. Neurotoxicity has not been observed. PK/parent (n=8): t½ 18.5 ± 6.8h, Vz 504 ± 234 L and CL 19.7 ± 6.1 L/h (none of these parameters showed evidence of dose dependency). 5.0 mg/m2 Cmax 122.4 ± 60.6 ng/mL; AUCtot 688.2 ± 212 ng/mL*h. Dose proportional increase in exposure and Cmax was observed over the dose range tested to date. At 5.0 mg/m2 the1-hr infusion Cmax is 3-fold higher and AUCtot 50% higher than for the same dose delivered over 3 hours. As predicted by allometric scaling from animals, Vz is ∼4-fold and t½ 2-fold higher than that of Epothilone D. Activity consisted of extended stable disease (a patient with colon cancer for 3 cycles). Dose-dependent increases in polymerized microtubules were observed: prior to infusion ∼10% of tubulin was in its polymerized form; this increased to 20%, 30%, 35% and 48% for the 1st 4 dose levels at infusion end. Conclusions: Accrual is continuing in order to define the optimal dose on this regimen. Exposure and Cmax remain linear within this dose range; slower clearance is observed for the same dose administered over 1 hour compared to 3 hours. [Table: see text]

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Therapeutic Potency of PI3K Pharmacological Inhibitors of Gastrointestinal Cancer

Middle East Journal of Digestive Diseases ◽

10.15171/mejdd.2018.122 ◽

2018 ◽

Vol 11 (1) ◽

pp. 5-16 ◽

Cited By ~ 2

Author(s):

Kamelia Hashemzadeh ◽

Mohammad Hassan Jokar ◽

Sima Sedighi ◽

Maliheh Moradzadeh

Keyword(s):

Clinical Trials ◽

Gastrointestinal Cancer ◽

Phase 1 ◽

Phosphatidyl Inositol ◽

Mtor Inhibitors ◽

In Vivo Studies ◽

Therapeutic Targeting ◽

Pi3k Inhibitors

Therapeutic targeting of phosphatidyl-inositol 3-kinase (PI3K) is considered as a possible strategy in several types of cancer, including gastrointestinal ones. In vitro and in vivo studies indicated the significance of proapoptotic and antiproliferative inhibition of PI3K. Although there are many phase 1 and 2 clinical trials on PI3K inhibitors in patients with gastrointestinal cancer, the molecular mechanism of PI3K targeting PI3K/ mTOR pathway is not clear. Panclass I, isoformselective, and dual PI3K/mTOR inhibitors are under investigation. This review aimed to indicate PI3K-dependent targeting mechanisms in gastrointestinal cancer and the evaluation of related clinical data.

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