GPC-100, a novel CXCR4 antagonist, improves in vivo hematopoietic cell mobilization when combined with propranolol.

Autologous Stem Cell Transplant (ASCT) is increasingly used to treat hematological malignancies. A key requisite for ASCT is mobilization of hematopoietic stem cells into peripheral blood, where they are collected by apheresis and stored for later transplantation. However, success is often hindered by poor mobilization due to factors including prior treatments.

Pharmacokinetics and Pharmacodynamics of Burixafor Hydrobromide (GPC-100), a Novel C-X-C Chemokine Receptor 4 Antagonist and Mobilizer of Hematopoietic Stem/Progenitor Cells, in Mice and Healthy Subjects.

Adequate mobilization of hematopoietic stem cells (HSCs), especially CD34 cells, is necessary for stem cell transplantation in patients with hematological malignancies or autoimmune diseases. Burixafor is an inhibitor of the C-X-C Chemokine Receptor 4 that disrupts the C-X-C motif chemokine 12 (CXCL12)/CXCR4 axis in the bone marrow, releasing HSCs into circulation. In mice, a single intravenous dose of burixafor was rapidly absorbed (time to maximum concentration, 5 minutes) and increased peripheral white blood cell counts within 30 minutes.

BU10038 as a safe opioid analgesic with fewer side-effects after systemic and intrathecal administration in primates.

Background: The marked increase in mis-use of prescription opioids has greatly affected our society. One potential solution is to develop improved analgesics which have agonist action at both mu opioid peptide (MOP) and nociceptin/orphanin FQ peptide (NOP) receptors. BU10038 is a recently identified bifunctional MOP/NOP partial agonist.

Disease modifying actions of interleukin-6 blockade in a rat model of bone cancer pain.

Metastasis of cancer to the skeleton represents a debilitating turning point in the lives of patients. Skeletal metastasis leads to moderate to severe ongoing pain along with bone remodeling that can result in fracture, events that dramatically diminish quality of life. Interleukin-6 (IL-6) levels are elevated in patients with metastatic breast cancer and are associated with a lower survival rate.

Mediation of Movement-Induced Breakthrough Cancer Pain by IB4-Binding Nociceptors in Rats.

Cancer-induced bone pain is characterized by moderate to severe ongoing pain that commonly requires the use of opiates. Even when ongoing pain is well controlled, patients can suffer breakthrough pain (BTP), episodic severe pain that "breaks through" the medication. We developed a novel model of cancer-induced BTP using female rats with mammary adenocarcinoma cells sealed within the tibia.

A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates.

Despite the critical need, no previous research has substantiated safe opioid analgesics without abuse liability in primates. Recent advances in medicinal chemistry have led to the development of ligands with mixed mu opioid peptide (MOP)/nociceptin-orphanin FQ peptide (NOP) receptor agonist activity to achieve this objective. BU08028 is a novel orvinol analog that displays a similar binding profile to buprenorphine with improved affinity and efficacy at NOP receptors.

Spinal Functions of B-Type Natriuretic Peptide, Gastrin-Releasing Peptide, and Their Cognate Receptors for Regulating Itch in Mice.

B-type natriuretic peptide (BNP)-natriuretic peptide receptor A (NPRA) and gastrin-releasing peptide (GRP)-GRP receptor (GRPR) systems contribute to spinal processing of itch. However, pharmacological and anatomic evidence of these two spinal ligand-receptor systems are still not clear. The aim of this study was to determine the spinal functions of BNP-NPRA and GRP-GRPR systems for regulating scratching activities in mice by using pharmacological and immunohistochemical approaches.

Behavioral and neurochemical analysis of ongoing bone cancer pain in rats.

Cancer-induced bone pain is described as dull, aching ongoing pain. Ongoing bone cancer pain was characterized after intratibial injection of breast cancer cells in rats. Cancer produced time-dependent bone remodeling and tactile hypersensitivity but no spontaneous flinching.

Effects of the NOP agonist SCH221510 on producing and attenuating reinforcing effects as measured by drug self-administration in rats.

Nociceptin/orphanin FQ peptide (NOP) receptor agonists attenuate morphine-induced conditioned place preference in rodents. However, it is not known whether NOP agonists have reinforcing properties or can inhibit mu opioid receptor (MOP)-mediated reinforcement as measured by drug self-administration in rodents. Further understanding the behavioral effects of NOP agonists could suggest them as having potential in attenuating reinforcing effects of opioids.

Differential effects of opioid-related ligands and NSAIDs in nonhuman primate models of acute and inflammatory pain.

Rationale: Carrageenan-induced hyperalgesia is a widely used pain model in rodents. However, characteristics of carrageenan-induced hyperalgesia and effects of analgesic drugs under these conditions are unknown in nonhuman primates.

Objective: The aims of this study were to develop carrageenan-induced hyperalgesia in rhesus monkeys and determine the efficacy and potency of agonists selective for the four opioid receptor subtypes in this model versus acute pain, as compared to non-steroidal anti-inflammatory drugs (NSAIDs).

Physiological function of gastrin-releasing peptide and neuromedin B receptors in regulating itch scratching behavior in the spinal cord of mice.

Pruritus (itch) is a severe side effect associated with the use of drugs as well as hepatic and hematological disorders. Previous studies in rodents suggest that bombesin receptor subtypes i.e.

Effects of spinally administered bifunctional nociceptin/orphanin FQ peptide receptor/μ-opioid receptor ligands in mouse models of neuropathic and inflammatory pain.

Nociceptin/orphanin FQ peptide receptor (NOP) agonists produce antinociceptive effects in animal models after spinal administration and potentiate μ-opioid receptor (MOP)-mediated antinociception. This study determined the antinociceptive effects of spinally administered bifunctional NOP/MOP ligands and the antinociceptive functions of spinal NOP and MOP receptors in mice. Antinociceptive effects of bifunctional NOP/MOP ligands BU08028 [(2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol] and SR16435 [1-(1-(2,3,3α,4,5,6-hexahydro-1H-phenalen-1-yl)piperidin-4-yl)-indolin-2-one] were pharmacologically compared with the putative bifunctional ligand buprenorphine, selective NOP agonist SCH221510 [3-endo-8-[bis(2-methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.

Inhibition of p38-MAPK signaling pathway attenuates breast cancer induced bone pain and disease progression in a murine model of cancer-induced bone pain.

Background: Mechanisms driving cancer-induced bone pain are poorly understood. A central factor implicated to be a key player in the process of tumorigenesis, osteoclastogenesis and nociception is p38 MAPK. We determined the role of p38 MAPK in a mouse model of breast cancer induced bone pain in which mixed osteolytic and osteoblastic remodeling occurs.