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. Source
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. Source
Morales-Lazaro S.L.,National Autonomous University of Mexico |
Serrano-Flores B.,National Autonomous University of Mexico |
Llorente I.,National Autonomous University of Mexico |
Hernandez-Garcia E.,National Autonomous University of Mexico |
And 9 more authors.
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 Δ9, 10, or 11 and Δ9 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. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Source
Khan S.S.,Rxbio Inc |
Kazmi S.A.,University of Karachi |
Anwer H.,University of Karachi
Journal of the Chemical Society of Pakistan | Year: 2013
Cyclic voltammetric study was used to analyze three new saponins (isolated from the seeds of Cicer aritinum) along with a known saponin soyasaponin I and β sitosterol glycoside isolated saponins as well as glycyrrhizin. These studies were carried out in aqueous medium at Glassy carbon (GCE) electrode vs. Ag|AgCl reference electrode. Results revealed that the voltammograms of Fe(III) with isolated saponins are irreversible while that of Fe(III)-glycyrrhizin complex is reversible. Even though precise Eo values of their Fe(III) complex could not be determined,it is clearly indicated that Fe(III) forms complexes with these saponins. The ability to form strong complexes with Fe(III) therefore reduces the availability of Fe(III) by saponins. Source
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.