JOHNSON CITY, TN, United States
JOHNSON CITY, TN, United States

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Mani N.,University of California at Berkeley | Murray J.,U.S. Food and Drug Administration | Gulick R.M.,Cornell University | Josephson F.,Swedish Medical Products Agency | And 5 more authors.
AIDS | Year: 2012

The resounding success of combination antiretroviral efficacy for both treatment-naïve and treatment-experienced patients - with 70-90% viral suppression rates in recent studies - has made registration trials for new agents challenging. With the inevitable specter of drug resistance, new agents must have a pathway to approval. The Forum for Collaborative HIV Research obtained input from concerned stakeholders including industry, clinical sciences, community advocacy, and regulatory sciences (Food and Drug Administration and European Medicines Agency) to discuss how safety and efficacy of new agents could be demonstrated. Recognizing the shortfalls of superiority or noninferiority trials in this environment, a new trial design for treatment-experienced patients, minimizing the risk for drug resistance but allowing full assessment of safety, was proposed. The antiviral efficacy of an active investigational drug would be assessed by comparison to placebo as an add-on to a failing regimen in a short, 10-14-day study followed by institution of an optimized background regimen (OBR) in both arms with investigational drug given to all patients. The follow-on stage would assess dose response, safety, durability of initial response, and development of resistance. Additionally, a second safety trial could be conducted comparing patients randomized to the investigational agent with a new OBR to those on a new OBR and placebo. Finally, approval decisions could consider other long-term safety endpoints. Exposing treatment-naïve patients to investigational agents remains a controversial issue; stakeholders have different interpretations of risk-benefit for trials in this population that necessitate careful consideration before initiating trials in them. © 2012 Wolters Kluwer Health | Lippincott Williams and Wilkins.

Foundation University and Rxbio Inc | Date: 2014-07-23

Here provided are new immunosuppressive compounds and novel therapeutics for improving tissue transplantation.

Patil R.,University of Tennessee Health Science Center | Fells J.I.,University of Tennessee Health Science Center | Szabo E.,University of Tennessee Health Science Center | Lim K.G.,University of Tennessee Health Science Center | And 6 more authors.
Journal of Medicinal Chemistry | Year: 2014

Lysophosphatidic acid (LPA) is a growth factor-like mediator and a ligand for multiple GPCR. The LPA2 GPCR mediates antiapoptotic and mucosal barrier-protective effects in the gut. We synthesized sulfamoyl benzoic acid (SBA) analogues that are the first specific agonists of LPA2, some with subnanomolar activity. We developed an experimental SAR that is supported and rationalized by computational docking analysis of the SBA compounds into the LPA2 ligand-binding pocket. © 2014 American Chemical Society.

PubMed | Rxbio Inc, National Autonomous University of Mexico, Hospital General Dr Manuel Gea Gonzalez and University of Tennessee Health Science Center
Type: Journal Article | Journal: The Journal of biological chemistry | Year: 2014

The transient receptor potential vanilloid 1 (TRPV1) ion channel is a polymodal protein that responds to various stimuli, including capsaicin (the pungent compound found in chili peppers), extracellular acid, and basic intracellular pH, temperatures close to 42 C, and several lipids. Lysophosphatidic acid (LPA), an endogenous lipid widely associated with neuropathic pain, is an agonist of the TRPV1 channel found in primary afferent nociceptors and is activated by other noxious stimuli. Agonists or antagonists of lipid and other chemical natures are known to possess specific structural requirements for producing functional effects on their targets. To better understand how LPA and other lipid analogs might interact and affect the function of TRPV1, we set out to determine the structural features of these lipids that result in the activation of TRPV1. By changing the acyl chain length, saturation, and headgroup of these LPA analogs, we established strict requirements for activation of TRPV1. Among the natural LPA analogs, we found that only LPA 18:1, alkylglycerophosphate 18:1, and cyclic phosphatidic acid 18:1, all with a monounsaturated C18 hydrocarbon chain activate TRPV1, whereas polyunsaturated and saturated analogs do not. Thus, TRPV1 shows a more restricted ligand specificity compared with LPA G-protein-coupled receptors. We synthesized fatty alcohol phosphates and thiophosphates and found that many of them with a single double bond in position 9, 10, or 11 and 9 cyclopropyl group can activate TRPV1 with efficacy similar to capsaicin. Finally, we developed a pharmacophore and proposed a mechanistic model for how these lipids could induce a conformational change that activates TRPV1.

Rxbio Inc | Date: 2014-08-20

Disclosed are compounds according to formula (I) as well as pharmaceutical compositions which include those compounds. Also disclosed are methods of using such compounds, which have activity as agonists or as antagonists of LPA receptors; such methods including treating cancer, producing radioprotection and/or radiomitigation, enhancing cell proliferation, treating a wound, treating apoptosis or preserving or restoring function in a cell, tissue, or organ, culturing cells, preserving organ or tissue function, and treating a dermatological condition.

Here provided are a salt of Z)O-octadec-9-en-1-yl O,O-dihydrogen phosphorothioate with an L-lysine addition in crystalline form and methods of making and using the same.

We have previously demonstrated that the small molecule octadecenyl thiophosphate (OTP), a synthetic mimic of the growth factor-like mediator lysophosphatidic acid (LPA), showed radioprotective activity in a mouse model of total-body irradiation (TBI) when given orally or intraperitoneally 30 min before exposure to 9 Gy radiation. In the current study, we evaluated the effects of OTP, delivered subcutaneously, for radioprotection or radiomitigation from -24 h before to up to +72 h postirradiation using a mouse TBI model with therapeutic doses at around 1 mg/kg. OTP was injected at 10 mg/kg without observable toxic side effects in mice, providing a comfortable safety margin. Treatment of C57BL/6 mice with a single dose of OTP over the time period from -12 h before to +26 h after a lethal dose of TBI reduced mortality by 50%. When administered at +48 h to +72 h postirradiation (LD50/30 to LD100/30), OTP reduced mortality by 34%. OTP administered at +24 h postirradiation significantly elevated peripheral white blood cell and platelet counts, increased crypt survival in the jejunum, enhanced intestinal glucose absorption and reduced endotoxin seepage into the blood. In the 6.4-8.6 Gy TBI range using LD50/10 as the end point, OTP yielded a dose modification factor of 1.2. The current data indicate that OTP is a potent radioprotector and radiomitigator ameliorating the mortality and tissue injury of acute hematopoietic as well as acute gastrointestinal radiation syndrome.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 194.80K | Year: 2011

No satisfactory medical interventions for radiation enteritis are available yet. We have demonstrated that polyamine inhibition by a-difluoromethylornithine orDFMO, a selective and irreversible inhibitor of ornithine decarboxylase (ODC, the primary rate-limiting enzyme in the production of polyamines) significantly protects the gastrointestinal (GI) tract from whole-body radiation exposure. Here we propose to further develop it into a highly efficient radioprotector/radiomitigator for indications (1) radiotherapy associated enteritis and (2) GI injury due to nuclear accidents or incidents. Aim #1. Evaluate the radioprotecting/mitigating effect of DFMO on GI injury Aim #2. Evaluate the effect of DFMO on cancer radiosensitivity Methods: (1) For efficacy studies under Aim #1, we will use a mouse model of abdomen-pelvis irradiation. Morphological evaluations include crypt survival and crypt-villus recovery. Intestinal barrier integrity will be evaluated by measuring plasma citrulline and serum endotxoin levels. (2) Under Aim #2, we will first evaluate the effect of DFMO on cancer growth and radiosensitivity in HCT116 and HT29 cell lines, and then move to mouse models of colon cancer and simulate abdomen-pelvis radiotherapy. Methods involved are cell culture, invitro clonogenic assay of tumor cell growth, Xenograft implantation of HCT116 cells and HT29 cells and measuring tumor volume Relevance to public health: The concept proposed in this project, if proved, will lead to a full-scale development program to advance DFMO into a highly efficient drug for managing radiation enteritis in cancer patients as well as GI injury due to unintended radiation exposure.

Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 297.09K | Year: 2015

DESCRIPTION provided by applicant The looming threat of nuclear attacks and recent non terrorist related accidents Fukushima nuclear disaster has increased national and global attention to the need for medical countermeasures RxBio has identified a first in class proprietary small molecule Rx which significantly protects the gut and the hematopoietic system from exposure to lethal doses of ionizing radiation We have demonstrated the radiomitigant efficacy of Rx in murine and non human primate NHP models for GI ARS Gastrointestinal Acute Radiation Syndrome RxBio has completed a spectrum of drug development activities in consultation with FDA The overall goal of this proposal is to complete manufacturing chemistry studies to support regulatory activities in advancing Rx lysine for eventual FDA licensure The Phase I program specific aims are to evaluate the raw material standards for acceptance to manufacture highly pure Rx lysine by examining the stability of oleyl alcohol and investigating potential degraded or source impurities of oleyl alcohol via identification and structural characterization and to investigate process improvement studies and stressing of current chemistry process in each manufacturing step and demonstrate the robustness of modified process via lab scale synthesis of highly pure API Proposed studies will be completed in months with two major deliverables a Establishing the acceptance criteria for oleyl alcohol for GMP scale up effort th month b Improved manufacturing process to generate highly pure Rx lysine and batch record for lab scale synthesis effort th month PUBLIC HEALTH RELEVANCE Inevitably nuclear accidents occur and nuclear attacks and radiation terrorism have become a real threat to our nation since September Currently there are no FDA approved medical countermeasures available today for treating radiation injury We are proposing to develop a novel class of radiation medical countermeasures to protect the American people and mankind from radiation injury

Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 222.83K | Year: 2015

DESCRIPTION provided by applicant Secretory diarrhea is a leading cause of death worldwide among children under the age of five Its pathology involves cystic fibrosis transmembrane conductance regulator CFTR which provides a primary pathway for Cl secretion Targeting CFTR to prevent reduce losses of electrolytes and water is a therapeutic strategy Lysophosphatidic acid LPA a naturally occurring phospholipid mediator acts through G protein coupled receptors GPCRs Our research group has demonstrated that the LPA GPCR inhibits CFTR dependent Cl transport in intestinal epithelial cells We have synthesized Rx a potent and metabolically stabilized agonist for the LPA GPCR We have demonstrated that Rx significantly inhibited cholera toxin CTX induced CFTR mediated secretory diarrhea in mice We propose to develop Rx into a highly effective anti diarrheal agent Aim Optimize the efficacy of Rx in inhibiting CTX induced diarrhea Determine the oral bioavailability of Rx in mice Determine and optimize the anti diarrheal effect of Rx by oral delivery Determine and optimize the anti diarrheal effect of Rx by parenteral delivery Aim Confirm the efficacy of Rx in inhibiting CTX induced diarrhea Aim Evaluate the anti diarrheal effect of Rx in inhibiting Escherichia coli toxin and Citrobacter rodentium infection induced diarrhea in mice Methods Oral Rx bioavailability under will be determined using tandem mass spectrometry detection LC MS MS For Rx andapos s efficacy studies under andamp we will use an open loop mouse model of CTX induced diarrhea We will confirm Rx andapos s efficacy under aim using a closed loop mouse model of CTX induced diarrhea We will also test Rx andapos s efficacy in a closed loop model of Escherichia coli heat stable toxin induced intestinal fluid secretion under aim We will also test Rx andapos s efficacy using a mouse model of C rodentium infection under aim Relevance to Public Health Rx can be developed into a highly effective anti diarrheal drug for the benefit of human beings PUBLIC HEALTH RELEVANCE Secretory diarrhea is a leading cause of death worldwide among children under the age of five No truly satisfactory therapeutic agents are available yet and oral rehydration remains the primary approach in managing secretory diarrhea We propose to develop Rx into a highly effective anti diarrheal agent

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